Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study.

Umberto Vespasiani-Gentilucci,Andrea Baiocchini,Adriano Maria Pellicelli,Sergio Morini,Davide Rosati,Simone Carotti,Paolo Gallo,Valerio Giannelli,Franca Del Nonno,Antonio Picardi,Francesco Valentini,Marco Delle Monache,Roberto Cecere,Giovanni Galati,Raffaele Antonelli-Incalzi,Antonio De Vincentis,Chiara Dell’Unto

doi:10.1155/2018/7564835

Abstract

Background & Aims Identifying NAFLD patients at risk of progression is crucial to orient medical care and resources. We aimed to verify if the effects determined by different single nucleotide polymorphisms (SNPs) could add up to multiply the risk of NAFLD and NASH-cirrhosis. Methods Three study populations, that is, patients diagnosed with NASH-cirrhosis or with noncirrhotic NAFLD and healthy controls, were enrolled. PNPLA3 rs738409, TM6SF2 rs58542926, KLF6 rs3750861, SOD2 rs4880, and LPIN1 rs13412852 were genotyped. Results One hundred and seven NASH-cirrhotics, 93 noncirrhotic NAFLD, and 90 controls were enrolled. At least one difference in allele frequency between groups was significant, or nearly significant, for the PNPLA3, TM6SF2, and KLF6 variants (p < 0.001, p < 0.05, and p = 0.06, resp.), and a risk score based on these SNPs was generated. No differences were observed for SOD2 and LPIN1 SNPs. When compared to a score of 0, a score of 1-2 quadrupled, and a score of 3-4 increased 20-fold the risk of noncirrhotic NAFLD; a score of 3-4 quadrupled the risk of NASH-cirrhosis. Conclusions The effects determined by disease-associated variants at different loci can add up to multiply the risk of NAFLD and NASH-cirrhosis. Combining different disease-associated variants may represent the way for genetics to keep strength in NAFLD diagnostics.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is becoming an epidemic in Western populations, with prevalence ranging from approximately 20% to 30% depending on the country and the different reports [1, 2]
When compared to a score of 0, with respect to noncirrhotic NAFLD patients, a genetic risk score of 3-4 almost quadrupled the risk of nonalcoholic steatohepatitis (NASH) cirrhosis. This is the first study aimed to verify if combining the presence of different polymorphisms of risk could increase the predictive power for NAFLD and, mainly, for its evolution to cirrhosis
The present results are proof of concept that the effects determined by disease-associated variants at different loci can add up to multiply the risk of NAFLD and of NASH cirrhosis

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is becoming an epidemic in Western populations, with prevalence ranging from approximately 20% to 30% depending on the country and the different reports [1, 2] Against these alarming numbers, only a minority of NAFLD patients evolve to cirrhosis and eventually to hepatocellular carcinoma (HCC), while the majority of them present a relatively benign disease, usually integrated in a dysmetabolic profile [3]. We aimed to verify if the effects determined by different single nucleotide polymorphisms (SNPs) could add up to multiply the risk of NAFLD and NASH-cirrhosis. The effects determined by disease-associated variants at different loci can add up to multiply the risk of NAFLD and NASH-cirrhosis. Combining different disease-associated variants may represent the way for genetics to keep strength in NAFLD diagnostics

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Results

Conclusion