Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study☆
Introduction
Serum uric acid levels are associated with hypertension, cardiovascular disease, and renal disease [1], [2], [3], [4], [5], [6]. However, it is debatable whether uric acid has a direct role in the pathogenesis of these diseases or acts through other risk factors [7], [8].
Serum uric acid levels are heritable, with estimates ranging from 0.25 to 0.73 [9], [10], [11], [12], [13], [14]. Results from segregation analyses are inconsistent, and it is uncertain if there is a major gene that determines levels of serum uric acid. Early studies suggested a major gene effect [15], [16], but more recent data support a multifactorial inheritance from multiple major genes and environmental factors [9], [11], [13], [14]. Suggestive linkage to serum uric acid levels has been demonstrated on chromosome 2, near a locus for the metabolic syndrome [17]. However, genome-wide linkage analyses have not been reported for uric acid. A further understanding of the genes involved in uric acid metabolism in the general population may improve the understanding of the relationship between uric acid and hypertension, cardiovascular disease, and renal disease and, subsequently, better elucidate some of the mechanisms involved in these diseases. Thus, we conducted heritability and genome-wide linkage analyses for uric acid in the Framingham Heart Study (FHS), a population-based sample.
Section snippets
Subjects
The study subjects are members of the offspring cohort in the FHS. The selection criteria and study design of the FHS have been described in detail previously [18], [19]. The study began in 1948 with the enrollment of 5209 participants, collectively referred to as the original cohort, from Framingham, Mass. Starting in 1971, 5124 individuals, adult children of the original cohort, and spouses of these adult children, referred to as the offspring cohort, were recruited. The members of the
Baseline characteristics
Characteristics of the 1258 offspring cohort subjects used in the analysis are presented in Table 1. The mean ages at the two examinations were 33 years (range, 10-64 years) and 41 years (range, 17-72 years), respectively. The mean serum uric acid levels at the two examinations were 5.6 mg/dL (range, 2.2-12.4 mg/dL) and 5.1 mg/dL (range, 1.2-11.8 mg/dL), respectively. The mean of the average of the two serum uric acid level measurements was 5.4 mg/dL (range, 2.1-10.3 mg/dL); this variable was
Discussion
We have found evidence for linkage to uric acid, with significant evidence for linkage on chromosome 15 for age-sex–adjusted uric acid according to the guidelines for interpreting linkage results [28]. Suggestive evidence for linkage was also found on chromosomes 2 and 8 for the age-sex–adjusted model. For the multivariable-adjusted model, the linkage signals at these loci weakened but did not completely disappear. Our report also confirms prior studies and demonstrates that serum uric acid is
References (36)
- et al.
Multipoint quantitative-trait linkage analysis in general pedigrees
Am J Hum Genet
(1998) Markov chain Monte Carlo segregation and linkage analysis for oligogenic models
Am J Hum Genet
(1997)- et al.
Effect of insulin on renal sodium and uric acid handling in essential hypertension
Am J Hypertens
(1996) - et al.
Serum uric acid in relation to age and physique in health and in coronary heart disease
Ann Intern Med
(1951) - et al.
Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. The Normative Aging Study
Am J Epidemiol
(1995) - et al.
Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases
Epidemiology
(1999) - et al.
Serum uric acid independently predicts mortality in patients with significant, angiographically defined coronary disease
Am J Nephrol
(2005) - et al.
Serum uric acid and renal prognosis in patients with IgA nephropathy
Nephron
(2001) - et al.
Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study
Hypertension
(2000) - et al.
Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study
Ann Intern Med
(1999)
Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?
Hypertension
The Clinical Lipid Research Clinic Family Study: familial determinants of plasma uric acid
Hum Genet
Inheritance and alcohol as factors influencing plasma uric acid levels
Acta Genet Med Gemellol (Roma)
Family resemblance for serum uric acid in a Jerusalem sample of families
Hum Genet
Heterogeneity in the familial aggregation of fasting serum uric acid level in five North American populations: the Lipid Research Clinics Family Study
Am J Med Genet
Commingling and segregation analysis of serum uric acid in five North American populations: the Lipid Research Clinics Family Study
Hum Genet
Segregation analysis of serum uric acid in the NHLBI Family Heart Study
Hum Genet
The genetics of gout and hyperuricemia—an analysis of nineteen families
J Clin Invest
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This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195).