The PNPLA3 SNP rs738409:G allele is associated with increased liver disease-associated mortality but reduced overall mortality in a population-based cohort

Meffert, Peter J.; Repp, Katja; Völzke, Henry; Weiss, Frank Ulrich; Homuth, Georg; Kühn, Jens Peter; Lerch, Markus M.; Aghdassi, Ali

doi:10.1016/j.jhep.2017.11.038

Cited by 35 publications

(41 citation statements)

References 11 publications

(5 reference statements)

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“…Interestingly, in our analyses, neither the PNPLA3 148M nor rs2281135‐A allele was associated with metabolic factors, including WHR, diabetes, total and HDL cholesterol, and triglycerides. This is consistent with published reports that 148M was not associated with metabolic changes in a study of over 100 metabolic measures . In another study of patients at high risk for cardiovascular events, 148M was inversely associated with total and low‐density lipoprotein cholesterol …”

Section: Discussionsupporting

confidence: 92%

“…This is consistent with published reports that 148M was not associated with metabolic changes in a study of over 100 metabolic measures. (35) In another study of patients at high risk for cardiovascular events, 148M was inversely associated with total and low-density lipoprotein cholesterol. (36) Multiple studies found relationships of PNPLA3 I148M with NAFLD, but reported associations with mortality from liver disease or all causes are limited.…”

Section: Discussionmentioning

confidence: 97%

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Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

Ünalp–Arida

Ruhl

2020

Hepatology

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Background and Aims Fatty liver causes premature death worldwide and requires long‐term health care. We examined relationships of liver disease markers, including patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) I148M, with mortality in the U.S. National Health and Nutrition Examination Survey, 1988‐1994, with 27 years of linked mortality data. Approach and Results We studied 13,298 viral hepatitis negative adults who fasted at least 4 hours using the nonalcoholic fatty liver disease (NAFLD) liver fat score and NAFLD fibrosis score. PNPLA3 I148M was genotyped in a subgroup of participants from 1991 to 1994 (n = 5,640). Participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to the National Death Index through 2015. During follow‐up (median, 23.2 years), cumulative mortality was 33.2% overall and 1.1% with liver disease, including primary liver cancer. Increased liver disease mortality was associated with PNPLA3 I148M (hazard ratio [HR], 2.9; 95% confidence interval [CI], 0.9‐9.8) and 148M genotypes (HR, 18.2; 95% CI, 3.5‐93.8), an intermediate (HR, 3.8; 95% CI, 1.3‐10.7) or high (HR, 12.6; 95% CI, 4.3‐36.3) NAFLD liver fat score, and a high NAFLD fibrosis score (HR, 12.2; 95% CI, 1.9‐80.6) adjusted for risk factors. Survival curves suggest that increased mortality risk with two 148M alleles was greatest beginning in the second decade of follow‐up. Overall, but not cardiovascular disease, mortality was associated with the PNPLA3 148M allele, and both mortality outcomes were associated with higher fat and fibrosis scores. Conclusions In the U.S. population, PNPLA3 I148M and higher NAFLD liver fat and fibrosis scores were associated with increased liver disease mortality. Genetic variant PNPLA3 I148M may complement other liver disease markers for NAFLD surveillance.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

Ünalp–Arida

Ruhl

2020

Hepatology

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“…survival advantage in women with alcohol-related cirrhosis is well-documented, [31][32][33] and it has recently been shown that this may relate, at least in part, to a sex-variant interaction with rs738409:G in PNPLA3. 34,35 The possibility of sex-variant interactions was also explored in the present study. The progressive increase in the risk of developing alcohol-related cirrhosis and HCC associated with carriage of PNPLA3 rs738409:G HCC was observed in both men and women.…”

Section: Accepted Articlementioning

confidence: 99%

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers

et al. 2020

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“…15 Recent studies have even indicated that the PNPLA3 GG genotype is associated with protection against type 2 diabetes 16 and cardiovascular disease. 17 Moreover, the effect of the PNPLA3 G variant on liver steatosis is regulated by adiposity. [18][19][20] Age-related skeletal muscle loss is another newly recognised risk factor for liver steatosis and fibrosis in lean NAFLD patients.…”

Section: Introductionmentioning

confidence: 99%

The PNPLA3 rs738409 C>G variant influences the association between low skeletal muscle mass and NAFLD: the Shanghai Changfeng Study

Xia

Chen

et al. 2019

Aliment Pharmacol Ther

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Summary Background Age‐related skeletal muscle loss and patatin‐like phospholipase domain‐containing 3 (PNPLA3) polymorphisms are both associated with increased liver steatosis and fibrosis in the absence of obesity. Aim To investigate the influence of PNPLA3 polymorphism on the relationship between skeletal muscle loss and non‐alcoholic fatty liver disease (NAFLD). Methods Liver fat content was measured using a quantitative ultrasound method, and liver fibrosis was assessed by NAFLD fibrosis, BARD and FIB‐4 scores in 3969 Chinese adults. The degree of sarcopenia was measured by weight‐adjusted appendicular skeletal muscle mass (ASM% = appendicular skeletal muscle mass(kg)/body weight(kg) 100%). Results The NAFLD proportion increased from 19.9% to 41.2% in men and 26.3% to 42.3% in women with decreasing ASM% quartiles (P < 0.001). Low ASM% was inversely associated with NAFLD in PNPLA3 CC (odds ratio [OR]: men, 0.735 [0.610‐0.885] and women, 0.812 [0.718‐0.918], both P = 0.001) and CG (OR: men, 0.673 [0.573‐0.790] and women, 0.798 [0.713‐0.893], both P < 0.001) but not GG genotype carriers. The association remained significant after adjustment for age, cigarette smoking, fat mass, interaction between fat mass and ASM%, obesity, diabetes and all components of metabolic syndrome. Subgroup analyses found that PNPLA3 GG gene variant did not increase the risk for NAFLD in individuals with low ASM% regardless of obesity status. Low ASM% also increased risk for liver fibrosis (all P < 0.05), which became insignificant after multiple adjustments. Conclusions Low ASM% is associated with NAFLD and liver fibrosis. Dissociation of sarcopenia and NAFLD was found in PNPLA3 GG genotype carriers. A stratification based on PNPLA3 genotypes might facilitate personalised treatment for NAFLD.

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The PNPLA3 SNP rs738409:G allele is associated with increased liver disease-associated mortality but reduced overall mortality in a population-based cohort

Cited by 35 publications

References 11 publications

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers

The PNPLA3 rs738409 C>G variant influences the association between low skeletal muscle mass and NAFLD: the Shanghai Changfeng Study

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