Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption

Abstract

IntroductionThe T allele of a single nucleotide polymorphism (SNP: rs2544390) in lipoprotein receptor-related protein 2 (LRP2) is associated with higher serum urate and risk of gout in Japanese individuals. SNP rs2544390 also interacts with alcohol consumption in determining hyperuricemia in this population. We investigated the association of rs2544390 with gout, and interaction with all types of alcohol consumption in European and New Zealand (NZ) Māori and Pacific subjects, and a Māori study cohort from the East Coast region of NZ’s North Island.MethodsRs2544390 was genotyped by Taqman®. From NZ a total of 1205 controls and 1431 gout cases clinically ascertained were used. Publicly available genotype and serum urate data were utilized from the Atherosclerosis Risk in Communities (ARIC) study and the Framingham Heart Study (FHS). Alcohol consumption data were obtained by consumption frequency questions in all study cohorts. Multivariate adjusted logistic regression was done using STATA.ResultsThe T allele of rs2544390 was associated with increased risk of gout in the combined Māori and Pacific Island cohort (OR = 1.20, P = 0.009), and associated with gout in the European subjects, but with a protective effect (OR = 0.79, PUnadjusted = 0.02). Alcohol consumption was positively associated with risk of gout in Māori and Pacific subjects (0.2% increased risk/g/week, P = 0.004). There was a non-additive interaction between any alcohol intake and the risk of gout in the combined Māori and Pacific cohorts (PInteraction = 0.001), where 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.ConclusionsAssociation of the T-allele with gout risk in the Māori and Pacific subjects was consistent with this allele increasing serum urate in Japanese individuals. The non-additive interaction in the Māori and Pacific subjects showed that alcohol consumption over-rides any protective effect conferred by the CC genotype. Further exploration of the mechanism underlying this interaction should generate new understanding of the biological role of alcohol in gout, in addition to strengthening the evidence base for reduction of alcohol consumption in the management of gout.

A novel polymorphism in protein kinase AMP‐activated catalytic subunit alpha 2 (PRKAA2) is associated with type 2 diabetes in the Han Chinese population

“…The significance of differences in the genotype distribution of each SNP between T2DM cases and controls was evaluated by logistic regression analysis. To determine whether the candidate polymorphism was independently associated with T2DM, multiple logistic regression analysis was performed with T2DM as the dependent variable and age, sex, BMI, and genotype information for the SNPs as independent variables . Haplotype interaction between the rs2746342 and rs2143754 polymorphisms in modulating FPG was tested by general linear model (GLM) univariate analyses after adjusting for covariates (age, sex, BMI) .…”

“…To determine whether the candidate polymorphism was independently associated with T2DM, multiple logistic regression analysis was performed with T2DM as the dependent variable and age, sex, BMI, and genotype information for the SNPs as independent variables. 19 Haplotype interaction between the rs2746342 and rs2143754 polymorphisms in modulating FPG was tested by general linear model (GLM) univariate analyses after adjusting for covariates (age, sex, BMI). 20 All analyses were performed using the Stata/SE version 12.0 (Stata Corp., College Station, TX, USA) and SPSS version 18.0 (SPSS, Chicago, IL, USA).…”

Interaction of the GCKR and A1CF loci with alcohol consumption to influence the risk of gout

“…Additionally, LRP2 was included as a sensitivity test on the basis of previously reported evidence for interaction of rs2544390 with alcohol consumption in determining the risk of gout in NZ Polynesian people [8]. …”

Twenty-eight loci that influence serum urate levels: analysis of association with gout

“…The lack of association could indicate pleiotropic effects (eg, at PDKZ1 ), and understanding these effects should yield insights into the aetiology of gout. The population-specific effects at ABCG2 , SLC22A11 , SLC22A12 and LRP2 in gout3 7 9 10 also highlight the necessity for transancestral studies, especially in populations with earlier onset and more severe gout, and a higher prevalence of comorbidities, such as those of Filipino and New Zealand (NZ) Ma¯ori and Pacific ancestry who have a prevalence of gout double that of European Caucasian 11–13…”