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

被引：1

作者：

Shankarappa, Bhagyalakshmi ^{[1
,2
]}

Mahadevan, Jayant ^{[3
]}

Murthy, Pratima ^{[3
]}

Purushottam, Meera ^{[2
]}

Viswanath, Biju ^{[2
,3
]}

Jain, Sanjeev ^{[3
]}

Devarbhavi, Harshad ^{[4
]}

Mysore, V. Ashok ^{[1
]}

机构：

[1] St Johns Med Coll Hosp, Dept Psychiat, Bengaluru 560034, India

[2] Natl Inst Mental Hlth & Neurosci, Dept Psychiat, Mol Genet Lab, Bengaluru 560030, India

[3] Natl Inst Mental Hlth & Neurosci, Dept Psychiat, Bengaluru 560030, India

[4] St Johns Med Coll Hosp, Dept Gastroenterol, Bengaluru 560034, India

来源：

INDIAN JOURNAL OF GASTROENTEROLOGY | 2023年 / 42卷 / 06期

基金：

英国惠康基金;

关键词：

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

D O I：

10.1007/s12664-023-01420-1

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 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 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 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. [GRAPHICS] .

引用

页码：800 / 807

页数：8