Epidemiologic and Genetic Studies of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease that includes steatosis (fat) steatohepatitis (inflammation around that fat) and fibrosis/cirrhosis (scarring) in the liver in the absence of significant alcohol use. NAFLD is expected to become the number one cause of liver disease in the world by 2020. There are few if any treatments for NAFLD presently. Our group has helped to determine that the prevalence of NAFLD in the Framingham Heart Study population is about 17% and that it is associated with abnormalities in serum lipid and glucose traits as well as high blood pressure. We have helped to form the Genetics of Obesity-Related Liver Disease (GOLD) Consortium in which we have found that NAFLD is about 26%–27% heritable and found 5 SNP variants near the genes PNPLA3, NCAN, GCKR, LYPLAL1, and PPP1R3B that associate with hepatic steatosis as measured using computed tomography in individuals of European ancestry. These variants explain about 20% of the heritability of the trait and have differential effects on related metabolic traits including development of NASH/fibrosis, serum lipid and glucose abnormalities.
Current projects include:
1. Examining the effects of these genetic variants in other ancestries
2. Identifying more genetic variants that associate with NAFLD through larger more powered meta-analyses and through meta-analyses of non-European ancestries and through candidate gene approaches
3. Identifying more rare variants that affect NAFLD through sequencing
4. Examining the effect of NAFLD on cardiovascular disease
5. Examining gene environment interactions
6. Examining predictive models of NAFLD that include genetic variants

Genetic Studies of Obesity 

                                                            32 loci associate with body mass index
Obesity is one of   the most menacing medical problems facing our society. It affects a sixth of the people worldwide, one third of Americans, and is   associated with development of many other metabolic diseases including diabetes,cardiovascular disease and NAFLD. There are few if any effective medical treatments for obesity. Through collaborative efforts in the Genetics of Anthropometric Traits Consortium (GIANT) we have helped to identify 32 SNP variants that reproducibly associate with body mass index, the most commonly used measure of obesity. These variants explain about 3% of the heritability of the trait. When taking together, individuals that carry more than 38 BMI increasing alleles are on average 17–21 pounds heavier than those with less than 21 BMI increasing alleles. We have also identified two copy number variants that associate with BMI near the genes NEGR1 and GPRC5B. Some of the genes near associating variants are known to affect hypothalamic control of appetite regulation (MC4R, SH2B1, BDNF, POMC) while others are suspected to play a role in peripheral effects of nutrient sensing and insulin secretion (GIPR). At most associating sites however, the genes near the variants have never before been connected to obesity giving us new insights into the biology of body weight regulation. We are also involved in studies of body fat distribution and fat mass.
Current projects include:
1. Identifying more genetic variants that associate with NAFLD through larger more powered meta-analyses and through meta-analyses of non-European ancestries
2. Identifying variants that associate with extreme obesity and determining how those relate to variants that affect common obesity.
3. Identifying variants that affect fat mass.

Functional Studies of NAFLD and Obesity

One of the exciting opportunities that human genetic studies have provided is new insights into diseases like obesity and NAFLD. We are working to make cellular and mouse models of these diseases with the hope of better understanding their mechanism of action and for screening for new drugs that may affect these processes that can be used to create novel therapeutics of these conditions.
Current projects include:
1. Assessing the effects on genetic variants that associate with NAFLD in liver cell lines, primary culture, iPS cells
2. Overexpressing/knocking down genes implicated by GWAS studies in the liver of mice to examine their effects
3. Making knockout, overexpressing mice of the genes implicated by GWAS studies to assess their effects in mice

Studies Related to Obesity and NAFLD in a Chinese Population

We have started a collaboration with Peking University scientists to characterize obesity and NAFLD in a Chinese population. This will involve collecting information on a population of individuals and characterizing how genetic, metabolomic, microbiome, and environmental influences affect obesity and NAFLD.
Current projects include:
1. Genetic studies of obesity and NAFLD
2. Metabolomic studies of obesity and NAFLD
3. Microbiome effects on obesity and NAFLD
4. Interventional studies of diet and physical activity on obesity and NAFLD