PNPLA3 GG Genotype and Carotid Atherosclerosis in Patients with Non-Alcoholic Fatty Liver Disease

Abstract

Background and AimTo evaluate if the presence of carotid atherosclerosis in patients with NAFLD, could be related to gene variants influencing hepatic fat accumulation and the severity of liver damage.MethodsWe recorded anthropometric, metabolic and histological data(Kleiner score) of 162 consecutive, biopsy-proven Sicilian NAFLD patients. Intima-media thickness(IMT), IMT thickening(IMT≥1 mm) and carotid plaques(focal thickening of >1.3 mm at the level of common carotid artery) were evaluated using ultrasonography. IL28B rs12979860 C>T, PNPLA3 rs738409 C>G, GCKR rs780094 C>T, LYPLAL1 rs12137855 C>T, and NCAN rs2228603 C>T single nucleotide polymorphisms were also assessed. The results were validated in a cohort of 267 subjects with clinical or histological diagnosis of NAFLD from Northern Italy, 63 of whom had follow-up examinations.ResultsCarotid plaques, IMT thickening and mean maximum IMT were similar in the two cohorts, whereas the prevalence of diabetes, obesity, NASH, and PNPLA3 GG polymorphism(21%vs.13%, p = 0.02) were significantly higher in the Sicilian cohort. In this cohort, the prevalence of carotid plaques and IMT thickening was higher in PNPLA3 GG compared to CC/CG genotype(53%vs.32%, p = 0.02; 62%vs.28%, p<0.001, respectively). These associations were confirmed at multivariate analyses (OR2.94;95%C.I. 1.12–7.71, p = 0.02, and OR4.11;95%C.I. 1.69–9.96, p = 0.002, respectively), although have been observed only in patients <50years. Also in the validation cohort, PNPLA3 GG genotype was independently associated with IMT thickening in younger patients only (OR: 6.00,95%C.I. 1.36–29, p = 0.01), and to IMT progression (p = 0.05) in patients with follow-up examinations.ConclusionPNPLA3 GG genotype is associated with higher severity of carotid atherosclerosis in younger patients with NAFLD. Mechanisms underlying this association, and its clinical relevance need further investigations.

T helper cell‑related cytokine gene polymorphisms and vitamin D pathway gene polymorphisms as predictors of survival probability in patients on renal replacement therapy

“…46 Our results demonstrated an association of IL28B rs12979860 TT genotype with a higher prevalence of CAD in HD patients. The IL28B rs12979860 TT polymorphic variant was associated with lower and TABLE 1 findings, suggesting a possible association of vitamin D pathway gene polymorphisms with survival probability in patients on RRT, we did not reveal associations between GC rs7041, rs1155563 and rs2298849, VDR rs2228570 and rs1 544410, as well as RXRA rs10881578, rs10776909, and rs749759 polymorphic variants and survival either since the start of RRT or since birth.…”

Non-alcoholic fatty liver disease - the heart of the matter

“…The PNPLA3 GG genotype has been associated with a higher severity of carotid atherosclerosis in young patients with NAFLD [8] . However, recently a variant of the TM6SF2 gene (E167K0) has been shown to be linked to fatty liver due to reduced secretion of very lowdensity lipoprotein lipoproteins.…”

Non-alcoholic fatty liver disease and risk of cardiovascular disease

“…Indeed, the effect of the TM6SF2-rs58542926-C risk allele on CVD risk was demonstrated by a large GWAS on myocardial infarction, which found that the T-allele (that was associated with reduced levels of plasma lipids) also conferred a reduced risk of myocardial infarction [59]. Conversely, the possible adverse effect of the PNPLA3-rs738409 on the development of CVD, expressed as the severity of carotid atherosclerosis, was reported in an observational study of 162 patients with NAFLD, in which the authors showed that patients carrying the homozygous GG genotype had increased carotid-artery intima-media thickness [77]; surprisingly, however, this observation was restricted only to the subjects at younger age. Thus, the putative role of PNPLA3 locus on CVD development has questionable evidence that needs to be further confirmed.…”