Patatin‐like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events

Abstract

Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin‐like phospholipase domain containing 3 (PNPLA3) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss‐of‐function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well‐established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low‐density lipoprotein serum levels (P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion: The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile. (Hepatology Communications 2018;2:798‐806)

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

“…(33) It was also shown that subsequent altered triglyceride turnover is mediated by I148M variant's sequestration of an essential cofactor for adipose triglyceride lipase activity, hence leading to HS. (34) The I148M variant appears to increase NAFLD risk through changes in lipid droplet biology within hepatocytes and hepatic stellate cells. (33,34) 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.…”

“…(34) The I148M variant appears to increase NAFLD risk through changes in lipid droplet biology within hepatocytes and hepatic stellate cells. (33,34) 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.…”

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Given the impact of these variants on hepatic lipid metabolism, their modulatory role in CVD risk has also been investigated. The PNPLA3 [ [34] , [35] , [36] ] and TM6SF2 [ 34 , [36] , [37] , [38] ] NAFLD risk variants are associated with a lower-risk lipoprotein profile characterized by lower plasma TG and/or LDL-C levels. Interestingly, the effect size of the TM6SF2 E167K variant on plasma TG levels is comparable to that of a lipoprotein lipase (LPL) activating variant [ 34 ].…”

Genetics of Non-Alcoholic Fatty Liver and Cardiovascular Disease: Implications for Therapy?

“…This may relate to reduced levels of circulating triglycerides (Tang et al, 2015). A recent prospective study of patients undergoing elective coronary angiography found that while there was a non-significant trend for a protective effect of the presence of PNPLA3 I148M and CAD >75% stenosis, when corrected for age, sex, use of statins, and serum highdensity lipoprotein, there was a significant protective effect (OR: 0.21, 95% CI 0.05-0.88, p = 0.03) (Rüschenbaum et al, 2018). Mendelian randomization has been used to assess the association of PNPLA3 I148M with ischemic heart disease (IHD), and although the risk of IHD increases with increased hepatic fat content, for which PNPLA3 I148M is a risk factor, there was no association with IHD (OR per M allele = 0.98, 95% CI 0.95-1.02, p = 0.79) (Lauridsen et al, 2018).…”