Relationship of Gout and Dyslipidemia
Gout is an inflammatory response to monosodium urate (MSU) crystals that may exist asymptomatically for months or years, until the first gout attack occurs. The genetic or biochemical factor/s predisposing certain people with urate crystals, but not all, to initiate a gout attack, are poorly understood. Co-existence of gout with dyslipidemia is very common therefore this study was designed to investigate the lipid-related pheno- and genotypes as additional risk factor/s for gout/serum urate along with testing of possible gene-environment interactions to influence the gout risk. New Zealand (NZ) participants gout cases (n=1198), defined by the American Rheumatology Association preliminary classification criteria, and self-reported controls (n=1084), were the basis for this study. For very low-density lipoprotein (VLDL) analysis, serum samples of 180 male gout cases and healthy controls were fractionated using size exclusion chromatography. Triglyceride (TG), cholesterol and apolipoprotein B (apo B) levels were measured using colorimetric assays and enzyme-linked immunosorbent assay (ELISA), respectively. The Mendelian Randomization approach investigated the causal associations of TG and serum urate in Atherosclerosis Risk in Communities (ARIC) and Framingham Heart Study (FHS) European cohorts where genetic data was either genotyped or imputed. Selected TG and apo B related SNPs were genotyped in NZ sample sets using Taqman genotyping. For gene-environment interaction analysis, alcohol consumption data were obtained by consumption frequency questions in all study cohorts. All analyses were performed using STATA. Results showed that VLDL TG levels were significantly higher in NZ European and Polynesian gout cases compared to non-gout controls. This increase was driven by the overproduction of VLDL particles in the European participants and by the TG-enrichment of existing VLDL particles in the Polynesian participants. Each mmol/L increase in VLDL TG was significantly associated with gout in the presence of HU in Europeans, with a similar trend in Polynesians (OR=7.61, P=0.011 and 2.84, P=0.069, respectively). The total adjusted apo B showed negative association with HU and positive association with risk of gout in NZ Polynesians. Mendelian Randomization provided evidence for causal association of TG in raising serum urate levels in combined ARIC and FHS European males only (βObservational=0.012 mmol/L, P=1.72×10-16; βMendelian Randomization=0.021 mmol/L, P=0.002, Pcorrected=0.012). However, in vice versa analysis, no evidence was observed for a direct causal association of serum urate with TG concentration. Among individually genotyped the T-allele of rs670 (Apo A-I) increased gout risk (OR meta=1.53, Pmeta=4.88×10-6) and the G-allele of rs5128 decreased the gout risk (OR meta=0.86, Pmeta=0.025) in combined Polynesians only. When tested for possible gene-environment interaction, the T-allele of rs2544390 SNP of LRP2 was associated with increased risk of gout in the combined Polynesians (OR=1.20, P=0.009), along with evidence for non-additive interaction of this locus with any alcohol intake to influence the risk of gout (PInteraction=0.001) in this population set. Any alcohol intake was associated with a 4.18-fold increased risk in the CC genotype group (P=6.6x10-5), compared with a 1.14-fold increased risk in the CT/TT genotype group (P=0.40). These effects were not observed in European subjects. Collectively, causal role of TG and its associated genes in increasing gout risk in the presence of HU. Also, alcohol consumption, as potential risk factor, has been identified to interact with a protective LRP2 genotype for increasing the gout risk.
Advisor: Merriman, Tony
Degree Name: Doctor of Philosophy
Degree Discipline: Biochemistry
Publisher: University of Otago
Keywords: Gout; hyperuricemia; Lipoproteins; Triglycerides; Dyslipidemia; Mendelian-Randomization; Alcohol; Apolipoproteins; Genetics
Research Type: Thesis