Abstract
Observational studies have shown that vitamin D binding protein (DBP) levels, a key determinant of 25-hydroxy-vitamin D (25OHD) levels, and 25OHD levels themselves both associate with risk of disease. If 25OHD levels have a causal influence on disease, and DBP lies in this causal pathway, then DBP levels should likewise be causally associated with disease. We undertook a Mendelian randomization study to determine whether DBP levels have causal effects on common calcemic and cardiometabolic disease. We measured DBP and 25OHD levels in 2,254 individuals, followed for up to 10 y, in the Canadian Multicentre Osteoporosis Study (CaMos). Using the single nucleotide polymorphism rs2282679 as an instrumental variable, we applied Mendelian randomization methods to determine the causal effect of DBP on calcemic (osteoporosis and hyperparathyroidism) and cardiometabolic diseases (hypertension, type 2 diabetes, coronary artery disease, and stroke) and related traits, first in CaMos and then in large-scale genome-wide association study consortia. The effect allele was associated with an age- and sex-adjusted decrease in DBP level of 27.4 mg/l (95% CI 24.7, 30.0; n = 2,254). DBP had a strong observational and causal association with 25OHD levels (p = 3.2 × 10(-19)). While DBP levels were observationally associated with calcium and body mass index (BMI), these associations were not supported by causal analyses. Despite well-powered sample sizes from consortia, there were no associations of rs2282679 with any other traits and diseases: fasting glucose (0.00 mmol/l [95% CI -0.01, 0.01]; p = 1.00; n = 46,186); fasting insulin (0.01 pmol/l [95% CI -0.00, 0.01,]; p = 0.22; n = 46,186); BMI (0.00 kg/m(2) [95% CI -0.01, 0.01]; p = 0.80; n = 127,587); bone mineral density (0.01 g/cm(2) [95% CI -0.01, 0.03]; p = 0.36; n = 32,961); mean arterial pressure (-0.06 mm Hg [95% CI -0.19, 0.07]); p = 0.36; n = 28,775); ischemic stroke (odds ratio [OR] = 1.00 [95% CI 0.97, 1.04]; p = 0.92; n = 12,389/62,004 cases/controls); coronary artery disease (OR = 1.02 [95% CI 0.99, 1.05]; p = 0.31; n = 22,233/64,762); or type 2 diabetes (OR = 1.01 [95% CI 0.97, 1.05]; p = 0.76; n = 9,580/53,810). DBP has no demonstrable causal effect on any of the diseases or traits investigated here, except 25OHD levels. It remains to be determined whether 25OHD has a causal effect on these outcomes independent of DBP. Please see later in the article for the Editors' Summary.
Highlights
Serum vitamin D levels are generally low in populations worldwide [1,2]
D binding protein (DBP) has no demonstrable causal effect on any of the diseases or traits investigated here, except 25-hydroxy-vitamin D (25OHD) levels. It remains to be determined whether 25OHD has a causal effect on these outcomes independent of DBP
We tested the relationships between rs2282679, DBP, and 25OHD in 2,254 Canadian Multicentre Osteoporosis Study (CaMos) participants; 69.5% were women, and 79.5% were of European descent
Summary
Serum vitamin D levels are generally low in populations worldwide [1,2]. Observational studies have implicated vitaminD-deficient states in several common diseases and related traits, including cardiovascular disease [3,4,5], type 2 diabetes [6,7], breast cancer [8], bladder cancer [9], colorectal cancer [10], chronic lung diseases such as asthma, bronchiectasis, and other lung infections [11,12,13,14]. Observational studies have shown associations between vitamin D deficiency (defined as serum 25-hydroxy-vitamin D [25OHD] level ,50 nmol/l) and a number of common diseases, it is not known whether these relationships are causal. One key determinant of 25OHD levels is vitamin D binding protein (DBP), a groupspecific component of serum globulin [22]. Observational studies have shown that vitamin D binding protein (DBP) levels, a key determinant of 25hydroxy-vitamin D (25OHD) levels, and 25OHD levels themselves both associate with risk of disease. We undertook a Mendelian randomization study to determine whether DBP levels have causal effects on common calcemic and cardiometabolic disease. Many people living in the US and Europe (in particular, elderly people, breastfed infants, people with dark skin, and obese individuals) have serum (circulating) 25hydroxy-vitamin D (25OHD) levels below 50 nmol/l, the threshold for vitamin D deficiency. Vitamin D is found naturally in oily fish and eggs, and is added to some other foods, including cereals and milk, but some people need to take vitamin D supplements to avoid vitamin D deficiency
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