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Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout

  • Original Article - Genes and Disease
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Abstract

The Arg64 allele of variant rs4994 (Trp64Arg) in the β3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Māori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman®. Māori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (β = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.

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Acknowledgments

This work was supported by the Health Research Council of New Zealand, Arthritis New Zealand, New Zealand Lottery Health and the University of Otago. The authors would like to thank Jill Drake (Canterbury District Health Board), Roddi Laurence, Chris Franklin, Meaghen House (all University of Auckland) and Gabrielle Sexton (University of Otago) for recruitment. We also thank Ria Akuhata and Nancy Aupouri of NPHCT for recruitment, coordinated by Dr. Jennie Harré Hindmarsh. The Atherosclerosis Risk in Communities and Framingham Heart study analyses (Project #834) were approved by the relevant Database of Genotype and Phenotype (dbGaP; www.ncbi.nim.nih/gov/dbgap) Data Access Committees. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant No. UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Framingham Heart Study and the Framingham SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University. The Framingham SHARe data used for the analyses described in this manuscript were obtained through dbGaP. This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or the NHLBI.

Funding

This study was funded by Grant 11/1075 from the Health Research Council of New Zealand.

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Authors and Affiliations

  1. Department of Biochemistry, University of Otago, Dunedin, New Zealand

    Tahzeeb Fatima, Sara Altaf, Amanda Phipps-Green, Ruth Topless, Tanya J. Flynn & Tony R. Merriman

  2. Department of Medicine, University of Otago, Christchurch, New Zealand

    Lisa K. Stamp

  3. Department of Medicine, University of Auckland, Auckland, New Zealand

    Nicola Dalbeth

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  1. Tahzeeb Fatima
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Correspondence to Tony R. Merriman.

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Fatima, T., Altaf, S., Phipps-Green, A. et al. Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout. Rheumatol Int 36, 255–261 (2016). https://doi.org/10.1007/s00296-015-3370-6

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