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A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis.

Authors
  • Shankarappa, Bhagyalakshmi1, 2
  • Mahadevan, Jayant3
  • Murthy, Pratima3
  • Purushottam, Meera4
  • Viswanath, Biju2, 3
  • Jain, Sanjeev3
  • Devarbhavi, Harshad5
  • Mysore V, Ashok1
  • 1 Department of Psychiatry, St John's Medical College Hospital, Bengaluru 560 034, India. , (India)
  • 2 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India. , (India)
  • 3 Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India. , (India)
  • 4 Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India. [email protected]. , (India)
  • 5 Department of Gastroenterology, St John's Medical College Hospital, Bengaluru, 560 034, India. , (India)
Type
Published Article
Journal
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology
Publication Date
Dec 01, 2023
Volume
42
Issue
6
Pages
800–807
Identifiers
DOI: 10.1007/s12664-023-01420-1
PMID: 37589914
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Genetic and epigenetic factors are associated with the development of alcohol-associated liver disease (AALD). The single nucleotide polymorphisms (SNPs), rs738409 in Patatin-like phospholipase domain-containing protein (PNPLA3) and rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) are strongly associated with AALD in different global populations, Hence, we analyzed the genetic risk score for these variants and deoxyribonucleic acid (DNA) methylation levels of the PNPLA3 and TM6SF2 genes among cases (alcohol liver cirrhosis) and controls (heavy drinkers without cirrhosis). We studied patients with alcohol use disorder (AUD) with cirrhosis (AUD-C + ve, n = 136) and without cirrhosis (AUD-C-ve, n = 107) drawn from the clinical services of St. John's Medical College Hospital (SJMCH) (Gastroenterology and Psychiatry) and Centre for Addiction Medicine (CAM), National Institute of Mental Health and Neurosciences, (NIMHANS). Genotype data was generated for rs738409 (PNPLA3) and rs58542926 (TM6SF2) and used to calculate unweighted genetic risk score (uGRS) and weighted genetic risk scores (wGRS). DNA methylation levels were estimated by pyrosequencing at PNPLA3 and TM6SF2 loci. Overall we observed a significantly higher genetic risk score (weighted genetic risk score, wGRS) in individuals with alcohol use disorder compared to control population (p = < 0.01). Further, uGRS and wGRS were associated with the diagnosis of cirrhosis, even after correcting for age of onset, quantity and frequency of drinking. We also found hypomethylation at CpG2 of TM6SF2 gene in AUD-C + ve compared to AUD-C-ve (P = 0.02). We found that a genetic risk score based on SNPs in the PNPLA3 and TM6SF2 genes was significantly associated with cirrhosis in patients with AUD, suggesting a potential utility in identifying patients at risk and providing pre-emptive interventions. These may include interventions that aim to alter DNA methylation, which may be one of the mechanisms through which elevated genetic risk may influence the development of cirrhosis. © 2023. Indian Society of Gastroenterology.

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