Hepatology : official journal of the American Association for the Study of Liver Diseases
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Comparative Study
Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents.
Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (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 triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians (P = 0.00161), 39.0% in African Americans (P = 0.00000496), and 15% in Hispanics (P = 0.00342). ⋯ The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths.
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Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA) DRB1*08:03 allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the DRB1*08:03-DQB1*06:01 (13% versus 6%; P = 0.000025; odds ratio [OR] = 2.22) and DRB1*04:05-DQB1*04:01 haplotypes (17% versus 13%; P = 0.044; OR = 1.38). Conversely, there were significant protective associations with the DRB1*13:02-DQB1*06:04 (2% versus 5%; P = 0.00093; OR = 0.27) and DRB1*11:01-DQB1*03:01 haplotypes (1% versus 4%; P = 0.03; OR = 0.37). The frequency of the DRB1*09:01-DQB1*03:03 haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%; P = 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (P = 0.0000015; OR = 1.83) of the DRβchain differed the most in patients with PBC, compared with healthy subjects. ⋯ This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC.
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Candidates with fulminant hepatic failure (Status-1A) receive the highest priority for liver transplantation (LT) in the United States. However, no studies have compared wait-list mortality risk among end-stage liver disease (ESLD) candidates with high Model for End-Stage Liver Disease (MELD) scores to those listed as Status-1A. We aimed to determine if there are MELD scores for ESLD candidates at which their wait-list mortality risk is higher than that of Status-1A, and to identify the factors predicting wait-list mortality among those who are Status-1A. Data were obtained from the Scientific Registry of Transplant Recipients for adult LT candidates (n = 52,459) listed between September 1, 2001, and December 31, 2007. Candidates listed for repeat LT as Status-1 A were excluded. Starting from the date of wait listing, candidates were followed for 14 days or until the earliest occurrence of death, transplant, or granting of an exception MELD score. ESLD candidates were categorized by MELD score, with a separate category for those with calculated MELD > 40. We compared wait-list mortality between each MELD category and Status-1A (reference) using time-dependent Cox regression. ESLD candidates with MELD > 40 had almost twice the wait-list mortality risk of Status-1A candidates, with a covariate-adjusted hazard ratio of HR = 1.96 (P = 0.004). There was no difference in wait-list mortality risk for candidates with MELD 36-40 and Status-1A, whereas candidates with MELD < 36 had significantly lower mortality risk than Status-1A candidates. MELD score did not significantly predict wait-list mortality among Status-1A candidates (P = 0.18). Among Status-1A candidates with acetaminophen toxicity, MELD was a significant predictor of wait-list mortality (P < 0.0009). Posttransplant survival was similar for Status-1A and ESLD candidates with MELD > 20 (P = 0.6). ⋯ Candidates with MELD > 40 have significantly higher wait-list mortality and similar posttransplant survival as candidates who are Status-1A, and therefore, should be assigned higher priority than Status-1A for allocation. Because ESLD candidates with MELD 36-40 and Status-1A have similar wait-list mortality risk and posttransplant survival, these candidates should be assigned similar rather than sequential priority for deceased donor LT.