The Causal Effect of Vitamin D Binding Protein (DBP) Levels on Calcemic and Cardiometabolic Diseases: A Mendelian Randomization Study

Leong, Aaron; Rehman, Waheed; Dastani, Zari; Greenwood, Celia M.T.; Timpson, Nicholas J.; Langsetmo, Lisa; Berger, Claudie; Fu, Lei; Wong, Betty; Malik, Suneil; Malik, Rainer; Hanley, David A.; Cole, David E. C.; Goltzman, David; Richards, J. Brent

doi:10.1371/journal.pmed.1001751

Cited by 64 publications

(52 citation statements)

References 71 publications

(78 reference statements)

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“…MR analysis published by our group studying the association of vitamin D-binding protein, a key determinant of 25OHD levels, with the risk of CAD. 52 Using the single polymorphism rs2282679 near the GC gene as an instrumental variable (whose effect allele was associated with an age-and sex-adjusted decrease in vitamin D-binding protein level of 27.4 mg/L), this study investigated the relationship of vitamin D-binding protein with multiple cardiometabolic outcomes in the CARDIoGRAM consortium and found no association (OR, 1.02; 95% CI, 0.99-1.05; P=0.31). Using an approach related to MR, Jorde et al 61 examined causal associations of 25OHD with the risk of CAD on 9528 subjects, but could not establish or exclude any causal relationship, possibly because of their relatively small sample size.…”

Section: Discussionmentioning

confidence: 99%

“…51 Although it has been argued that vitamin D-binding protein, encoded by GC, can act independently of vitamin D to produce clinical phenotypes, this does not seem to be the case for CAD. 52 For rs12785878 (DHCR7), a large MR study on vitamin D levels and blood pressure showed a small but significant association with hypertension 53 (OR, 0.92; 95% confidence interval [CI], 0.87-0.97; P=0.001), a major risk factor for CAD. 54 By querying the results for rs12785878 in the ICBP consortium, 38 a large GWAS meta-analysis of 200 000 subjects of European descent, we found that this SNP was not associated with systolic or diastolic blood pressure (P=0.703 and P=0.121, respectively).…”

Section: Linkage Disequilibrium (Ld) and Pleiotropy Assessmentmentioning

confidence: 99%

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Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease

Manousaki

Mokry

Ross

et al. 2016

Circ Cardiovasc Genet

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104

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Given this uncertainty, clinical practice guidelines do not support vitamin D supplementation for CAD risk reduction andBackground-Observational studies support a possible association between decreased vitamin D levels and risk of coronary artery disease (CAD); however, it remains unclear whether this relationship is causal. We aimed to evaluate whether genetically lowered vitamin D levels influence the risk of CAD using a Mendelian randomization approach. Methods and Results-In this 2-stage Mendelian randomization study, we first identified single-nucleotide polymorphisms associated with 25-hydroxyvitamin D (25OHD) levels in the SUNLIGHT consortium (n=33 996), then tested them for possible violation of Mendelian randomization assumptions. A count of risk alleles was tested for association with 25OHD levels in a separate cohort (n=2347). Alleles were weighted by their relative effect on 25OHD and tested for their combined effect on CAD in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study (22 233 cases/64 762 controls). Four single-nucleotide polymorphisms were identified to be associated with 25OHD levels, all in or near genes implicated in 25OHD synthesis, transport or metabolism. A count of these risk alleles was strongly associated with 25OHD (n=2347, F-test statistic=49.7, P=2×10 −12). None of the single-nucleotide polymorphisms associated with 25OHD levels were associated with CAD (all P values >0.6). The Mendelian randomization odds ratio (OR) for CAD was 0.99 (95% confidence interval, 0.84-1.17; P=0.93; I 2 =0) per SD decrease in log-transformed 25OHD levels. These results persisted after sensitivity analyses for population stratification and pleiotropy. Conclusions-Genetically lowered 25OHD levels were not associated with increased risk of CAD in a large, well-powered study, suggesting that previous associations between circulating 25OHD levels and CAD are possibly confounded or due to reverse causation. (Circ Cardiovasc

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Section: Discussionmentioning

confidence: 99%

Section: Linkage Disequilibrium (Ld) and Pleiotropy Assessmentmentioning

confidence: 99%

Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease

Manousaki

Mokry

Ross

et al. 2016

Circ Cardiovasc Genet

Self Cite

104

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“…A MR analysis was used by adopting a two-stage least-squares (2SLS) (Leong et al, 2014) estimator that regressed each outcome against predicted values of 25(OH)D level per composite GC SNP score using the command “ivreg2” in the Stata SE13.1 software package. This method allows for the estimation of the unconfounded association of genetically predicted concentrations of 25(OH)D with cognition.…”

Section: Methodsmentioning

confidence: 99%

State- and trait-dependent associations of vitamin-D with brain function during aging

Kueider‐Paisley

Tanaka

et al. 2016

Neurobiology of Aging

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We investigated whether: 1) serum levels of 25-hydroxyvitamin D [25(OH)D]; and 2) single nucleotide polymorphisms (SNPs) in the group-specific component (GC) gene regulating serum 25(OH)D levels are associated with cognition in older individuals; and 3) whether causal relationships exist between 25(OH)D and cognition during aging. Data from 1207 participants in the Baltimore Longitudinal Study of Aging were analyzed (mean follow-up 10.4 years) to test associations between serum 25(OH)D and cognition. Two GC SNPs were used to derive a composite genetic risk score associated with lower 25(OH)D concentrations. Lower serum 25(OH)D and higher GC composite scores were associated with lower executive function at baseline. Mendelian randomization analyses suggested a causal relationship between lower serum 25(OH)D and poorer executive function and psychomotor speed. The SNP score was also associated with lower performance on measures of visuospatial abilities at baseline but with attenuated declines over time in visuospatial abilities and executive function. Widespread associations between vitamin-D regulatory SNPs and cognition suggest a mechanistic basis for the relationship between serum 25(OH)D levels and cognition during aging.

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“…The altered expression of DBP has also been observed in other autoimmune diseases with underlying vitamin D (un)related working mechanisms such as rheumatoid arthritis and [69] and granulomatosis with polyangiitis [26]. However in another Mendelian randomization study, DBP had no demonstrable causal effect on calcemic (osteoporosis and hyperparathyroidism) and cardiometabolic diseases (hypertension, type 2 diabetes, coronary artery disease and stroke) [70].…”

Section: Vitamin D Binding Protein: What's In a Name?mentioning

confidence: 95%

Behind the scenes of vitamin D binding protein: More than vitamin D binding

Delanghe

Speeckaert

2015

Best Practice & Research Clinical Endocrinology & Metab

148

124

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The Causal Effect of Vitamin D Binding Protein (DBP) Levels on Calcemic and Cardiometabolic Diseases: A Mendelian Randomization Study

Cited by 64 publications

References 71 publications

Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease

Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease

State- and trait-dependent associations of vitamin-D with brain function during aging

Behind the scenes of vitamin D binding protein: More than vitamin D binding

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