Elsevier

Metabolism

Volume 54, Issue 11, November 2005, Pages 1435-1441
Metabolism

Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study

https://doi.org/10.1016/j.metabol.2005.05.007Get rights and content

Abstract

Serum uric acid levels are associated with hypertension, cardiovascular disease, and renal disease. Uric acid has been shown to be heritable; however, genome-wide linkage analyses have not been reported. Genome-wide multipoint variance components linkage analyses with 401 markers spaced at approximately 10 centimorgan (cM) were conducted on 1258 subjects of the Framingham Heart Study, using the average of two serum uric acid measurements obtained in examinations 1 and 2 around 1971 and 1979. Covariates in fully adjusted model included sex, age, body mass index (BMI), serum creatinine, alcohol consumption, diabetes, diuretic treatment, and triglycerides. To investigate possible pleiotropic effects between uric acid and covariates that may have a genetic component, bivariate linkage analyses of uric acid with BMI, triglycerides, and glucose were conducted at the uric acid linkage regions. The heritability of uric acid was 0.63. The highest multipoint log-of-the-odds (LOD) score was 3.3 at 50 cM on chromosome 15 for age-sex–adjusted uric acid, but decreased to 1.5 after multivariable adjustment. Additional evidence of linkage was seen on chromosomes 2 (LOD score 1.1 at 4 cM) and 8 (LOD score 1.7 at 6 cM) for multivariable-adjusted uric acid. Pleiotropic effects were only found between uric acid and glucose and BMI at chromosomes 8 and 15 linkage locations, respectively. We have identified several novel loci linked to uric acid. We found possible pleiotropic effects between uric acid and BMI and glucose. Further research is necessary to identify the genes involved in uric acid metabolism and their roles in hypertension, cardiovascular disease, and renal disease.

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

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      Previous studies on the relation between SUA and atherosclerosis have also identified gender differences in the risk of atherosclerosis associated with SUA.17,18 Studies have shown that blood uric acid level is a multifactorial trait that is strongly controlled by genes in addition to environmental factors,19 and there are significant differences in blood uric acid concentrations between men and women.20 In addition, studies have shown that the biologic effects of uric acid differ between men and women; there are many gender differences in the influence of uric acid on the developmental stage of carotid artery atherosclerosis.21,22

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    This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195).

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