ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2224

Interactions between Serum Urate-Associated Genetic Variants and Sex on Gout Risk in a European Population

Ravi K. Narang1, Ruth Topless2, Murray Cadzow3, Gregory Gamble4, Lisa K. Stamp5, Tony R. Merriman3 and Nicola Dalbeth6, 1Bone and Joint Research Group, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand, 2Department of Biochemistry, University of Otago, Dunedin, New Zealand, 3University of Otago, Dunedin, New Zealand, 4Department of Medicine, University of Auckland, Auckland, New Zealand, 5University of Otago, Christchurch, New Zealand, 6Department of Medicine, Faculty of Medical and Health Sciences., University of Auckland, Auckland, New Zealand

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords:

Session Information

Date: Tuesday, October 23, 2018

Title: Metabolic and Crystal Arthropathies – Basic and Clinical Science Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Sex-specific differences in the effect size of genetic variants on serum urate levels have been described, with SLC2A9 variants having a greater influence on serum urate in women and ABCG2 variants exerting a greater effect in men.  However, it is unclear whether serum urate-associated genetic variants display sex-specific differences in gout risk.  The aim of this study was to systematically examine whether serum urate-associated genetic variants differ in their influence on gout risk in men and women. 

Methods: This research was conducted using the UK Biobank Resource.  Participants of European ethnicity, aged 40-69 years, and with genome-wide genotypes were included.  Exclusions were: self-reported sex mismatch with genetic sex, genotyping quality control failure, and related individuals.  Gout was defined using a validated definition (self-report of gout or urate-lowering therapy use).  The thirty single nucleotide polymorphisms (SNPs) associated with serum urate reported by Köttgen et al (Nature Genetics 2013) were tested for their association with gout in men and women.  Gene-sex interactions on gout risk were analysed using logistic regression models that included an interaction term.  Age, body mass index, renal failure and diuretic use were included as variables in all models.  A further sensitivity analysis was performed by excluding pre-menopausal women.  Data are reported at experiment-wide significance (P<0.0017).

Results: Data were available for 359,876 participants, including 7,342 gout cases (2.0%).  Gout was present in 6768 (4.1%) men and 574 (0.3%) women; odds ratio (95% CI) for men 13.42 (12.32-14.62) compared to women.  In the group overall, association of gout at experiment-wide significance was observed for 22 of the 30 serum urate-associated SNPs tested.  In men, experiment-wide association was observed for the same 22 SNPs, and in women for four of the 30 SNPs.  Evidence for gene-sex interaction was observed for ABCG2 (rs2231142) and PDZK1 (rs1471633), with the interaction at PDZK1 driven by an absence of effect in women and at ABCG2 by an amplified effect in men (Table).  Similar findings were observed in the sensitivity analysis when excluding pre-menopausal women.  For the other SNPs tested, including SLC2A9 (Table), no significant gene-sex interactions were observed.

Conclusion: In a European population, ABCG2 and PDZK1 gene-sex interactions exist for gout risk, with serum urate-raising alleles exerting a greater influence on gout risk in men than in women.  In contrast, other serum urate-associated variants including SLC2A9, do not demonstrate significant gene-sex interactions for gout risk.  

 

Table: Association and interaction between selected serum urate-associated genetic variants and sex for gout risk according to risk allele presence.

Gene

SNP

Serum urate raising allele

Women

Men

Gene-sex interaction*

Risk allele absent

Referent OR

Risk allele present

OR (95% CI)

Risk allele absent

OR (95% CI)

Risk allele present

OR (95% CI)

P

ABCG2

rs2231142

T

1

1.62 (1.35-1.94)

11.99 (10.81-13.30)

28.65 (25.73-31.90)

4.59×10-5

PDZK1

rs1471633

A

1

0.92 (0.77-1.10)

10.54 (9.00-12.34)

13.61 (11.69-15.85)

3.67×10-4

SLC2A9

rs12498742

A

1

4.13 (2.05-8.30)

18.09 (8.85-36.98)

55.62 (27.78-111.37)

0.42

Abbreviations: CI, confidence interval; OR, odds ratio. * Adjusted for body mass index, age, renal failure, diuretic use

Disclosure: R. K. Narang, None; R. Topless, None; M. Cadzow, None; G. Gamble, None; L. K. Stamp, Amgen Inc., 8; T. R. Merriman, None; N. Dalbeth, Horizon, 5,Kowa, 5,Amgen Inc., 2,AstraZeneca/Ironwood, 2,AbbVie Inc., 8,Pfizer, Inc., 8,Janssen, 8.

To cite this abstract in AMA style:

Narang RK, Topless R, Cadzow M, Gamble G, Stamp LK, Merriman TR, Dalbeth N. Interactions between Serum Urate-Associated Genetic Variants and Sex on Gout Risk in a European Population [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/interactions-between-serum-urate-associated-genetic-variants-and-sex-on-gout-risk-in-a-european-population/. Accessed .

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