Race and Vitamin D Binding Protein Gene Polymorphisms Modify the Association of 25-Hydroxyvitamin D and Incident Heart Failure: The ARIC (Atherosclerosis Risk in Communities) Study

Abstract

Objectives: This study sought to determine if low serum 25-hydroxyvitamin D (25[OH]D) is associated with incident heart failure (HF) and if the association is: 1) partly mediated by traditional cardiovascular risk factors; 2) stronger among whites than blacks; and 3) stronger among those genetically predisposed to having high levels of vitamin D binding protein (DBP).

Background: Suboptimal 25(OH)D is a potential cardiovascular risk factor.

Methods: A total of 12,215 ARIC (Atherosclerosis Risk in Communities) study participants free of HF at baseline (1990 to 1992; median age, 56; 24% black) were followed through 2010. Total serum 25(OH)D was measured at baseline using liquid chromatography-mass spectrometry. Incident HF events were identified by a hospital discharge code of ICD9-428 and parallel International Classification of Diseases codes for HF deaths.

Results: During 21 years of follow-up, 1,799 incident HF events accrued. The association between 25(OH)D and HF varied by race (p-interaction = 0.02). Among whites, risk was 2-fold higher for those in the lowest (≤17 ng/ml) versus highest (≥31 ng/ml) quintile of 25(OH)D. The association was attenuated but remained significant with covariate adjustment. In blacks there was no overall association. In both races, those with low 25(OH)D and the rs7041 G allele, which predisposes to high DBP, were at greater risk (p-interaction = 0.01).

Conclusions: Low serum 25(OH)D was independently associated with incident HF among whites, but not among blacks. However, in both races, low 25(OH)D was associated with HF risk among those genetically predisposed to high DBP. These findings provide novel insight into metabolic differences that may underlie racial variation in the association between 25(OH)D and cardiovascular risk.

Keywords: ARIC; heart failure; race; vitamin D; vitamin D binding protein.

Figure 1

Association of serum 25(OH)D with risk of incident HF: The ARIC Study 1990-2010. Biomarkers modeled as restricted cubic splines with knots at the 5^th, 27.5^th, 50^th, 72.5^th and 95^th percentiles, and are adjusted for age and sex.

Figure 1

Association of serum 25(OH)D with risk of incident HF: The ARIC Study 1990-2010. Biomarkers modeled as restricted cubic splines with knots at the 5^th, 27.5^th, 50^th, 72.5^th and 95^th percentiles, and are adjusted for age and sex.

Figure 2

Adjusted* hazard ratios (95% confidence intervals) of baseline serum 25(OH)D with incident heart failure stratified by rs7041, the ARIC Study 1990-2010. * Adjusted for age, sex, and race. Participants with the GG genotype and the highest quintile of vitamin D are the reference for all comparisons. P-interaction = 0.01 for rs7401 and 25(OH)D quintiles on HF risk.