Genetic Variants and Associations of 25-Hydroxyvitamin D Concentrations With Major Clinical Outcomes

JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 11/2012; 308(18):1898-1905. DOI: 10.1001/jama.2012.17304
Source: PubMed


CONTEXT Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. OBJECTIVE To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies. MAIN OUTCOME MEASURE Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up. RESULTS Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism. CONCLUSION Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

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Available from: Cassianne Robinson-Cohen, Jan 15, 2014
    • "The African American population has an increased activity of 25-hydroxyvitamin D-1-α-hydroxylase (CYP27B1), either driven by increased parathormone activity or by racial differences in CYP27B1 affinity for substrate, which results into lower serum 25-OHD levels.[3738] Racial difference in variable vitamin D receptor affinity for vitamin D metabolites may explain similar variation in the prevalence of low vitamin D across other races with the observation of at least one vitamin D receptor polymorphism (FokI) which is known to differ by race and ethnicity.[394041] "
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    ABSTRACT: Background:Fatigue is a common presenting complaint of patients in the primary care offices. Low levels of vitamin D have been associated with fatigue in cancer patients. Normalization of vitamin D level improves their fatigue. Whether low vitamin D plays a role in fatigue in medically stable patients is not known.Aims:This prospective non-randomized therapeutic study observed the prevalence of low vitamin D in fatigue and the effect of normalization of vitamin D on fatigue.Material and Methods:One hundred and seventy four adult patients, who presented in our primary care office with fatigue and stable chronic medical conditions,completed fatigue assessment questionnaires. Patients with low vitamin D levels received ergocalciferol therapy for 5 weeks. Scores of pre- and post-treatment fatigue assessment questionnaires were compared.Results:Prevalence of low vitamin D was 77.2% in patients who presented with fatigue. After normalization of vitamin D levels fatigue symptom scores improved significantly (P < 0.001) in all five subscale categories of fatigue assessment questionnaires.Conclusion:The prevalence of low vitamin D is high in patients who present with fatigue and stable chronic medical conditions, if any. Normalization of vitamin D levels with ergocalciferol therapy significantly improves the severity of their fatigue symptoms.
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    • "Rathored et al have also found that the patients with ff genotypes in rs2228570 were at high risk of multidrug-resistant tuberculosis with smear-positive disease.56 In a multicenter clinical trial, Levin et al recently investigated the relationship of common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and VDR with low 25(OH)D levels, and found some minor alleles at rs7968585 and rs7968585 within the VDR gene that were related to low 25(OH)D3.57 The results of these studies suggest that VDR gene polymorphisms can be important for the susceptibility of inflammatory diseases, which may be due to the lower 25(OH)D3 status affected by VDR gene polymorphisms. "
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    ABSTRACT: Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role in the pathogenesis of the diseases. In this article, we review recent epidemiological and interventional studies of vitamin D in various inflammatory diseases. The potential mechanisms of vitamin D in regulating immune/inflammatory responses in inflammatory diseases are also discussed.
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    • "The rs4588 and rs7041 SNPs were associated with 25(OH)D levels in Hispanics and African Americans. Combinations of these alleles appear to alter DBP concentration, the affinity for 25(OH)D, and 25(OH) levels [17, 18]. In a cross-section study, Santos et al. found that the AA genotype of rs4588 and TT genotypic of rs7044 and CT-AT/AT-AT (GC1f-2/2-2) were associated with lower 25(OH)D levels in healthy girl [19]. "
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    ABSTRACT: There is a high prevalence of vitamin D deficiency worldwide, but how to define vitamin D deficiency is controversial. Currently, the plasma concentration of total 25-hydroxyvitamin D [25(OH)D] is considered an indicator of vitamin D status. The free hormone hypothesis states that protein-bound hormones are inactive while unbound hormones are free to exert biological activity. The majority of circulating 25(OH)D and 1,25(OH)2D is tightly bound to vitamin D binding protein (DBP), 10-15% is bound to albumin, and less than 1% of circulating vitamin D exists in an unbound form. While DBP is relatively stable in most healthy populations, a recent study showed that there are gene polymorphisms associated with race and ethnicity that could alter DBP levels and binding affinity. Furthermore, in some clinical situations, total vitamin D levels are altered and knowing whether DBP is also altered may have treatment implications. The aim of this review is to assess DBP concentration in different physiological and pathophysiological conditions. We suggest that DBP should be considered in the interpretation of 25(OH)D levels.
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