Combining Gene Variants to Improve Risk Prediction for Metabolic (Dysfunction)- Associated Fatty Liver Disease and Its Progression to Cirrhosis in Indian Individuals With Type 2 Diabetes

NCT06289387 | Completed DMC

• 1 other identifier: MMDEF001
• Study Type: observational
• Target: 1,000
• Locations: 1 country
• Sites: 1

Brief Summary

Type 2 diabetes and metabolic (dysfunction)-associated fatty liver disease (MAFLD) often exist together. The prevalence of MAFLD is about 15-30% in healthy people and around 60-70% in people with type 2 diabetes. Moreover, type 2 diabetes accelerates the progression of liver disease in MAFLD. MAFLD is a spectrum of liver conditions, ranging from simple fatty liver (low risk for progression), progressing to steatohepatitis (MASH) with no or mild fibrosis, advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although diabetes is the strongest predictor of advanced fibrosis in MAFLD, however, only a small proportion of people with type 2 diabetes and MAFLD (about 5-7%) develop a clinically significant liver disease, but the burden of MAFLD is such that even a small proportion of patients developing cirrhosis will lead to a huge strain on the health care system in India. MAFLD is predicted to be the leading indication for liver transplantation in coming years. At present, MAFLD/MASH is the second most common indication for liver transplantation in the USA as well as in India. The question is why around 5-7% patients amongst MAFLD population develop fibrosis and cirrhosis. A growing body of evidence suggest that the disease develops because of a complex process in which several factors, including genetic susceptibility and environmental insults, are involved. There are several gene variants that have been incriminated in the development and progression of MAFLD. The most common genes associated with MAFLD are PNPLA3, TM6SF2, GCKR, and MBOAT7. The loss-of-function gene variant HSD17B13 seems to protect from NAFLD. There are a few studies from India about the role of PNPLA3 and TM6SF2 in MAFLD. However, these studies used USG for the diagnosis of MAFLD, which does not provide any information regarding fibrosis of the liver. The data regarding other three genetic variants are scarce from Indian individuals.

Conditions

Type2diabetes

Outcome Measures

Primary Outcomes (1)

• Role of the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 genetic variants in the development and progression of MASLD.

  To evaluate the role of the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 genetic variants in the development and progression of MASLD (steatosis, fibrosis, cirrhosis as measured by transient elastography, MRI-PDFF, dynamic MRI of the liver) in Indian individuals with type 2 diabetes

  One Year

Secondary Outcomes (6)

• Correlation between body fat percentage (DEXA-measured) and the genetic variants

  One Year

• Correlation between lean body mass (as measured by DEXA) and the genetic variants

  One Year

• Correlation between bone mineral content (DEXA-measured) and the genetic variants

  One Year

• Correlation between fibrosis-4 score (FIB-4) and the genetic variants

  One Year

• Correlation between MASLD fibrosis score (NFS) and the genetic variants

  One Year

Study Arms (1)

Individuals with or without diabetes

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals with or without diabetes will be enrolled

You may qualify if:

• Individuals with or without T2DM between ages 30 to 70 years

You may not qualify if:

• Age below 30 years Patients with hepatitis B, hepatitis C or HIV disease Patients with significant alcohol intake (\>14 drinks/week in men and \>10 drinks/week in women).
• Patients on corticosteroids and chemotherapeutic agents.

Sponsors & Collaborators

• Medanta, The Medicity, India: lead

Study Sites (1)

Medanta Division of Endocrinology & Diabetes

Gurgaon, Haryana, 122001, India

Location

Related Publications (7)

• Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, Choi PC, Kowo M, Chan AW, Merrouche W, Sung JJ, de Ledinghen V. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010 Feb;51(2):454-62. doi: 10.1002/hep.23312.

  PMID: 20101745 RESULT

• Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011 Jun;53(6):1883-94. doi: 10.1002/hep.24283. Epub 2011 May 14.

  PMID: 21381068 RESULT

• Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, Vogt TF, Hobbs HH, Cohen JC. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014 Apr;46(4):352-6. doi: 10.1038/ng.2901. Epub 2014 Feb 16.

  PMID: 24531328 RESULT

• Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, Motta BM, Kaminska D, Rametta R, Grimaudo S, Pelusi S, Montalcini T, Alisi A, Maggioni M, Karja V, Boren J, Kakela P, Di Marco V, Xing C, Nobili V, Dallapiccola B, Craxi A, Pihlajamaki J, Fargion S, Sjostrom L, Carlsson LM, Romeo S, Valenti L. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015 Feb;61(2):506-14. doi: 10.1002/hep.27490.

  PMID: 25251399 RESULT

• Holmen OL, Zhang H, Fan Y, Hovelson DH, Schmidt EM, Zhou W, Guo Y, Zhang J, Langhammer A, Lochen ML, Ganesh SK, Vatten L, Skorpen F, Dalen H, Zhang J, Pennathur S, Chen J, Platou C, Mathiesen EB, Wilsgaard T, Njolstad I, Boehnke M, Chen YE, Abecasis GR, Hveem K, Willer CJ. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet. 2014 Apr;46(4):345-51. doi: 10.1038/ng.2926. Epub 2014 Mar 16.

  PMID: 24633158 RESULT

• Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, Boren J, Montalcini T, Pujia A, Wiklund O, Hindy G, Spagnuolo R, Motta BM, Pipitone RM, Craxi A, Fargion S, Nobili V, Kakela P, Karja V, Mannisto V, Pihlajamaki J, Reilly DF, Castro-Perez J, Kozlitina J, Valenti L, Romeo S. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology. 2016 May;150(5):1219-1230.e6. doi: 10.1053/j.gastro.2016.01.032. Epub 2016 Feb 2.

  PMID: 26850495 RESULT

• Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, Liu Y, Kozlitina J, Stender S, Wood GC, Stepanchick AN, Still MD, McCarthy S, O'Dushlaine C, Packer JS, Balasubramanian S, Gosalia N, Esopi D, Kim SY, Mukherjee S, Lopez AE, Fuller ED, Penn J, Chu X, Luo JZ, Mirshahi UL, Carey DJ, Still CD, Feldman MD, Small A, Damrauer SM, Rader DJ, Zambrowicz B, Olson W, Murphy AJ, Borecki IB, Shuldiner AR, Reid JG, Overton JD, Yancopoulos GD, Hobbs HH, Cohen JC, Gottesman O, Teslovich TM, Baras A, Mirshahi T, Gromada J, Dewey FE. A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. N Engl J Med. 2018 Mar 22;378(12):1096-1106. doi: 10.1056/NEJMoa1712191.

  PMID: 29562163 RESULT

Study Design

• Study Type: observational
• Observational Model: ECOLOGIC OR COMMUNITY
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Consultant

Study Record Dates

• First Submitted: February 26, 2024
• First Posted: March 1, 2024
• Study Start: January 20, 2024
• Primary Completion: July 29, 2025
• Study Completion: July 29, 2025
• Last Updated: August 3, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)