Background Recently the SNP identified as rs1260326, in the glucokinase regulatory protein (GCKR) was associated with hypertriglyceridemia in adults. Since accumulation of triglycerides in hepatocytes represents the hallmark of the steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, since recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver recently, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. Methods and Results We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans and 135 Hispanics). All underwent an OGTT and fasting lipoprotein subclasses measurement by proton NMR. A subset of 142 children underwent a fast gradient MRI to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians p=0.00014; African Americans p=0.00417) large VLDL (Caucasians p=0.001; African Americans p=0.03) and with fatty liver (Caucasians p= 0.034; African Americans p= 0.00002; and Hispanics p= 0.016). The PNPLA3, but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglycerides levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance Caucasians (p=0.00161), 39.0% in African Americans (p=0.00000496), and 15% in Hispanics (p=0.00342). Conclusions The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL, and triglycerides levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths.

The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). Conclusion A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size.

Routine genetic screening of patients with TAAD provides information that enables genetically personalized care and permits identification of novel mutations responsible for aortic pathology. Analysis of large data sets of variants of unknown significance that include associated clinical features will help define the mutational spectrum of known genes underlying this phenotype and potential identify new candidate loci.

Background & Aims: Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the study of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. Methods: We performed WES and deep phenotyping of nineteen unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center. Results: Analysis of the exome in 19 cases identified four monogenic disorders in five unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed Type 3 Familial Partial Lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver

The rs626283 variant in the MBOAT7 gene is associated with NAFLD and may affect glucose metabolism by modulating intra-hepatic fat content in Caucasian obese children and adolescents.