80 The A allele is also strongly associated with T2D,81 linking over-nutrition/obesity with its metabolic complications. Studies in NAFLD/NASH will now be

of interest. The A allele contains the first EGFR inhibiton intron of fat mass and obesity-associated gene [FTO] and another gene, fantom (FTM). FTO and FTM are expressed in the hypothalamus and suppressed by fasting, implicating roles in appetite suppression.82 Like Alms1, FTM is a structural component of basal bodies, indicating the potential relevance to cilial function. In support of multiple gene interactions, Loos et al. found summation in the effects of FTO and MC4R with fat mass and risk of obesity.77 Likewise, in Han Cabozantinib cell line Chinese, the combined effects of three genes, one in the estrogen receptor, two in peroxisome-proliferation activator receptor-gamma (PPAR-γ), was greater than any individual gene; collectively, they conferred

> 5-fold (OR 5.3) increased risk of severe obesity (Table 3).83 Robust studies linking individual genes to development of fatty liver have been lacking until recently. The patatin-like phosphatase family consists of nine genes, five collectively designated as the adiponutrin family (PNPLA1-5).84,85 The proteins are expressed in WAT and liver, and their action is believed to complement hormone-sensitive lipase (HSL), a key enzyme involved with adipocyte lipolysis.84 Genetic variations in HSL have been previously linked to obesity, glucose intolerance and dyslipidemia—all relevant

to NASH.86 In 2008, Romeo et al. used GWAS to identify a before SNP, rs738409, within PNPLA3 that was strongly associated with increased hepatic fat content.87 In subjects drawn from the multiethnic Dallas Heart Study mentioned earlier,70PNPLA3 (rs738409 G allele) was present with highest frequency in Hispanics, intermediate in whites and lowest in blacks.87 Hepatic fat content was two-fold greater for G allele homozygotes than for non-carriers of this allele, accounting for all the ethnic differences in MRS-determined hepatic triglyceride content. Another PNPLA3 allele (rs6006460 [T]) was associated with lower hepatic fat content and is most common in African Americans, the group with lowest prevalence of NAFLD.70 The association between PNPLA3 (rs738409 G allele) and hepatic fat content has been confirmed in Finnish and Argentinian cohorts,88,89 and is independent of age, gender, BMI and insulin resistance. In data presented at a recent meeting, PNPLA3 polymorphisms were associated with fibrotic severity of NASH.90,91 Environmental factors, in particular dietary composition, undoubtedly play a role in facilitating the imbalance between energy intake and consumption that underlies the present pandemic of over-nutrition.