Genome-wide analysis of hepatic lipid content in extreme obesity

Abstract

Individuals with type 2 diabetes have an increased risk of developing nonalcoholic fatty liver disease (NAFLD), and NAFLD patients are also at greater risk for developing type 2 diabetes. Although the relationship between type 2 diabetes and NAFLD is highly interconnected, the pathogenic mechanisms linking the two diseases are poorly understood. The goal of this study was to identify genetic determinants of hepatic lipid accumulation through association analysis using histological phenotypes in obese individuals. Using the Illumina HumanOmniExpress BeadChip assay, we genotyped 2300 individuals on whom liver biopsy data were available. We analyzed total bilirubin levels, which are linked to fatty liver in severe obesity, and observed the strongest evidence for association with rs4148325 in UGT1A (P<5.0 × 10−93), replicating previous findings. We assessed hepatic fat level and found strong evidence for association with rs4823173, rs2896019, and rs2281135, all located in PNPLA3 and rs10401969 in SUGP1. Analysis of liver transcript levels of 20 genes residing at the SUGP1/NCAN locus identified a 1.6-fold change in expression of the LPAR2 gene in fatty liver. We also observed suggestive evidence for association between low-grade fat accumulation and rs10859525 and rs1294908, located upstream from SOCS2 and RAMP3, respectively. SOCS2 was differentially expressed between fatty and normal liver. These results replicate findings for several hepatic phenotypes in the setting of extreme obesity and implicate new loci that may play a role in the pathophysiology of hepatic lipid accumulation.

Association of patatin-like phospholipase domain-containing protein 3 gene polymorphisms with susceptibility of nonalcoholic fatty liver disease in a Han Chinese population

“…Subsequently, Kitamoto et al [13] performed another GWAS that containing 3 genes ( PNPLA3 , SAMM50 , and PARVB ) in the Japanese population, and the results showed that rs2896019 and rs3810622 in the PNPLA3 gene were associated with decreased serum TGs, increased AST and ALT in NAFLD patients, suggested that these 2 SNPs might play an important role in the development of NAFLD. DiStefano et al [14] carried out a GWAS in obese individuals of Caucasian population, found that the rs2896019 of PNPLA3 gene was associated with hepatic fat grades, might participate in the pathophysiology of hepatic lipid accumulation. In general, accumulating evidence has shown that the effect of PNPLA3 polymorphisms may be vital for the occurrence and development of NAFLD.…”

“…Moreover, a recent study suggested that rs2896019 loci might affect hepatic lipid accumulation. [14] …”

Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells

“…RNA was isolated from liver wedge biopsies obtained intraoperatively [39–41]. A portion of the biopsy tissue was fixed in neutral buffered formalin, stained with hematoxylin and eosin, and histologically evaluated as part of clinical standard of care using NASH Clinical Research Network (CRN) criteria [42], as described [40]. Patients with histologic or serologic evidence for other chronic liver diseases were excluded from this study.…”

High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease–related fibrosis

“…In all participants, wedge biopsies of the liver were obtained intraoperatively from similar anatomic locations. The tissue was sectioned so that one-fourth to one-third of it was submerged directly in RNA later (Applied Biosystems/Ambion; Austin, TX) and stored at −80°C for subsequent miRNA sequence analysis, and th e remainder was fixed in neutral buffered formalin, stained with hematoxylin and eosin, and histologically evaluated as part of clinical standard of care using NASH CRN criteria [18], as previously described [19]. Patients with histologic or serologic evidence for other chronic liver diseases were excluded from this study.…”