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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) affects about 20%– 30% of the general population. [1] In addition to being at risk for non-alcoholic steatohepatitis (NASH), leading to cirrhosis and its complications, [1] NAFLD patients are at higher risk of systemic and cardiovascular diseases. [2] surrogate markers of NAFLD, namely fatty liver index, [3] and elevated ALT [4] and GGT [5] have been associated with carotid atherosclerosis and incident cardiovascular disease, respectively
In the last few years, data arising from genome-wide (GWAS) or candidate association studies identified single nucleotide polymorphisms (SNPs) in genes involved in metabolic homeostasis, inflammation, oxidative stress and fibrogenesis, as associated with NAFLD and its severity
Patatin-like phospholipase-3 (PNPLA3)/ adiponutrin, rs738409 C.G SNP, remains the most validated risk gene in this setting. [15,16] Because NAFLD is the liver expression of a systemic metabolic dysregulation, we hypothesized that SNPs of genes associated with NAFLD and its severity -PNPLA3, GWAS-derived genes like neurocan (NCAN), glucokinase regulatory protein (GCKR), lysophospholipase-like 1 (LYPLAL1) [17], and IL28B which have been recently associated with hepatic lobular inflammation and fibrosis [18] - could be linked to the severity of systemic, and in particular cardiovascular alterations in this setting of patients
Summary
Nonalcoholic fatty liver disease (NAFLD) affects about 20%– 30% of the general population. [1] In addition to being at risk for non-alcoholic steatohepatitis (NASH), leading to cirrhosis and its complications, [1] NAFLD patients are at higher risk of systemic and cardiovascular diseases. [2] surrogate markers of NAFLD, namely fatty liver index, [3] and elevated ALT [4] and GGT [5] have been associated with carotid atherosclerosis and incident cardiovascular disease, respectively. In the last few years, data arising from genome-wide (GWAS) or candidate association studies identified single nucleotide polymorphisms (SNPs) in genes involved in metabolic homeostasis, inflammation, oxidative stress and fibrogenesis, as associated with NAFLD and its severity. [15,16] Because NAFLD is the liver expression of a systemic metabolic dysregulation, we hypothesized that SNPs of genes associated with NAFLD and its severity -PNPLA3, GWAS-derived genes like neurocan (NCAN), glucokinase regulatory protein (GCKR), lysophospholipase-like 1 (LYPLAL1) [17], and IL28B which have been recently associated with hepatic lobular inflammation and fibrosis [18] - could be linked to the severity of systemic, and in particular cardiovascular alterations in this setting of patients. To 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
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