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

Alcohol use disorder Alcoholic liver cirrhosis DNA methylation Deoxyribonucleic acid (DNA) Human genetics PCR Patatin-like phospholipase domain-containing 3 protein (PNPLA3) Pyrosequencing Single nucleotide polymorphism Transmembrane 6 superfamily member 2 protein (TM6SF2)

Journal

Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology
ISSN: 0975-0711
Titre abrégé: Indian J Gastroenterol
Pays: India
ID NLM: 8409436

Informations de publication

Date de publication:
Dec 2023
Historique:
received: 13 02 2023
accepted: 20 06 2023
pubmed: 17 8 2023
medline: 17 8 2023
entrez: 17 8 2023
Statut: ppublish

Résumé

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.

Sections du résumé

BACKGROUND BACKGROUND
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).
METHOD METHODS
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.
RESULTS RESULTS
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).
CONCLUSION CONCLUSIONS
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.

Identifiants

DOI: 10.1007/s12664-023-01420-1 PMID: 37589914
pubmed: 37589914
doi: 10.1007/s12664-023-01420-1
pii: 10.1007/s12664-023-01420-1
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

800-807

Subventions

Organisme : Department of Biotechnology, Ministry of Science and Technology, India
ID : DBT/PR17316/MED/31/326/2015
Organisme : The Wellcome Trust DBT India Alliance
ID : IA/CPHI/20/1/505266
Organisme : Indian Council of Medical Research
ID : 3/1/3/42/M/2014-NCD-I

Informations de copyright

© 2023. Indian Society of Gastroenterology.

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Auteurs

Bhagyalakshmi Shankarappa (B)

Department of Psychiatry, St John's Medical College Hospital, Bengaluru 560 034, India.
Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India.

Jayant Mahadevan (J)

Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India.

Pratima Murthy (P)

Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India.

Meera Purushottam (M)

Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India. meera.purushottam@gmail.com.

Biju Viswanath (B)

Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India.
Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India.

Sanjeev Jain (S)

Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India.

Harshad Devarbhavi (H)

Department of Gastroenterology, St John's Medical College Hospital, Bengaluru, 560 034, India.

Ashok Mysore V (A)

Department of Psychiatry, St John's Medical College Hospital, Bengaluru 560 034, India.

Classifications MeSH