SNPMiner Trials by Shray Alag

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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation I148M

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 7 clinical trials

Clinical Trials


1 Body Composition and Metabolic Manifestations of Insulin Resistance in Adolescents With Polycystic Ovary Syndrome: Ectopic Fat Deposition and Metabolic Markers: Intervention and Follow-up Portion

This project, "A double-blind placebo-controlled randomized clinical trial assessing the efficacy of metformin for hepatic fat in adolescents and young adults with polycystic ovary syndrome", proposes exploring the use of novel and noninvasive methodologies in an at-risk adolescent and young adult population with polycystic ovary syndrome (PCOS) who may gain long-term health benefits from early detection and treatment of non-alcoholic fatty liver disease (NAFLD). PCOS is a common condition that frequently presents in adolescence and young adulthood and is defined by elevated androgens (male hormones) in the blood leading to 1. hirsutism and acne and 2. menstrual abnormalities or amenorrhea. Affected individuals are at increased risk of developing insulin resistance (a precursor of diabetes), NAFLD and lipid (cholesterol) abnormalities.These features are all associated with the metabolic syndrome, a rising major public health concern. Recently, an association between PCOS and NAFLD has been noted but has only been superficially studied in the adolescent and young adult population. The susceptibility of certain PCOS patients to developing NAFLD is theorized to be due to having underlying insulin resistance, elevated androgen levels, and a genetic predisposition. Metformin is an insulin sensitizing medication widely used to treat type 2 diabetes mellitus that may have beneficial effects on insulin resistance-related conditions including PCOS and NAFLD. Although widely used in PCOS, its effect on NAFLD in this group has not been previously studied. The primary aims of this proposal are: 1) To determine whether PCOS with liver fat >/=4.8% treated with metformin for six months will have a decline in percentage liver fat compared to a placebo group. 2) To measure the association of the PNPLA3 I148M allele with NAFLD in PCOS at baseline (n=40). 2b) To measure the association of percentage liver fat with biomarkers of NAFLD, dyslipidemia, insulin resistance and body composition at baseline (n=40) and after a placebo-controlled intervention with metformin in PCOS with liver fat >4.8% (n=20). The goal of this research proposal is to explore the use of novel and noninvasive technologies in a young and at risk population. Dr. Sopher hopes to use the results of this research to lay the groundwork for the prevention and treatment of NAFLD and other metabolic disorders in adolescents and young adults with PCOS and to prevent lifelong morbidity associated with PCOS.

NCT02500147
Conditions
  1. Polycystic Ovary Syndrome
  2. Non-Alcoholic Fatty Liver Disease
  3. Metabolic Syndrome
Interventions
  1. Drug: Metformin
  2. Drug: Placebo
MeSH:Polycystic Ovary Syndrome Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Metab Metabolic Syndrome Syndrome
HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis Polycystic ovaries

2) To measure the association of the PNPLA3 I148M allele with NAFLD in PCOS at baseline (n=40). --- I148M ---

The proportion of PCOS subjects with the high risk I148M PNPLA3 allele in the PCOS groups with elevated and normal liver fat will be compared using a chi-squared or Fisher's Exact test.. --- I148M ---

Other IR indices that will be evaluated are whole body insulin sensitivity (WBIS) and insulin area under the curve; 6) Genetic evaluation: A blood sample for the PNPLA3 I148M allele (baseline only). --- I148M ---

Primary Outcomes

Description: To compare percentage liver fat by magnetic resonance spectroscopy in the metformin group and placebo group to baseline and between the groups in order to determine if metformin is efficacious for reducing liver fat compared to placebo in adolescents and young women with Polycystic Ovary Syndrome (PCOS)

Measure: Difference in percentage liver fat between Metformin arm and Placebo arm in adolescents and young adults with PCOS and with elevated percentage liver fat (>/=4.8%)

Time: 6 months

Secondary Outcomes

Description: The proportion of PCOS subjects with the high risk I148M PNPLA3 allele in the PCOS groups with elevated and normal liver fat will be compared using a chi-squared or Fisher's Exact test.

Measure: Proportion of PCOS subjects with the PNPLA3 allele comparing those with elevated percentage liver fat (>/=4.8%) and those with normal percentage liver fat (<4.8%) by magnetic resonance spectroscopy

Time: 6 months

Description: The association of percent liver fat with insulin resistance as measured by HOMA-IR will be measured by correlation/regression. Change in HOMA-IR with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat by magnetic resonance spectroscopy with insulin resistance as measured by HOMA-IR in adolescents with PCOS

Time: 6 months

Description: The association of percent liver fat with triglycerides will be measured by correlation/regression. Change in triglycerides with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with triglycerides

Time: 6 months

Description: The association of percent liver fat with visceral adipose tissue will be measured by correlation/regression. Change in visceral adipose tissue with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with visceral adipose tissue

Time: 6 months

Description: The association of percent liver fat with total body adipose tissue will be measured by correlation/regression. Change in total body adipose tissue with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with total body adipose tissue

Time: 6 months

Description: The association of percent liver fat with pancreatic polypeptide will be measured by correlation/regression. Change in pancreatic polypeptide with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with pancreatic polypeptide

Time: 6 months

Description: The association of percent liver fat with M30 will be measured by correlation/regression. Change in M30 with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with M30, a hepatic apoptosis marker

Time: 6 months

2 Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia

The aims of the study are: 1. To investigate if carriers of apolipoprotein (apo) CIII loss-of-function (LOF) mutations produce less apo-CIII that results in reduction of large very low-density lipoprotein (VLDL) particle secretion as compared to non-carriers of these variants and compare the results with carriers of apo-CIII gain-of-function (GOF) to elucidate the role of apo-CIII in hepatic lipid metabolism. 2. To study if carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations produce less large VLDL particles to transport fat out of the liver as compared to non-carriers. 3. To test whether the specific mutations in the apo-CIII, TM6SF2 and PNLPLA3 genes are reflected in changes of liver de novo lipogenesis (DNL), liver fat, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), plasma lipid and apolipoprotein kinetics and fasting concentrations in carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations as compared to non-carriers. 4. To study the effects of APOE, angiopoietin (ANGPTL3 and ANGPTL8) or endothelial lipase (LIPG) genotypes on liver fat metabolism, lipid and apolipoprotein metabolism and lipid phenotypes.

NCT04209816
Conditions
  1. Non-alcoholic Fatty Liver
  2. Atherogenic Dyslipidemia
  3. Insulin Resistance
Interventions
  1. Diagnostic Test: Lipoprotein kinetics
MeSH:Fatty Liver Non-alcoholic Fatty Liver Disease Insulin Resistance Dyslipidemias
HPO:Abnormal circulating lipid concentration Hepatic steatosis Insulin resistance

2. To study if carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations produce less large VLDL particles to transport fat out of the liver as compared to non-carriers. --- E167K --- --- I148M ---

3. To test whether the specific mutations in the apo-CIII, TM6SF2 and PNLPLA3 genes are reflected in changes of liver de novo lipogenesis (DNL), liver fat, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), plasma lipid and apolipoprotein kinetics and fasting concentrations in carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations as compared to non-carriers. --- E167K --- --- I148M ---

Inclusion Criteria: - persons who have provided written consent - apo-CIII loss-of-function mutation (heterozygous) or apo-CIII gain-of-function mutations (heterozygous) or TM6SF2 E167K mutation (homozygous) or PNLPLA3 I148M or apoE or LIPG or ANGPTL3 or ANGPTL8 LOF and GOF variants. --- E167K --- --- I148M ---

m² at inclusion Exclusion Criteria: - Patients with Type 1 and 2 diabetes, BMI > 40 kg/m2, - ApoE2/2 phenotype, thyrotropin concentration outside normal range, - Lipid-lowering drugs - Blood pressure >160 mmHg systolic and/or > 105 diastolic mmHg - Liver failure or abnormal liver function tests >3 x upper limit of normal - Intestinal disease - Pregnancy, breastfeeding - Patients with volume depletion Inclusion Criteria: - persons who have provided written consent - apo-CIII loss-of-function mutation (heterozygous) or apo-CIII gain-of-function mutations (heterozygous) or TM6SF2 E167K mutation (homozygous) or PNLPLA3 I148M or apoE or LIPG or ANGPTL3 or ANGPTL8 LOF and GOF variants. --- E167K --- --- I148M ---

Primary Outcomes

Description: Production rate, mg/day

Measure: Difference in the rate of production of VLDL Apo B

Time: Baseline

Description: Production rate, mg/kg/day

Measure: Difference in the rate of production of VLDL Triglycerides

Time: Baseline

Description: Production rate, mg/kg/day

Measure: Difference in the rate of production of VLDL ApoC-III and apoE

Time: Baseline

Description: Rate of disappearance, pools/day

Measure: Difference in the Fractional Catabolic Rate of VLDL Apo B

Time: Baseline

Description: Rate of disappearance, pools/day

Measure: Difference in the Fractional Catabolic Rate of VLDL Triglycerides

Time: Baseline

Description: Rate of disappearance, pools/day

Measure: Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE

Time: Baseline

Description: Measure of newly synthesized triglycerides in VLDL, μmol/l

Measure: Difference in de novo lipogenesis

Time: Baseline

Description: Percentage of liver fat measured with magnetic resonance spectroscopy

Measure: Difference in liver fat

Time: Baseline

Description: Remnant lipoproteins and lipoprotein fraction composition, mg/L

Measure: Difference in atherogenic dyslipidemia

Time: Baseline

Description: Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

Measure: Difference in insulin resistance

Time: Baseline

Description: ApoA, mg/dl

Measure: Difference in apoprotein A concentration

Time: Baseline

Description: ApoB, mg/dl

Measure: Difference in apoprotein B concentration

Time: Baseline

Description: ApoC, mg/dl

Measure: Difference in apoprotein C concentration

Time: Baseline

Description: ApoE, mg/dl

Measure: Difference in apoprotein E concentration

Time: Baseline

Description: Rate of turnover, pools/day

Measure: Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B

Time: Baseline

Description: Rate of turnover, pools/day

Measure: Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B

Time: Baseline

Description: Measured lipoprotein lipase activity, mU/ml

Measure: Lipolytic activity

Time: Baseline

Description: Measured hepatic lipase activity, mU/ml

Measure: Hepatic lipase activity

Time: Baseline

3 A Phase 2, Randomised, Placebo Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Metabolic Cofactor Supplementation in Obese Subjects With Non-Alcoholic Fatty Liver Disease (NAFLD)

This short-term, randomized, placebo-controlled, investigator-initiated trial aims to establish metabolic improvements in NAFLD subjects by dietary supplementation with cofactors N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside and serine. Concomitant use of pivotal metabolic cofactors via simultaneous dietary supplementation will stimulate three different pathways to enhance hepatic β-oxidation and this study's hypothesis is that this will result in decreased amount of fat in the liver.

NCT04330326
Conditions
  1. Non-alcoholic Fatty Liver Disease (NAFLD)
Interventions
  1. Drug: Metabolic Cofactor Supplementation
  2. Drug: Sorbitol
MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease
HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Inclusion Criteria: - Men and women (18-70 years old) - Body mass index >27kg/m2 - Triglyceride levels ≤354 mg/dl and LDL chol ≤175 mg/dl - No history of medication use for hepatic steatosis - Increased liver fat (>5.5%) --- I148M ---

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Inclusion Criteria: - Men and women (18-70 years old) - Body mass index >27kg/m2 - Triglyceride levels ≤354 mg/dl and LDL chol ≤175 mg/dl - No history of medication use for hepatic steatosis - Increased liver fat (>5.5%) --- I148M --- --- I148M ---

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Non-alcoholic Fatty Liver Disease (NAFLD) Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease In this study, investigators aim to lower liver fat content in obese patients with NAFLD by increasing the hepatic levels of pivotal metabolic cofactors via simultaneous dietary supplementation of serine, L-carnitine, N-acetylcysteine (NAC) and nicotinamide riboside (NR). --- I148M ---

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Non-alcoholic Fatty Liver Disease (NAFLD) Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease In this study, investigators aim to lower liver fat content in obese patients with NAFLD by increasing the hepatic levels of pivotal metabolic cofactors via simultaneous dietary supplementation of serine, L-carnitine, N-acetylcysteine (NAC) and nicotinamide riboside (NR). --- I148M --- --- I148M ---

Primary Outcomes

Description: The change in liver fat content as well as subcutaneous abdominal and intra-abdominal fat content between the placebo and cofactor treatment arms in NAFLD patients from baseline to 2 weeks, 6 weeks and 10 weeks.

Measure: Magnetic Resonance Spectroscopy (MRS) Measurement

Time: 2 weeks, 6 weeks and 10 weeks

Secondary Outcomes

Description: Body weight will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: Change in body weight from baseline

Time: 10 weeks

Description: Change in heart rate will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: ECG Measurement

Time: 10 weeks

Description: Systolic and Diastolic Blood Pressure will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: Change in Blood Pressure from baseline

Time: 10 weeks

Description: Waist and hip circumference will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: Change in waist and hip circumference from baseline

Time: 10 weeks

Description: Complete blood count includes number of blood cells. Complete blood count test will be performed to measure possible toxic effects of the metabolic cofactor supplementation on hematological system.

Measure: Change of complete blood count (number of blood cells) from baseline

Time: 10 weeks

Description: Complete blood count includes concentration of hemoglobin. Complete blood count test will be performed to measure possible toxic effects of the metabolic cofactor supplementation on hematological system.

Measure: Change of complete blood count (hemoglobin) from baseline

Time: 10 weeks

Description: Kidney function tests (creatinine, urea, uric acid) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on kidney function.

Measure: Changes in kidney function tests (creatinine, urea, uric acid) from baseline

Time: 10 weeks

Description: Kidney function tests (sodium, potassium) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on kidney function.

Measure: Changes in kidney function tests (sodium, potassium) from baseline

Time: 10 weeks

Description: Liver function tests (ALT, AST, GGT, ALP) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on liver function.

Measure: Changes in liver function tests [Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transferase (GGT), Alkaline phosphatase (ALP)] from baseline

Time: 10 weeks

Description: Liver function tests (Total Bilirubin, Albumin) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on liver function.

Measure: Changes in liver function tests (Total Bilirubin, and Albumin) from baseline

Time: 10 weeks

Description: Creatinine kinase (CK) level will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Changes in creatinine kinase (CK) level from baseline

Time: 10 weeks

Description: Blood lipid levels (total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C)) will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Changes in blood lipid levels (total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C)) from baseline

Time: 2 weeks, 6 weeks and 10 weeks

Description: Blood glucose levels will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Changes in blood glucose levels from baseline

Time: 10 weeks

Description: Blood insulin level will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Change in blood insulin level from baseline

Time: 10 weeks

Description: Thyroid-stimulating hormone (TSH) level will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Change in thyroid-stimulating hormone (TSH) level from baseline

Time: 10 weeks

Description: The change in gut microbiota between the placebo and the treatment arms in NAFLD patients. Feces and saliva samples will be collected to assess changes in gut microbiota. Instructions on specimen collection will be given during the first visit. Microbiota will be assessed using shot-gun metagenomic techniques.

Measure: Microbiota analysis

Time: 2 weeks, 6 weeks and 10 weeks

Description: This process aiming to monitoring of adverse events of metabolic cofactor supplementation. Adverse events and serious adverse events will be monitored continuously and all adverse events that occur at any time during the study will be reported in Case Report Forms. Any symptoms of intestinal discomfort or other side effects will be carefully recorded and all study subjects will be informed to contact (by phone or text message) the investigators immediately if they experience any symptoms of discomfort or any side effects during the intervention period.

Measure: Monitoring of adverse events

Time: 10 weeks

4 Effects of Overfeeding Followed by Weight Loss on Liver Fat Content and Adipose Tissue Inflammation

A. BACKGROUND Accumulation of fat in the liver due to non-alcoholic causes (NAFLD) is associated with hepatic insulin resistance, which impairs the ability of insulin to inhibit the production of glucose and VLDL . This leads to increases in serum glucose, insulin and triglyceride concentrations as well as hyperinsulinemia. Recent epidemiologic studies have shown that a major reason for the metabolic syndrome as well as the accompanying increased risk of cardiovascular disease and type 2 diabetes is overconsumption of simple sugars. The investigators have recently shown that overeating simple sugars (1000 extra calories/day, "CANDY" diet) increases liver fat content by 30% within 3 weeks (4), and recapitulates features of the metabolic syndrome such as hypertriglyceridemia and a low HDL cholesterol concentration. The fatty acids in intrahepatocellular triglycerides may originate from peripheral lipolysis, de novo lipogenesis, uptake of chylomicron remnants by the liver and from hepatic uptake of fatty acids released during intravascular hydrolysis of triglyceride-rich lipoproteins (the spillover pathway). A classic study using stable isotope methodology by the group of Elisabeth Parks showed that in subjects with NAFLD, the excess intrahepatocellular triglycerides originate from peripheral lipolysis and de novo lipogenesis. It is well-established that ingestion of a high carbohydrate as compared to high fat diet stimulates de novo lipogenesis in humans. Meta-analyses comparing isocaloric high fat and high carbohydrate diets have shown that high carbohydrate but not high fat diets increase increase serum triglycerides and lower HDL cholesterol. Since hypertriglyceridemia results from overproduction of VLDL from the liver, these data suggest the composition of the diet influences hepatic lipid metabolism. Whether this is because overfeeding fat leads to preferential deposition of fat in adipose tissue while high carbohydrate diets induce a relative greater increase in liver fat is unknown. There are no previous studies comparing effects of chronic overfeeding of fat as compared to carbohydrate on liver fat or and the sources of intrahepatic fatty acids. A common polymorphism in PNPLA3 at rs738409 (adiponutrin) gene is associated with a markedly increase liver fat content. This finding has been replicated in at least 20 studies across the world. The investigators have shown that PNPLA3 is regulated by the carbohydrate response element binding protein 1. Mice overexpressing the human I148M PNPLA3 variant in the liver exhibit an increase in liver triglycerides and cholesteryl esters on a high sucrose but not high fat diet. These data suggest that overfeeding a high carbohydrate as compared to a high fat diet may increase liver fat more in subjects carrying the I148M allele than in non-carriers. B. HYPOTHESIS The investigators hypothesize that overfeeding a high fat as compared to an isocaloric high carbohydrate diet influences the source of intrahepatocellular triglycerides. During a high fat diet, relatively more of intrahepatocellular triglycerides originate from peripheral lipolysis and less from DNL than during a high carbohydrate diet in the face of a similar increase in liver fat. It is also possible given the lack of previous overfeeding data comparing 2 different overfeeding diets that the high fat diet induces a smaller increase in liver fat than a high carbohydrate diet even in the face of an identical increase in caloric intake because a greater fraction of ingested fat is channeled to adipose tissue than the liver. The investigators also hypothesize that liver fat may increase more in carriers than non-carriers of the I148M variant in PNPLA3 during a high carbohydrate than a high fat diet. C. SPECIFIC AIMS The investigators wish to randomize, using the method of minimization (considers baseline age, BMI, gender, liver fat, PNPLA3 genotype) 40 non-diabetic subjects with NAFLD as determined by the non-invasive score developed in our laboratory or previous knowledge of liver fat content based on MRS to overeat either a high carbohydrate or high fat diet (1000 extra calories per day) for 3 weeks. Before and after the overfeeding diets, will measure liver fat content by 1H-MRS and the rate of adipose tissue lipolysis using doubly labeled water (DDW) and [1,1,2,3,3-2H5] glycerol as described in detail below. The investigators also wish to characterize glucose, insulin, fatty acid and triacylglyceride profiles before and while on the experimental diet. An adipose tissue biopsy is taken to determine whether expression of genes involved in lipogenesis or lipolysis, or those involved in adipose tissue inflammation change in response to overfeeding, and for measurement of LPL activity. After overfeeding, both groups will undergo weight loss to restore normal weight as described in our recent study. The metabolic study is repeated after weight loss.

NCT02133144
Conditions
  1. NAFLD
Interventions
  1. Behavioral: overeating fat
  2. Behavioral: overeating carbohydrate
MeSH:Inflammation Weight Loss
HPO:Decreased body weight Weight loss

The investigators have shown that PNPLA3 is regulated by the carbohydrate response element binding protein 1. Mice overexpressing the human I148M PNPLA3 variant in the liver exhibit an increase in liver triglycerides and cholesteryl esters on a high sucrose but not high fat diet. --- I148M ---

These data suggest that overfeeding a high carbohydrate as compared to a high fat diet may increase liver fat more in subjects carrying the I148M allele than in non-carriers. --- I148M ---

The investigators also hypothesize that liver fat may increase more in carriers than non-carriers of the I148M variant in PNPLA3 during a high carbohydrate than a high fat diet. --- I148M ---

Primary Outcomes

Measure: Liver fat content (1H-MRS) and intra-abdominal and subcutaneous fat (MRI)

Time: 3 weeks

Description: the rate of DNL and adipose tissue lipolysis is measured using doubly labeled water (DDW) and [1,1,2,3,3-2H5] glycerol

Measure: De novo lipogenesis (DNL) and measurement of lipolysis

Time: 3 weeks

Secondary Outcomes

Description: Laboratory tests including fasting glucose, insulin, C-peptide, liver enzymes, total, LDL and HDL cholesterol and TG concentrations PNPLA3 genotyping is performed also

Measure: Analytical procedures

Time: 3 weeks

Other Outcomes

Description: Needle biopsies of abdominal subcutaneus tissue will be taken for subsequent isolation of RNA for measurements of gene expression (by quantitative PCR). Fat cell size is also measured.

Measure: Biopsies and analysis of subcutaneus adipose tissue

Time: 3 weeks

Description: Indirect calorimetry is the method by which metabolic rate is estimated from measurements of oxygen (O2) consumption and carbon dioxide (CO2) production.

Measure: Indirect calorimetry

Time: 3 week

5 A Phase 1, Double Blind, Randomised, Placebo-Controlled, Multi-centre, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD2693 in Patients With Non-alcoholic Steatohepatitis (NASH) With Fibrosis Stage 0-3 and Homozygous for the PNPLA3 148M Risk Allele

This study is intended to investigate the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD2693, following subcutaneous (SC) administration of multiple ascending doses in patients with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage 0 to 3 and homozygous for the patatin-like phospholipase domain-containing 3 (PNPLA3) 148M risk allele.

NCT04483947
Conditions
  1. Non-alcoholic Steatohepatitis (NASH)
Interventions
  1. Drug: AZD2693
  2. Other: Placebo
MeSH:Fatty Liver Non-alcoholic Fatty Liver Disease
HPO:Hepatic steatosis

- Provision of signed, written, and dated informed consent for mandatory Genetic PNPLA3 I148M determination genetic/biomarker, for inclusion or exclusion in the clinical study. --- I148M ---

- Mandatory PNPLA3 Genetic Biomarker and Companion Diagnostic Development Sample: - The participant will be excluded from the study if consent for the PNPLA I148M Genetic Biomarker Sample is not given. --- I148M ---

- The mandatory consent will include assessment of PNPLA3 I148M status as well as additional genotyping of gene variants associated with PNPLA3 expression. --- I148M ---

Primary Outcomes

Description: Safety and tolerability will be evaluated in terms of number of participants with adverse events and/or abnormal values of vital signs and/or clinical laboratory and/or electrocardiogram and/or renal assessments and/or blood assessments.

Measure: Number of participants with adverse events

Time: Up to 36 weeks (From Screening to Final Visit)

Secondary Outcomes

Description: The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed.

Measure: Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Time: Baseline (Day 1), Week 8, Week 12

Description: The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed.

Measure: Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Time: Baseline (Day 1), Week 8, Week 12

Description: The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.

Measure: Absolute change from baseline in Alanine Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.

Measure: Percent change from baseline in Alanine Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.

Measure: Absolute change from baseline in Aspartate Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.

Measure: Percent change from baseline in Aspartate Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.

Measure: Absolute change from baseline in Gamma Glutamyl Transferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic health compared to placebo will be assessed.

Measure: Percent change from baseline in Gamma Glutamyl Transferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on ELF score will be assessed.

Measure: Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on ELF score will be assessed.

Measure: Percent change from baseline in ELF score

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.

Measure: Absolute change from baseline in plasma cholesteryl ester 16:1/16:0 ratio.

Time: Days 1, 8, 29, 36, 50, 64, and 78

Description: The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.

Measure: Percent change from baseline in plasma cholesteryl ester 16:1/16:0 ratio.

Time: Days 1, 8, 29, 36, 50, 64, and 78

Description: The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.

Measure: Absolute change from baseline in disease-specific biomarkers

Time: Days 1, 8, 29, 36, 50, 64, and 78

Description: The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.

Measure: Percentage change from baseline in disease-specific biomarkers

Time: Days 1, 8, 29, 36, 50, 64, and 78

Description: To characterise effects of AZD2693 on lipid handling compared to placebo.

Measure: Absolute change from baseline β-Hydroxybutyrate and lipid profile

Time: Days 1, 8, 29, 36, 50, 64, and 78

Description: To characterise effects of AZD2693 on lipid handling compared to placebo

Measure: Percent change from baseline β-Hydroxybutyrate and lipid profile

Time: Days 1, 8, 29, 36, 50, 64, and 78

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations

Measure: Maximum observed plasma drug concentration (Cmax)

Time: Day 1 to Day 162

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time to reach maximum observed plasma concentration (tmax)

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz)

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h))

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations

Measure: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)

Time: Day 1 to Day 162

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC)

Time: Day 1 to Day 162

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations

Measure: Mean residence time (MRT)

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time delay between drug administration and the first observed concentration in plasma (tlag)

Time: Day 1 to Day 162

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz (Vz/F)

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)

Time: Day 1 to Day 162

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)

Time: Day 1 to Day 162

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Observed maximum plasma concentration divided by the dose administered (Cmax/D)

Time: Day 1 to Day 162

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time of the last quantifiable concentration (tlast)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Maximum observed plasma drug concentration at steady state (Cssmax)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Minimum observed drug concentration at steady state (Cssmin)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time to reach maximum observed plasma concentration at steady state (tssmax)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the concentration-time curve in the dose interval (AUCss)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Observed maximum plasma concentration divided by the dose administered (Cssmax/D)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Accumulation ratio based on Cmax (RacCmax)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Accumulation ratio based on AUC (RacAUC)

Time: Day 1 to Day 162

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Temporal change parameter in systemic exposure (TCP)

Time: Day 1 to Day 162

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2))

Time: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last))

Time: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2))

Time: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last))

Time: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR)

Time: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose

6 The Role of the PNPLA3, TM6SF2 and MBOAT7 Genetic Variants in the Response to Silybin-phospholipid Complex, Vitamin D and Vitamin E Based Therapy for Non-alcoholic Fatty Liver Disease Patients

Patatin-like phospholipase domain-containing protein-3 (PNPLA3), the transmembrane 6 superfamily member 2 protein (TM6SF2) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are involved in non-alcoholic fatty liver disease (NAFLD) development and worsening. Following the actual scientific knowledge, some studies have identified the genetic background surrounding NAFLD, counting up to forty different genetic variants that seem to exert also a crucial role in the disease evolution, according to the natural history, until hepatocellular carcinoma onset. However, few data exist regarding their influence on the treatment response. The aim was to explore the effect of 303 mg of silybin-phospholipids complex, 10 mg of vitamin-D and 15 mg of vitamin-E twice a day for six months in NAFLD patients carrying PNPLA3-rs738409, TM6SF2-rs58542926 and MBOAT7-rs641738 genetic variants. The assessed mutations are independently associated with no response to a silybin/vitamin D-based therapy and could be useful therapeutic predictive markers in this context.

NCT04640324
Conditions
  1. Non-Alcoholic Fatty Liver Disease
  2. Insulin Resistance
Interventions
  1. Drug: Nutraceutical therapy
MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Insulin Resistance
HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis Insulin resistance

One hundred two patients with histological diagnosis of NAFLD followed by the Hepatogastroenterology Division of the University of Campania "Luigi Vanvitelli, between January and October 2017 were screened, after signing an informed consent, for the PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 genetic variants and thirty-two met the inclusion criteria for the study and showed at least one among PNPLA3 I148I/M, I148M/M, TM6SF2 167E/K, 167K/K and MBOAT7 TMC4C/T or TMC4T/T genetic variants, were enrolled together with sixty patients without the mutations. --- I148M ---

Primary Outcomes

Description: The HOMA-IR was calculated using the following formula: fasting insulin (μU/mL) × plasma glucose (mmol/L)/22.5. The investigators considered the patients responder if at least one of the following criteria was addressed: normalization of the HOMA-IR (<2.5) at the end of treatment starting from baseline values greater than 2.5; reduction of the HOMA-IR ≥ 2 points at the end of treatment in comparison to baseline.

Measure: Number of participants in each study group which shown an improvement from baseline of insulin resistance assed by HOMA-IR

Time: Six months

Secondary Outcomes

Description: The ALT levels were assessed using a colorimetric commercially available kits and expressed as IU/L. The investigators also considered the parameter improved from the baseline in case of normalization (<45 IU/L).

Measure: Mean change in ALT levels from baseline

Time: Six months

Description: The insulin levels were measured enzymatically using commercially available kits and expressed as micro-IU/ml. The investigators also considered the parameter improved from the baseline in case of normalization (<24 micro-IU/ml).

Measure: Mean change in insulin levels from baseline

Time: Six months

Description: The CRP levels were measured enzymatically using commercially available kits and expressed as mg/dl. The investigators also considered the parameter improved from the baseline in case of CRP normalization (<0.6 mg/dL) or reduction of at least 1 mg/dL.

Measure: Mean change in CRP levels from baseline

Time: Six months

Description: TBARS assay was performed using 10 μl of serum. The cromogen TBARS was quantified using a spectrophotometer at a wavelength of 532nm with 1,1,3,3-tetramethoxyprophane as a standard. The amount of TBARS was expressed as nmol/μg of protein. The investigators also considered the parameter improved from the baseline in case of TBARS reduction of at least 10 nmol/μg

Measure: Mean change in TBARS levels from baseline

Time: Six months

7 The Effect of Dietary Fat Quality Modification for Liver Fat Content in Participants With Different Variants in PNPLA3 Gene - Liver, Diet and Genetic Background (LIDIGE STUDY)

PNPLA3 rs738409 (I148M) variant is associated with hepatic liver accumulation and chronic liver diseases including non-alcoholic fatty liver disease. It has been shown that obesity augments genetic risk but studies investigating the interaction of PNPLA3 rs738409 risk variant and diet are scarce. The aim is to investigate the effect of dietary fat quality modification in participants with different variants of the PNPLA3 gene (rs738409). The primary outcome is the change in liver fat measured by magnetic resonance imaging in the randomized controlled 12-week dietary intervention trial.

NCT04644887
Conditions
  1. Liver Fat
Interventions
  1. Other: Dietary intervention: Healthy diet
  2. Other: Dietary intervention: Control diet

Liver, Diet and Genetic Background PNPLA3 rs738409 (I148M) variant is associated with hepatic liver accumulation and chronic liver diseases including non-alcoholic fatty liver disease. --- I148M ---

PNPLA3 rs738409 (I148M) variant is associated with hepatic liver accumulation and chronic liver diseases including NAFLD. --- I148M ---

Primary Outcomes

Description: The primary outcome is the change in liver fat measured by magnetic resonance imaging

Measure: Liver fat

Time: 12 weeks

Secondary Outcomes

Description: The hepatic condition will be monitored by ultrasound

Measure: Hepatic condition monitored by ultrasound

Time: 12 weeks

Description: The hepatic condition will be monitored by elastography

Measure: Hepatic condition monitored by elastography

Time: 12 weeks

Description: The hepatic condition will be monitored by calculating and comparing Fibrosis-4 index, NAFLD Fibrosis Score, hepatic steatosis index, the fatty liver index and NAFLD liver fat score.

Measure: Hepatic condition monitored by calculated indexes

Time: 12 weeks

Description: Changes in glucose metabolism (oral glucose tolerance test, 0, 30 min and 2 h samples)

Measure: Glucose metabolism

Time: 12 weeks

Description: Concentrations of total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides

Measure: Serum lipid profile

Time: 12 weeks

Description: Serum circulating concentrations of high-sensitivity C-reactive protein

Measure: Inflammatory markers

Time: 12 weeks

Description: Mass spectrometry based metabolomics analysis

Measure: Plasma metabolomic profile

Time: 12 weeks

Description: Mass spectrometry based lipidomics analysis

Measure: Plasma lipidomic profile

Time: 12 weeks

Description: The DNA/RNA of gut microbiota will be extracted and collected for high throughput metagenomics and metatranscriptomics to observe changes in type and composition of gut microbiota.

Measure: Gut microbiota

Time: 12 weeks

Description: Fatty acid composition of plasma phospholipids, cholesteryl esters and triglycerides

Measure: Fatty acid composition of plasma lipid fractions

Time: 12 weeks


HPO Nodes


HP:0001392: Abnormality of the liver
Genes 1400
TNFSF11 UBR1 TRNK B3GLCT PEX3 NDUFS4 SCYL1 TREX1 CASP8 IARS1 SLC25A13 TRAPPC11 ABCC2 ALG9 GTF2IRD1 CAVIN1 EPB41 CD247 RASA2 APC NHLRC2 PEX3 TSHR NGLY1 ARVCF FANCM UCP2 ND1 ANTXR1 SDHD NELFA RREB1 NLRP3 HPGD CD70 LETM1 KIF3B IFT172 NPHP3 ARSA ASS1 TCF4 WDR35 SHPK RFX6 PSAP PEX11B PEX6 ERCC4 PAX4 SETBP1 HBB APOB RIT1 CEP164 ZAP70 ZIC3 STK11 STN1 GPC1 CYP27A1 GNPTAB DYNC2H1 PEX11B PDGFRL PEX1 PKLR GALK1 AP1S1 TTC7A BRIP1 TREX1 HSD3B7 PLIN1 FDX2 CD81 TNFRSF13B SEC24C POLG2 UROS KLF11 IL36RN PIK3CA CLDN1 SLC37A4 PIGA CD96 CYBA ERCC8 AKT2 FANCG FOXF1 TET2 NDUFV2 GLIS3 DLD PEX2 GNS AKT2 SLC25A20 RRAS2 CASP10 TNPO3 XRCC4 PC NEUROD1 WDR19 NOD2 CEP290 PTRH2 CCDC115 C8ORF37 CPOX SLC13A5 NSMCE2 HAMP VPS45 FBP1 SPTB PRKCD SPECC1L CBS DNAJB11 COG8 HOXD13 RNU4ATAC KMT2E PKD2 TTC21B PKD2 PDX1 NPHP1 AKR1D1 IFT27 CBL PHKG2 PEX19 USB1 NLRP3 SPTB TMEM70 PEX26 CR2 PEX12 SEC63 SPOP ACVRL1 FAH STX11 HNF4A SDHA NEK1 MADD ERCC8 PDGFB FANCL CPLX1 FAS ALDOB PSAP TCIRG1 CALR PEX16 ACADVL RINT1 FAN1 TET2 TKT RFX5 SLC2A1 VPS33A HMGCL MYRF RFT1 SLC4A1 XK NGLY1 DLL4 PCSK1 MSH2 C11ORF95 MVK MCM4 FLI1 AGPAT2 TINF2 ARSA IYD CFTR CR2 CASK ESCO2 LRP5 AGA TRIM37 MET NLRP3 SMPD1 KRT18 FANCF IGF2R NCKAP1L WDPCP GATA6 BBS9 LACC1 ACADVL APPL1 IFT80 CPT1A PEX1 IGF2 KIF20A STAT1 DLL4 PLEKHM1 RMRP KRAS IFT140 UQCRFS1 PEX12 HNF1A PRKCSH TRNN SCO1 BTK SLC25A15 MSH6 PEX13 ERCC8 BSCL2 SLC39A4 NDUFB11 RBCK1 HNRNPA2B1 PALLD RNASEH2B UGT1A1 NDUFAF8 SLC44A1 PSMB9 CCND1 AHCY ATPAF2 SMAD4 SKIV2L SNX10 HMBS TERT ALG8 ABCC8 SC5D TMEM216 NPC1 POMC FANCI FAS SLC22A5 SCARB2 HBB HFE LDLRAP1 HADH MMAA MYBPC3 PEX6 MET NOTCH2 PEX10 CTLA4 RPGRIP1L TRIM28 NPC2 SCYL1 ALMS1 CP VCP TUFM IDUA SBDS COG6 RFXAP GPC3 B9D1 TRHR DHDDS TTC7A PEX14 CYP19A1 INTU SLCO1B3 PTEN NLRP1 TIMMDC1 BBS7 DUOX2 HNF4A COG5 LDLR MMEL1 DNASE1L3 RASGRP1 FANCA DLD COG4 MARS1 PCK2 SOS1 KRT18 IARS1 ENG SCNN1B TYMP HNF1A DHFR GPI LPIN2 TGFB1 MAN2B1 KCNQ1OT1 TTC21B NPM1 NDUFS4 SLC2A1 HNF1A TSHB IL18BP ANK1 CTLA4 MMUT PCSK9 CEP19 KLF1 POLG2 IL21R APC IRF5 IL17RC SAR1B TERT PIGM PEX1 ERBB3 LYZ DYNC2H1 ATAD3A DNAJC21 CTNNB1 MPI PEX14 CFTR PSAP IFT80 RHBDF2 PPARG RTL1 TGFB1 MKS1 DDOST HBA2 TRNE TSFM NDUFB9 NPHP3 EWSR1 GCGR POU6F2 PLPBP PMM2 IDUA SFTPA2 IRAK4 APC HBG2 SLC29A3 RAG2 PEX10 JAK1 GBA MMUT JMJD1C SLC30A10 CPT2 NDUFS6 PALB2 GALT OCLN ETFDH TBX1 WDR19 FLNC NCF4 FASLG COX4I2 IFT172 RFXANK PEX12 PIEZO1 EPB41 BCS1L GBA CORIN ENG SPTA1 PTPN3 PHKB AGA RAG2 TPI1 FECH ALAS2 IL17F MADD MKKS FANCC PYGL LIMK1 PEPD BLK AMACR MCCC1 TWNK MKS1 CNOT1 APC ATP7B NCF1 CD3D NDUFAF1 IL2RB RNU4ATAC CDKN2A NDUFA6 SAA1 FARSA PMS1 IL7R RNASEH2A FAH GAA ABCB11 BRCA2 NDUFS2 TTC37 LMNA SPTA1 PKHD1 ND3 IL17RA KRAS TMEM216 KLF1 IGLL1 BRCA2 DPAGT1 SPTB IGHM PEX16 FASLG PEX10 SOX10 SLC39A8 FAM111B DNAJC19 GDF2 INSR HLA-DRB1 MRPL44 PEX13 NDUFA1 CYBB NEU1 CD3E BSCL2 ATP6AP1 MLH1 PTPRC BCHE TNNI3 GPIHBP1 SNX10 KRT8 PTPN11 CC2D2A FBP1 ACAD9 GNPTAB IDUA CTSK XPR1 ACVRL1 TFAM CYBB TFR2 POLG HADHB MTTP NRAS ARSA LPIN2 CC2D2A CLCN7 DOLK NEU1 ADA SETBP1 FANCB STAT3 ABCB4 PEX6 PEX2 PEX10 ETFB SFTPC SLX4 TSC1 SLC25A13 PGM1 A2ML1 RPGRIP1L PHKG2 HMBS MEFV GABRD ITCH BRCA2 SEMA4A PLAGL1 TRMT5 PALB2 NDUFAF2 ASXL1 ABCG5 DMPK USP18 VPS33B TMEM67 UFD1 HYMAI C1QBP AXIN1 TREX1 HNF1B HNF4A ASAH1 SLC29A3 NOTCH2 UBE2T SRP54 GBA DKC1 JAK2 TSHR TCIRG1 BBS5 POLG2 ERCC6 MMAB HBB NFKB1 IL1RN KCNQ1 TMEM126B ACADM EIF2AK3 ABCB4 DNAJC19 TALDO1 ARL6 PEX12 AP1S1 STEAP3 UNC13D PEX5 HADHA HFE SP110 NFKB2 TRAPPC11 PHKA2 ANK1 IDS CPT1A RNF43 PCCB NDUFAF4 SETD2 KCNN4 ERCC4 CTLA4 INPP5E HMGCS2 DZIP1L NEUROG3 PEX16 JAM2 COG1 POU2AF1 PEX19 DIS3L2 CD28 POLG PEX5 RHAG ADA2 BPGM UROD BCS1L RBPJ WDR19 MRPS7 HNRNPA1 BMPER CPT2 H19-ICR SLC25A13 ADAR TMEM67 MTRR GYPC MLH3 HBA2 GFM1 EFL1 TERC DDRGK1 FOS BOLA3 TF GLB1 MEG3 BBS12 DPM1 AIRE LIG4 PARN HSD3B7 ATP7B PIGS TPO BBS2 PEX11B TRIM37 GLB1 PPARG DCLRE1C SCNN1A UQCRB GPC3 CYP7B1 ALG9 NHP2 IGF2 EXTL3 MAN2B1 COMT PRKCD BLNK MYORG IL2RG OSTM1 IL7R SLC17A5 GCLC ABCG8 SMPD1 APC ETFA RHAG WT1 SPRTN LIPA RAB27A RAG2 SDHC IER3IP1 NR1H4 SMAD4 CYTB BTNL2 ADAMTSL2 INVS GDF2 PSMB4 CLCN7 FGFR2 GNE PEX6 ARHGAP31 JAK2 MS4A1 GNE G6PD BBIP1 DHCR7 MPI TINF2 INSR ERCC6 CAVIN1 ATP6AP2 LBR BBS1 IFNG KIT RRM2B LIPE HNF4A LMNA JAK3 BMP2 ABCG8 PIK3C2A LMBRD1 IFT172 PEX3 NBAS IFT140 BTK AMACR HBG1 CTBP1 LZTFL1 BTNL2 PEPD KCNJ11 GALT GAA SNX14 MFN2 SEC63 MYC ERCC6 DYNC2I1 TP53 CASR NKX2-5 BBS10 RAD51C NAB2 MPV17 TMEM67 GALE PSAP PEX13 REST TGFBR2 PRPS1 PLEKHM1 TTC8 CLIP2 ABCC8 H19 CYBC1 ELN RAG1 PKD1 NPHP1 EPB42 CLEC7A HIRA GP1BB DYNC2LI1 TCIRG1 CYP27A1 SLC26A4 PMM2 FERMT3 HSD17B4 PEX3 ELN FUCA1 EXTL3 HJV TMEM67 MYD88 AGGF1 ARSB MOGS RIPK1 KCNN4 NDUFAF5 HFE NOTCH1 PMS2 DUOXA2 FOXP3 WDR19 USP9X TRMU ND4 SDCCAG8 AP3B1 CBL APOC2 LPL CD28 PKHD1 SON LIPE PPOX TCF3 SUMF1 CA2 HESX1 CC2D2A PDGFRB CEP83 STXBP2 TARS2 GLRX5 HNF1B PCK1 IFT122 TET2 SLC40A1 BBS4 SLC7A7 ARL6 ABHD5 BCS1L STK11 PEX2 PCCA TTC37 DOCK6 DAXX INPPL1 DIS3L2 KRAS TNFRSF13C PRSS1 AP1B1 HSD17B10 SF3B1 SLC25A19 TERT DYNC2I2 TNFRSF1B FANCD2 SLC30A10 IL7R LMNA AGL GPC4 FECH H19-ICR TRNV NAGA RMND1 CIITA KIT GBA G6PC3 CEP290 PEX26 GUCY2D NDUFB10 TRMU TJP2 TMEM67 DNAJC21 PEX26 IL12RB1 SH2D1A XRCC4 SLC25A4 IDUA IL2RA ARG1 PEX19 NDUFA11 NDUFS3 MED25 GBA SLC35C1 HJV IQCB1 MRPL3 SP110 EPB42 VPS13A NAGA SERPINA1 NHP2 SLC4A1 ATP8B1 LIG4 ADK SLC25A20 RAG1 CEP55 RRAS SLC22A5 SKIV2L CLDN1 PSAP TREX1 ZAP70 ALDOB LMNA GATA2 ND2 ND5 IFIH1 IFNGR1 BRCA1 SLC7A7 NDUFS7 FGFRL1 APOE GATA6 JAM3 GCDH UGT1A1 CBS AP3D1 SOS2 ABCA1 NPHP3 TKFC FOXRED1 LIPA PEX3 CSPP1 ACAT1 PCCB CASP10 ALDH7A1 TNFRSF13C FADD BLVRA PPARG GCK KPTN MECP2 LBR AP1B1 PCCA SBDS KCNH1 SLCO1B3 MRAS MRPS28 TNFSF11 CYP7B1 DCDC2 PDGFRA PEX1 SLC25A15 NPHP3 ADA SLC20A2 LIPA PRF1 ND3 TRAF3IP1 ACAD9 GBA SLC4A1 GBA JAK2 TNFRSF11A SUMF1 GUSB CD40LG MSH2 DHCR7 LARS1 MMACHC F5 MIF GUSB ABCC2 NSD2 TRIM32 GBA LBR NCF2 MAN2B1 CEP290 FOXP3 RAC2 PKD1 TNFSF15 RELA SDHA TPP2 SDCCAG8 CIDEC RAG1 STAT6 CDKN1C IFT43 HAVCR2 HMGCL HBB SLC4A1 ACP5 XIAP RNASEH2A IL2RG ATP7A SPTB POLR3A AGPAT2 BTK CARS2 ALG13 ERCC1 ATRX TMEM231 ND1 COG7 IDUA MUC5B COG4 PRKCD NPHP4 LRRC8A RMRP SPINK1 PIEZO1 MPC1 EARS2 ABHD5 NDUFAF3 LCAT PSAP ABCA1 ABCD3 C1S CPA1 KCNJ11 LONP1 CTCF GANAB MSH6 TSC2 PEX14 DGUOK TNFSF12 TMEM107 PEX16 SLCO2A1 COG2 SDHB TRNL1 IDS CHD7 SLC37A4 BSCL2 DPM2 NAGS B2M ARSA CTNNB1 TNNT2 SRP54 CAV1 RPS20 SLCO1B1 DYNC2LI1 LYST PLIN1 CD19 HMOX1 APOA1 ADAMTS13 CCDC47 CYP7A1 ND2 SLC25A1 EIF2AK3 CPOX CPOX CIDEC ITCH APC2 SERPINA1 GPD1 PTRH2 LYRM4 GBA UGT1A1 APOE PFKM POLG TNFRSF1A SPIB CLCN7 YARS2 NSD1 NDUFS8 F5 KCNN3 LMNB2 DYNC2I1 RHAG GNMT HYOU1 TBX1 TNFSF12 EPCAM JAK2 PEX14 ATP8B1 TBL2 MLH1 AKR1D1 TBX19 ATP11C FANCE PDGFRA TGFB1 CTNS NCF2 PNPLA2 TNFRSF1B CEP120 DDRGK1 RFC2 FUCA1 SLCO1B1 PSTPIP1 NPHP3 SLC40A1 CTRC UGT1A1 NDUFS1 TMEM165 RNASEH2C NSD2 TRNW LHX3 FH RRM2B NOP10 PEX5 PEX19 IL12A IL6 FLT1 CD19 SURF1 LTBP3 SMPD1 BBS1 MPV17 B9D2 BRCA1 BSCL2 MPL PSMB8 DCTN4 KRIT1 CLCA4 CTSC LRP5 PROP1 ASL CLCN7 TRIP13 SLC25A19 FCGR2A MST1 ANKS6 ALDOA TRAF3IP2 TBX1 IDS SRSF2 TRIM28 WDPCP ALG8 CD79A PIK3R1 NOP10 TRNS1 TRAF3IP1 ALG2 RAF1 SCNN1G COG6 CD79B HEXB CTSA CPT2 PRDM16 STOX1 ASAH1 SC5D NDUFS7 HK1 TALDO1 NUBPL RPGRIP1 COX15 MAGT1 PAX8 ABCA1 STEAP3 HADHA TERC PHKA2 RTEL1 INS CYBA NDUFB3 PEX12 GPC3 HADH CASR SMAD4 RASGRP1 HBB CASR GBE1 RERE DMPK ICOS FADD MAD2L2 DCDC2 PNPLA6 SKI LMNA ABCB11 EOGT WT1 SEC23B TRNW ICOS RFX5 SLC25A13 ABCB4 GLB1 DCLRE1C ALMS1 NCF1 HBG2 CYBC1 CDAN1 FGA PARS2 LRPPRC RPGRIP1L IL2RG LHX4 KCNH1 TBX19 CDIN1 ACOX1 HBB TMPRSS6 TNFRSF13B LMNA TET2 HAMP NRAS PEX26 TP53 PNPLA2 POU1F1 WRAP53 FAS ABCG8 SAMHD1 WDR35 NDUFV1 ATP7A RFXAP TMEM199 G6PC1 PEX6 CCDC28B KRAS GTF2I DGUOK HGSNAT APOA1 NHP2 TG NEK8 IFIH1 TERT RUNX1 CLPB RNASEH2C ALG1 CIITA HADHA COX14 SLC11A2 RNU4ATAC OFD1 XYLT1 WDR35 EFL1 CD27 BMPR1A PEX2 RBM8A ATP8B1 MKS1 POLD1 NSMCE2 RAD51 POMC MMUT PRKCSH HBA1 CAV1 XRCC2 ITK VHL BICC1 RECQL4 AUH ERCC6 PKLR FARSB RAB27A NAGLU CTC1 PRSS2 PEX5 SLC5A5 LYST GBA JAG1 MYPN C4B LETM1 STX1A RFWD3 APC CFTR CEP290 WHCR GPC4 ICOS RFXANK CDKN1B ERCC8 HPD CA2 ND6 ACADM PRKAR1A MLXIPL VIPAS39 LZTR1 HLA-DRB1 MPL INPP5E PAX8 CD55 HLA-DRB1 MVK DKC1 DLK1 DYNC2I2 APOE KRT8 UGT1A1 POU1F1 SGSH GPR35 BAZ1B ERCC4 NDUFAF1 FBN1 RFT1 HBA1 WT1 TERC PIK3CA GNAS ATP6V1B2 PEX1 CPT2 ATP6 COA8 ACOX1 TCTN2 GANAB TMEM67 KCNAB2 VPS33A GALNS CEL PYGL NEU1 XIAP GALM BTD PRKAR1A FGFR2 MVK
HP:0003119: Abnormal circulating lipid concentration
Genes 313
PSMB4 LCAT SLC37A4 BSCL2 ATAD3A UBR1 FLCN PEX3 LDLRAP1 PEX6 COL7A1 TBL1X PLVAP CAV1 SLC25A13 DHCR7 PPARG GTF2IRD1 CAVIN1 PIK3R5 MYO5A PLIN1 TRNE COL7A1 CAVIN1 RTL1 APOA1 DLK1 LEP CYP7A1 EBP PEX7 PMM2 NGLY1 LDLR CIDEC LIPE APOC3 GPD1 UCP2 SLC29A3 LMNA ABCG8 DCAF17 SPIB LMBRD1 RSPO1 ABCG5 ZMPSTE24 KCNJ11 CPT2 TRNK AEBP1 TMEM43 LEPR APOB TBL2 SYNE1 PIGT ALB LRP6 CYP27A1 PEX12 EBP RTL1 ABCA1 CTNS PNPLA2 MTTP CLIP2 APOB RFC2 LMNA NPHS2 FECH PNLIP SGPL1 PYGL LMNA LMNA LIMK1 CCT5 PEX5 CYP27A1 IL12A HSD3B7 PLIN1 APOB EMD PEX10 SMPD1 NADK2 ELN BSCL2 PSMB8 LMNB2 FARSA SLC37A4 TANGO2 AKT2 GHR DLD ACOX2 LMNA CFHR1 SLC25A20 APOC2 LPL MEF2A LIPE NUP107 TNPO3 ACTN4 PANK2 PEX16 CCDC115 MEG3 IQSEC2 GHR STXBP2 NSMCE2 CETP AGL SAR1B LMAN1 HAVCR2 PLA2G7 DEAF1 CPT2 BSCL2 NPHS1 GK GLA ABCA1 CAV1 GPIHBP1 KCNJ1 PHKG2 PHKA2 APOA2 RAI1 AGL PEX12 PPP1R17 HADH ACAD9 MEG3 STX11 ACAD8 HNF4A TRMU MTTP CETP IL12RB1 OCRL GYS2 XRCC4 APOA5 PEX19 LMNA CFH ACADVL PEX2 PEX10 TFG HMGCL SLC25A13 ALMS1 SLC25A13 APTX APOA5 ABCD1 PHKG2 NADK2 LMNA AGPAT2 LMNA DCAF17 MSMO1 LMNA ABCG5 SLC7A7 DMPK PIGH PEX26 PNPLA2 FHL1 SMPD1 TMEM199 ACADVL G6PC1 ABCA1 GTF2I CPT1A LIPA PCSK9 TDP1 ACADM PPARG RAI1 ANGPTL3 HNF1A LBR FBN1 UNC13D SCO1 SLC2A3 RAI1 PEX13 BSCL2 LIPC PHKA2 ADCY3 CAV3 TRNE CPT1A XRCC4 NSDHL LIPA CFHR3 PSMB9 PRF1 POLD1 APOC3 POLR3A NSMCE2 OCRL DHCR7 MMACHC DHCR24 ABCC8 SC5D CAV1 NPC1 POU2AF1 NUP107 SLC22A5 PEX19 MCFD2 RAB27A ALB MC4R LDLRAP1 PEX5 TDP1 CPT2 LYST JAG1 TNFSF15 TBCK SLC25A13 GALNT2 LMNA PEX5 NPC2 CIDEC ALMS1 HTT LPL SETX CYP11A1 ABCA2 DYRK1B XIAP CYP11A1 FOS ACADM PEX14 CYP19A1 MMP1 DLK1 ZMPSTE24 POLR3A AGPAT2 LCAT LDLR MMEL1 EPHX2 COG4 PEX11B SLC12A1 APOE PPARG ABHD5 AR ACAD8 LCAT ABCA1 PEX2 BAZ1B TTPA PLA2G4A TANGO2 LTC4S FLII PEX1 FDFT1 SLC52A1 CPT2 SYNE2 ABCG8 PCSK9 CEP19 PEX7 IRF5 PHYH SAR1B DGAT1 PYGL ABCD1 PEX1 TRNL1 UBE3B
HP:0001824: Weight loss
Genes 337
NABP1 PTPN22 MC2R NOS1 LMNA DNAJC13 GALC IGH HSPG2 RPS20 NPM1 HLCS VPS35 ZBTB16 RHBDF2 CUL4B CDKN2C EWSR1 VHL SLC39A4 SDHD POU6F2 RRM2B SIGMAR1 FANCM SCNN1A IKZF1 PRNP AKT1 TP53 MALT1 KCNJ11 ATM IL6 MPL TCF4 PALB2 GALT IL12B TSHR HLA-DPA1 KRT10 EPCAM JAK2 EDN3 TP53 CFTR IL10 RAD51C NAB2 POLG FANCE GCK REST TGFBR2 KRT1 B2M TGFB1 SDHD GBA IGH SCNN1B CHEK2 H19 ATRIP DCTN1 BCOR SDHB GATA4 SLC9A6 FANCC SNCA TRAIP RARA BRIP1 PIK3R1 MEN1 ERCC3 TXNRD2 CACNA1S RB1 ERCC4 NRTN BRCA1 MPL PTEN CDKN2A PIK3CA PMS1 CDKN2B CCND1 FANCG BRCA2 HLA-DPB1 POLG MLX TRIP13 AVP PMS2 FOXP3 MST1 SLC22A4 CBL DLST COL12A1 BRCA2 TTR MAFB PLA2G6 SRSF2 TRIM28 DNMT3A EDNRB RBBP8 THPO PCNT SDHAF1 CRLF1 KDSR STAT5B SCNN1G SDHB CTLA4 ECE1 EPAS1 TET2 MRAP SPG11 COL6A2 SNCA CDH23 SUCLA2 GBA DAXX MLH1 BCL2 DIS3L2 FOXP1 KRAS IL23R STAT3 SLC6A8 PRKAR1A RRM2B TYMP FANCD2 RNF168 ERCC2 EIF4G1 LRRK2 SMAD4 GNPTAB IGH NDP NBN LPIN2 MAD2L2 NF1 SDHAF2 HLA-DQB1 CENPJ FANCL CALR FANCB WT1 UNC80 FAN1 PRTN3 TET2 VPS13A NOD2 HLA-B SEMA3D PRNP SDHD SLX4 SDHD GJA1 GIGYF2 TLR4 PRNP FLI1 GJB3 ABCC8 TP53 TSHR GATA2 SDHC BRCA2 STAR SEMA4A SDHA IRF2BP2 PALB2 TET2 IFNGR1 BRCA1 ASXL1 PSAP GJB4 CACNA1S KIF1B TRPV4 STAT3 FANCF RET PTEN LMNA ALS2 KCNJ18 UBE2T KRAS JAK2 ACAT1 STAT4 PTEN HLA-DRB1 ACADM C4A EIF2AK3 TMEM127 RUNX1 ZMPSTE24 MAX CCND1 CCR1 MDH2 HTT UBAC2 BTK SLC2A3 MSH6 HFE BIRC3 UNC80 MEFV TP53 BMPR1A PLK4 PALLD FAS MECP2 HLA-DQB1 BCL10 ERCC4 BCL6 NUMA1 PADI4 RAD51 JAK2 SCNN1G MSH2 F5 XRCC2 CNTNAP1 PDX1 FANCI COL6A3 ERAP1 SDHC POLG CDC73 JAK2 HLA-DRB1 PTPN22 KIF1B PML TRIM28 FIP1L1 MLH3 STAT6 RFWD3 HTT HAVCR2 HMGCL TBL1XR1 RET FH KLRC4 PTPN22 ERCC4 HLA-B KCNJ18 BMPR1A HLA-DRB1 SDHB MPL ATRX ATP7B AK2 IL10 FANCA VHL HLA-DRB1 LRP12 TRIM37 GABRA3 IL12A-AS1 SCNN1A GPC3 NNT SCNN1B TYMP CDKN1B DCTN1 ATR GPR35 CIITA HLA-DQA1 NOD2 CDKN1A CENPE FUS WT1 SLC25A11 RET JPH3 SDHB JPH3 IL12A WT1 CD244 LIPA CEP152 SLC11A1 COL6A1 GDNF ERCC5 SEMA3C NFKBIL1 BTNL2 NALCN INS HLA-B CYP24A1 PANK2 SDHA
Protein Mutations 2
I148M P12A