title: Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  Rs2544390 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Association 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.
authors.forename: Humaira
authors.initials: H
authors.lastname: Rasheed
authors.forename: Amanda
authors.initials: A
authors.lastname: Phipps-Green
authors.forename: Ruth
authors.initials: R
authors.lastname: Topless
authors.forename: Jade E
authors.initials: JE
authors.lastname: Hollis-Moffatt
authors.forename: Jennie Harré
authors.initials: JH
authors.lastname: Hindmarsh
authors.forename: Christopher
authors.initials: C
authors.lastname: Franklin
authors.forename: Nicola
authors.initials: N
authors.lastname: Dalbeth
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jones
authors.forename: Douglas H N
authors.initials: DH
authors.lastname: White
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000428:Alcohol Drinking / Q000009:adverse effects* / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006073:Gout / Q000235:genetics*; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D008297:Male; D008875:Middle Aged; D009520:New Zealand / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D014527:Uric Acid / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C476844:LRP2BP protein, human; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D014527:Uric Acid