Five genetic variants in humans, including four newly-identified loci, associate with Nonalcoholic Fatty Liver Disease (NAFLD), according to a study published on March 10 in the open-access journal PLoS Genetics. Investigators from the GOLD (Genetics of Obesity-related Liver Disease) consortium found that approximately one quarter of the variation in NAFLD is influenced by genetic factors, with the loci identified in this study accounting for about 20% of this variation.

NAFLD is a condition where fat accumulates in the liver (steatosis) and can lead to liver inflammation (nonalcoholic steatohepatitis or NASH) and permanent liver damage (fibrosis/cirrhosis). NAFLD affects anywhere from 11% to 45% of some populations and is associated with obesity, hypertension, and problems regulating serum lipids or glucose. All the identified genetic variants found increased fat deposition in the liver. However, only some affected development of inflammation/permanent damage of the liver or development of serum lipid/glucose abnormalities.

"These findings will help us to better diagnose, manage, and treat NAFLD in the future and help explain why some but not all people with obesity develop particular complications of obesity; some carry genetic variants that predispose them to some but not other metabolic diseases." said author Elizabeth K. Speliotes. Co-author Ingrid Borecki also said "The effects of these variants on NAFLD are substantial and possibly could be incorporated into clinical algorithms in the future to better classify people into risk categories. This work comes at a time when the number of people affected by these liver abnormalities is increasing, along with the prevalence of obesity in our population."

Currently, only weight loss and possibly increased physical activity can decrease hepatic steatosis. This study provides possible new drug targets for therapeutic intervention of NAFLD. Further, the comprehensive examination of the effects of these genetic variants on multiple traits can help guide development of therapeutics against the gene targets implicated by these variants so that we can choose targets that have specific effects on a desired disease while minimizing unwanted side effects.

Financial Disclosure: This work was partially supported by NIH grants T32 DK07191-32 to Daniel Podolsky (for Elizabeth K Speliotes), F32 DK079466-01 to EKS, NIH K23DK080145-01 to EKS, and R01DK075787 to Joel N. Hirschhorn. The AGES-Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Old Order Amish Study was supported by NIH research grants K01 DK067207, R01 AG18728, R01HL088119, U01 HL72515, and U01 HL084756. Partial funding was also provided by the Diabetes Research and Training Center of Maryland (P60 DK079637) and the Nutrition and Obesity Research Center of Maryland (P30DK072488). Laura M. Yerges-Armstrong was supported by NIH training grants T32AG000262 and F32AR059469. Ruben Hernaez was supported by the American Diabetes Association Mentor-Based Postdoctoral Fellowship Program (7-07-MN-08). The NHLBI Family Heart Study was supported by NIDDK R01DK075681 (to Ingrid B Borecki) and NHLBI R01HL087700. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713). Several clinical centers use support from General Clinical Research Centers or Clinical and Translational Science Awards in conduct of NASH CRN Studies (grants UL1RR024989, M01RR000750, M01RR00188, ULRR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR020359). The MIGen study was funded by the US National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute's STAMPEED genomics research program. Marta Tomas was supported by the Beatriu de Pino´s postdoctoral fellowship, Generalitat de Catalunya (2007BP-B100068, MT), and Red HERACLES, ISCIII (RD06/0009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: Eric E. Schadt [one of the authors] is an employee of Pacific Biosciences.

Citation:

"Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits."
Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, et al. (2011)
PLoS Genet 7(3): e1001324. doi:10.1371/journal.pgen.1001324