Clinical research study
Nature Versus Nurture in Gout: A Twin Study

https://doi.org/10.1016/j.amjmed.2011.11.010Get rights and content

Abstract

Background

Gouty arthritis (gout) is the most common inflammatory arthritis in the United States and several other countries. Some rare forms of gout have a known genetic basis, but the relative importance of genetic factors on the risk for the lifetime prevalence of gout is not clear.

Methods

We performed a heritability analysis for hyperuricemia and gout among 514 unselected, all-male twin pairs who were a part of the National Heart, Lung, and Blood Institute twin study, a prospective observational cohort study. Statistical analyses were performed using structural equation models and maximum likelihood methods. The covariates used for adjustment in the structural equation models were identified using bivariate logistic regressions.

Results

The study population included 253 monozygotic (MZ) and 261 dizygotic (DZ) twin pairs, aged 48 (±3) years at baseline and followed for a mean of 34 years. The lifetime prevalence of gout did not differ between MZ and DZ twins. The concordance of hyperuricemia was 53% in MZ and 24% in DZ twin pairs (P <.001). Models that quantified the relative contribution of genetic and environmental factors on phenotypic variance showed that individual variability in gout was substantially influenced by environmental factors shared between co-twins and not by genetic factors. In contrast, individual differences in hyperuricemia were influenced significantly by genetic factors.

Conclusion

Hyperuricemia is a genetic trait. Outside the context of rare genetic disorders, risk for gout is determined by the environment. This has implications for prevention and treatment approaches.

Section snippets

Materials and Methods

All participants provided informed consent, and the original data collection was approved by institutional review boards of the participating sites. We used the data from the National Heart, Lung, and Blood Institute (NHLBI) twin study (NCT 00005124), presently housed at SRI International (Menlo Park, CA). The history and methodology of this cohort have been described.20, 21, 22 The NHLBI twin study was initiated in 1955 by the National Academy of Sciences/National Research Council, which

Results

The study subjects were twins enrolled in the NHLBI twin study (NCT 00005124). Table 1 provides the descriptive measures of the study cohort; 253 MZ and 261 DZ twin pairs were included. The baseline age range was 42 to 55 years. These individuals had been followed for a mean of 34 years. The last examination included 174 individuals (age range 76-86 years). The lifetime prevalence of gout (ie, prevalence anytime during observation in the study) did not differ significantly between MZ and DZ

Discussion

Our results confirm the previously reported strong heritability of hyperuricemia but suggest that environmental factors are more important in the phenotypic expression of gout. The difference in heritability between hyperuricemia and gout is not entirely surprising. Hyperuricemia, a critical predisposing factor for gout, is invariably present in gout but not vice versa. Vitart et al6 reported that only 10% of those with hyperuricemia eventually develop gout. The Normative Aging Study suggests

Conclusions

Our analysis of data collected on 514 male twin pairs through the NHLBI twin study suggests that the phenotype of gout is determined primarily by environmental factors. This has implications for prevention and treatment of the disease. Future larger twin studies must be performed to assess whether there is a detectable heritable component to gout and whether our observations are valid among women.

Acknowledgements

This work was supported by grant HL51429 from the National Heart, Lung, and Blood Institute. We acknowledge Dorit Carmelli, PhD (formerly of SRI International), Terry Reed, PhD (Indiana University Medical Center), Philip A. Wolf, MD (Boston University Medical Center) and Bruce L. Miller, MD (Harbor/UCLA Medical Center) for their rigor in overseeing data collection at their research sites.

References (38)

  • H.K. Choi et al.

    Pathogenesis of gout

    Ann Intern Med

    (2005)
  • T.R. Mikuls et al.

    New insights into gout epidemiology

    Curr Opin Rheumatol

    (2006)
  • V. Vitart et al.

    SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout

    Nat Genet

    (2008)
  • B.A. Charles et al.

    A genome-wide association study of serum uric acid in African Americans

    BMC Med Genomics

    (2011)
  • N. Cummings et al.

    Genome-wide scan identifies a quantitative trait locus at 4p15.3 for serum urate

    Eur J Hum Genet

    (2010)
  • D. Dinour et al.

    Homozygous SLC2A9 mutations cause severe renal hypouricemia

    J Am Soc Nephrol

    (2010)
  • A. Doring et al.

    SLC2A9 influences uric acid concentrations with pronounced sex-specific effects

    Nat Genet

    (2008)
  • M. Kolz et al.

    Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations

    PLoS Genet

    (2009)
  • A. So et al.

    Uric acid transport and disease

    J Clin Invest

    (2010)
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    Funding: This study was supported by NHLBI grant HL51429.

    Conflict of Interest: None.

    Authorship: All authors had access to the data and played a role in writing this manuscript.

    Clinical trials.gov: NCT 00005124.

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