Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK.
Nature Genetics (Impact Factor: 29.35). 11/2011; 43(11):1131-8. DOI: 10.1038/ng.970
Source: PubMed


Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

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Available from: Mark Caulfield, Oct 07, 2015
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    • "Through review of GWAS, we found 63 SNPs associated to different obesity related phenotypes [8-20,35,36], and 58 of these SNPs were consistently associated with BMI, WC or WHR [8-20]. In the present study, we included SNPs that were available in all three cohorts. "
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    ABSTRACT: Background Cross-sectional data suggests that a low level of plasma ascorbic acid positively associates with both Body Mass Index (BMI) and Waist Circumference (WC). This leads to questions about a possible relationship between dietary intake of ascorbic acid and subsequent changes in anthropometry, and whether such associations may depend on genetic predisposition to obesity. Hence, we examined whether dietary ascorbic acid, possibly in interaction with the genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHR), associates with subsequent annual changes in weight (∆BW) and waist circumference (∆WC). Methods A total of 7,569 participants’ from MONICA, the Diet Cancer and Health study and the INTER99 study were included in the study. We combined 50 obesity associated single nucleotide polymorphisms (SNPs) in four genetic scores: a score of all SNPs and a score for each of the traits (BMI, WC and WHR) with which the SNPs associate. Linear regression was used to examine the association between ascorbic acid intake and ΔBW or ΔWC. SNP-score × ascorbic acid interactions were examined by adding product terms to the models. Results We found no significant associations between dietary ascorbic acid and ∆BW or ∆WC. Regarding SNP-score × ascorbic acid interactions, each additional risk allele of the 14 WHR associated SNPs associated with a ∆WC of 0.039 cm/year (P = 0.02, 95% CI: 0.005 to 0.073) per 100 mg/day higher ascorbic acid intake. However, the association to ∆WC only remained borderline significant after adjustment for ∆BW. Conclusion In general, our study does not support an association between dietary ascorbic acid and ∆BW or ∆WC, but a diet with a high content of ascorbic acid may be weakly associated to higher WC gain among people who are genetically predisposed to a high WHR. However, given the quite limited association any public health relevance is questionable.
    Nutrition Journal 05/2014; 13(1):43. DOI:10.1186/1475-2891-13-43 · 2.60 Impact Factor
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    • "In the absence of such RCTs however, integrative studies of genetic variants specifically related to ALT levels may provide another route to help judge whether ALT is directly causal in MetS (i.e., “Mendelian randomisation [MR] analysis”[35]). A substantial proportion of the variance of ALT is explained by genetic factors, with heritability estimates reported to range between 22 to 48%.[36]–[38] Significant allelic associations with ALT have been reported for several genetic variants in genome-wide association studies (GWAS),[39]–[41] however multiple associations with several cardiometabolic traits have also been observed for majority of the identified loci. In addition, the population variations in circulating levels of ALT accounted for by these variants are very low, ranging from 0.20 to 0.36%.[39]–[41] "
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    ABSTRACT: Elevated baseline circulating alanine aminotransferase (ALT) level has been demonstrated to be associated with an increased risk of the metabolic syndrome (MetS), but the nature of the dose-response relationship is uncertain. We performed a systematic review and meta-analysis of published prospective cohort studies to characterize in detail the nature of the dose-response relationship between baseline ALT level and risk of incident MetS in the general population. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science up to December 2013. Prospective studies in which investigators reported relative risks (RRs) of MetS for 3 or more categories of ALT levels were eligible. A potential nonlinear relationship between ALT levels and MetS was examined using restricted cubic splines. Of the 489 studies reviewed, relevant data were available on 29,815 non-overlapping participants comprising 2,125 incident MetS events from five prospective cohort studies. There was evidence of a linear association (P for nonlinearity = 0.38) between ALT level and risk of MetS, characterised by a graded increase in MetS risk at ALT levels 6-40 U/L. The risk of MetS increased by 14% for every 5 U/L increment in circulating ALT level (95% CI: 12-17%). Evidence was lacking of heterogeneity and publication bias among the contributing studies. Baseline ALT level is associated with risk of the MetS in a linear dose-response manner. Studies are needed to determine whether the association represents a causal relationship.
    PLoS ONE 04/2014; 9(4):e96068. DOI:10.1371/journal.pone.0096068 · 3.23 Impact Factor
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    • "These serum subclasses were classified as follows: chylomicrons and extremely large VLDL particles (average particle diameter at least 75 nm); five different VLDL subclasses: very large VLDL (average particle diameter of 64.0 nm), large VLDL (53.5 nm), medium VLDL (44.5 nm), small VLDL (36.8 nm), and very small VLDL (31.3 nm); intermediate-density lipoprotein (IDL) (28.6 nm); three LDL subclasses: large LDL (25.5 nm), medium LDL (23.0 nm), and small LDL (18.7 nm); and four HDL subclasses: very large HDL (14.3 nm), large HDL (12.1 nm), medium HDL (10.9 nm), and small HDL (8.7 nm)40. This methodology has recently been applied in various extensive epidemiological and genetics studies414243 with consistent findings with respect to lipoprotein genetics44. "
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    ABSTRACT: Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.
    Scientific Reports 04/2014; 4:4650. DOI:10.1038/srep04650 · 5.58 Impact Factor
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