Genetic Link To Advanced Fatty Liver Disease

Researchers at Massachusetts General Hospital found that patients with nonalcoholic fatty liver disease (NAFLD) who carry an allele of the PNPLA3 gene have an increased risk of developing advanced disease, including nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis.

A second study supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) validates these findings and further concludes that in pediatric patients, the same allele is associated with earlier disease presentation. Both studies are available in the September issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases (AASLD).

NAFLD is the most common cause of chronic liver disease and afflicts an estimated 20%-30% of the general population and 67%-75% of the obese population. The precise mechanism responsible for the development of the NASH phenotype is yet to be clarified. Genome-wide association (GWA) studies are an important initial step in the identification of these genetic factors because they evaluate the genotypic-phenotypic association in large population-based cohorts and have identified susceptibility loci in numerous diseases.

Recently, GWA studies identified an important genetic variant associated with the presence of NAFLD. Whether these genetic variants also determine disease severity is unknown. To find out, researchers at the NIDDK evaluated single nucleotide polymorphism (SNP) genotypes in 894 primarily Caucasian adults, compared with a control group of 336 Caucasians.

The patient population was recruited from 1 of 3 National Institutes of Health (NIH) sponsored NASH-Clinical Research Network (NASH-CRN) multicenter studies, as well as a cohort of individuals with NASH at the NIH Clinical Center. Study participants had histological evidence of NAFLD or NASH determined by biopsy obtained prior to enrollment. The focus of the study was the PNPLA3 locus on chromosome 22, and especially the non-synonymous coding SNP rs738409 G.

Results indicate that the rs738409 G allele was significantly associated with increased steatosis, portal inflammation, and lobular inflammation. For all of these parameters, genotypes containing rs738409 G were associated with more severe disease. After adjustment for age, gender, body mass index (BMI), diabetes type 2 and alcohol consumption, all associations remained significant.

“Our findings suggest that the rs738409 G allele may predispose patients to fat accumulation in the liver, but that other factors, environmental or hereditary, may be required for the development of inflammation, cellular injury and fibrosis,” says study leader T. Jake Liang, M.D. “However, once patients develop NASH, the rs738409 G allele predisposes them to more severe injury.”

NAFLD is becoming increasingly prevalent in pediatric patients, prompting the researchers to also search for an association between the PNPLA3 SNPs and disease severity in 223 children enrolled in the same study groups as the adults. While no association was found, the presence of the rs738409 G allele was associated with a younger age at the time of liver biopsy, suggesting a younger age of disease presentation.

Concurrent research at Massachusetts General Hospital also identified the G allele of rs738409 in PNPLA3 as a potential risk factor for NAFLD. The Mass General team examined SNPs at 7 loci associated with steatosis in 592 patients of European ancestry from the CRN and 1,405 ancestry-matched controls from the MIGen study. No association was observed between rs738409 G and BMI, triglyceride levels, and high and low-density lipoprotein levels, or diabetes. None of the variants at the other six other loci were associated with NAFLD.

The results suggest that certain inherited variations in lipid metabolism precede and could lead to the development of liver disease. The analysis indicates that genetic variation at PNPLA3 confers a markedly increased risk of severe histological features of NAFLD, without a strong effect on metabolic syndrome component traits. Given that PNPLA3 appears to be part of a family of enzymes that affect lipid metabolism, this suggests that altering lipid metabolism, particularly within the liver, can affect accumulation of fat and subsequent development of NAFLD.

Study leader Elizabeth Speliotes, M.D., Ph.D., M.Ph., concludes, “Through genetic analyses, we may be able to delineate the causal pathways that lead to specific disease complications of metabolic risk factors such as NAFLD and, in the future, selectively target them for therapeutic intervention.”

Source: Wiley – Blackwell