Abstract
BACKGROUND: Hyperphosphatemia has been associated with coronary artery calcification (CAC) mostly in chronic kidney dis-ease, but the association between phosphate levels within the normal phosphate range and CAC is unclear. Our objectives were to evaluate associations between phosphate levels and CAC among men and women from the general population and assess causality through Mendelian randomization. METHODS AND RESULTS: CAC, measured by electron-beam computed tomography, and serum phosphate levels were assessed in 1889 individuals from the RS (Rotterdam Study). Phenotypic associations were tested through linear models adjusted for age, body mass index, blood pressure, smoking, prevalent cardiovascular disease and diabetes, 25-hydroxyvitamin D, total calcium, C-reactive protein, glucose, and total cholesterol: high-density lipoprotein cholesterol ratio. Mendelian randomiza-tion was implemented through an allele score including 8 phosphate-related single-nucleotide polymorphisms. In phenotypic analyses, serum phosphate (per 1 SD) was associated with CAC with evidence for sex interaction (Pinteraction =0.003) (men β, 0.44 [95% CI, 0.30– 0.59]; P=3×10−9; n=878; women β, 0.24 [95% CI, 0.08– 0.40]; P=0.003; n=1011). Exclusion of hyperphos-phatemia, chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2) and prevalent cardiovascular disease yielded similar results. In Mendelian randomization analyses, instrumented phosphate was associated with CAC (total population β, 0.93 [95% CI: 0.07–1.79]; P=0.034; n=1693), even after exclusion of hyperphosphatemia, chronic kidney disease and prevalent cardiovascular disease (total population β, 1.23 [95% CI, 0.17– 2.28]; P=0.023; n=1224). CONCLUSIONS: Serum phosphate was associated with CAC in the general population with stronger effects in men. Mendelian randomization findings support a causal relation, also for serum phosphate and CAC in subjects without hyperphosphatemia, chronic kidney disease, and cardiovascular disease. Further research into underlying mechanisms of this association and sex differences is needed.
| Original language | English |
|---|---|
| Article number | e023024 |
| Journal | Journal of the American Heart Association |
| Volume | 11 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 2 Aug 2022 |
Bibliographical note
Sources of FundingThe generation and management of GWAS genotype data for the Rotterdam Study (RS‐I, RS‐II, RS‐III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. The GWAS data sets are supported by the Netherlands Organization of Scientific Research Investments (No. 175.010.2005.011, 911‐03‐012); the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center; the Research Institute for Diseases in the Elderly (014‐93‐015); and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research Netherlands Consortium for Healthy Aging, Project No. 050‐060‐810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Bosman is supported by a grant from Health~Holland (PhosphoNorm; LSHM18029).
Publisher Copyright: © 2022 The Authors.
