Abstract
Background: Serum uric acid (SUA) has gradually been recognized as a potential risk factor for cardiovascular disease (CVD). However, whether the relationship is causal remains controversial. Methods: We employed two methods to demonstrate the importance of SUA in CVD development. First, we examined the onset sequence of hyperuricemia in relation to five cardiometabolic (CM) diseases. Second, we conducted a Mendelian randomization (MR) study to causally infer the relationship between SUA and CVD. The information collected from the Cardiovascular Disease Risk Factors Two-Township Study (CVDFACTS) and Taiwan Biobank was used, respectively. Results: The onset sequence study showed that hyperuricemia and hypo-alpha-lipoproteinemia (low HDL-C) have earlier ages of onset than other CM diseases. For the MR analysis, the high weighted genetic risk score (WGRS) group had a significantly increased cumulative lifetime risk of CVD compared with the low WGRS group (OR = 1.62, (1.17−2.23), P = 0.003). Sensitivity analysis using the WGRS derived from other populations’ SUA-influential SNPs revealed similar results. Conclusions: We showed that hyperuricemia is an earlier-onset metabolic disorder than hypertension, hypertriglyceridemia, and diabetes mellitus, indicating that high SUA plays an upstream role in CM development. Moreover, our MR study results support the idea that hyperuricemia may play a causal role in CVD development. Further validation studies in more populations are needed.
Highlights
Cardiovascular disease (CVD) is one of the leading causes of death worldwide
Evidence suggests that uric acid (UA) has a complex participatory role in hypertension and atherosclerosis pathogenesis, whether the relationship between Serum uric acid (SUA) and cardiovascular disease (CVD) is causal remains controversial because no clinical trials have been conducted [4,5]
A recently published SUA-genome-wide association study (GWAS) of 12,281 Chinese participants demonstrated that among the 30 satisfactorily replicated SUA-single nucleotide polymorphisms (SNPs) identified in European populations, nine SNPs on six genes are replicated in the Chinese population [18]
Summary
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. An estimated 17.5 million people die from CVDs annually, which accounts for 31% of global deaths [1]. We have previously presented the cohort in the Cardiovascular Disease Risk Factors Two-Township Study (CVDFACTS) to demonstrate the onset sequences of the five components [10]. Conducting an MR study on the relationship between SUA and CVD in such a metabolic disease-prone population is warranted. In this MR study, we first determined the Han Chinese-specific SUA-associated SNPs through two-stage GWAS from the Taiwan Han Chinese Biobank (TWB). These SNPs were subsequently used to construct, through linear combination, a weighted genetic risk score (WGRS) as the SUA long-term exposure dosage for evaluating the causality between SUA and CVD. We conducted a sensitivity analysis to validate our findings, in which we employed the WGRS constructed from SNPs reported in the literature (WGRSL)
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