Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Chen, Vincent; Chen, Yanhua; Du, Xiaomeng; Handelman, Samuel K.; Speliotes, Elizabeth K.

doi:10.1111/liv.14321

Cited by 44 publications

(50 citation statements)

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“…In addition, 2 studies used International Statistical Classification of Diseases and Related Health Problems (ICD) codes in the UKBB cohort to identify individuals with NAFLD and advanced fibrosis or cirrhosis. 44 , 45 Both found positive associations below genome-wide significance: for example, using an additive model of inheritance, Emdin et al. found the association between rs641738C>T and cirrhosis as β 1.22 (SE 0.06, p = 0.03), using an additive genetic model.…”

Section: Resultsmentioning

confidence: 99%

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Teo

Abeysekera

Adams

et al. 2021

Journal of Hepatology

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Background & Aims A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. Results Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02–0.05], p z = 4.8×10 –5 ) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05–1.3], p z = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03–1.45], p z = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT ( p z = 0.002) and lower serum triglycerides ( p z = 1.5×10 –4 ). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including ‘cirrhosis’). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change (‘variant’) in one gene ( ‘MBOAT7’ ) was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

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Section: Resultsmentioning

confidence: 99%

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Teo

Abeysekera

Adams

et al. 2021

Journal of Hepatology

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“… Main mechanisms are derived from the literature, pleiotropic effects are those identified by Chen et al . …”

Section: Common Genetic Causes Of Cirrhosis In Europeansmentioning

confidence: 99%

“…The same variants in PNPLA3 , TM6SF2 , HSD17B13 and SERPINA1 predisposed to alcoholic and metabolic cirrhosis in the Geisinger Health Study including 46 544 European individuals . The novelty of the study by Chen et al extended to the evaluation of the impact of risk variants on non liver‐related traits. In line with independent findings, both the HFE and SERPINA1 variants decreased circulating lipids, thereby possibly contributing to fatty liver by inducing endoplasmic reticulum stress and impairment of lipoprotein secretion …”

Section: Common Genetic Causes Of Cirrhosis In Europeansmentioning

confidence: 99%

“…In addition, hepatic fat has recently emerged as a major determinant of iron stores by facilitating iron absorption, especially in carriers of HFE p.C282Y and SERPINA1 p.E342K . Chen et al also highlighted that HFE p.C282Y favours haemoglobinization, thereby protecting against iron deficiency and anaemia, which might have provided an evolutionary advantage to carriers . An intriguing finding was that cirrhosis risk variants in PNPLA3 , TM6SF2 and HSD17B13 were also associated with higher haemoglobin levels, as well as with other blood traits.…”

Section: Common Genetic Causes Of Cirrhosis In Europeansmentioning

confidence: 99%

“…1 In this issue of Liver International, Chen et al examined, by unbiased genome-wide screening coupled with the validation of strong candidates, the main common genetic variants predisposing to cirrhosis in Europeans. 2 The study was conducted in a large population-based cohort, namely UK Biobank including 1088 individuals with and 407 873 without cirrhosis, and validated in the Michigan Genomic initiative cohort of 875 surgical patients with and 31 221 without cirrhosis.…”

Section: Uncovering the Genetics Of Cirrhosis: New Plots For The Usuamentioning

confidence: 99%

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Uncovering the genetics of cirrhosis: New plots for the usual suspects

Valenti

2020

Liver International

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Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality

et al. 2022

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ImportanceAlcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk.ObjectiveTo investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease–related mortality.Design, Setting, and ParticipantsThis prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021.ExposuresSelf-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment.Main Outcomes and MeasuresThe primary outcomes were incident cirrhosis and HCC cases and liver disease–related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models.ResultsA total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease–related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease–related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease–related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease–related mortality in persons with excessive drinking and obesity.Conclusions and RelevanceThis study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease–related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.

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Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

Cited by 44 publications

References 69 publications

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Uncovering the genetics of cirrhosis: New plots for the usual suspects

Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality

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