Common genetic determinants of vitamin D insufficiency: a genome-wide association study

Wang, Thomas J.; Zhang, Feng; Richards, J. Brent; Kestenbaum, Bryan; Meurs, Joyce B. J. van; Berry, Diane J.; Kiel, Douglas P.; Streeten, Elizabeth A.; Ohlsson, Claes; Koller, Daniel L.; Peltonen, Leena; Cooper, Jason D.; O’Reilly, Paul F.; Houston, Denise K.; Glazer, Nicole L.; Vandenput, Liesbeth; Peacock, Munro; Shi, Julia; Rivadeneira, Fernando; McCarthy, Mark I.; Pouta, A; Boer, Ian H. de; Mangino, Massimo; Kato, Bernet; Smyth, Deborah J.; Booth, Sarah L.; Jacques, Paul F.; Burke, Greg; Goodarzi, Mark O.; Cheung, Ching‐Lung; Wolf, Myles; Rice, Kenneth; Goltzman, David; Hidiroglou, Nick; Ladouceur, Martin; Wareham, Nicholas J.; Hocking, Lynne J.; Hart, Deborah; Arden, N K; Cooper, Cyrus; Malik, Suneil; Fraser, William D.; Hartikainen, Anna Liisa; Zhai, Guangju; Macdonald, Helen; Forouhi, Nita G.; Loos, Ruth J.F.; Reid, David M.; Hakim, Alan J.; Dennison, Elaine; Liu, Yongmei; Power, Chris; Stevens, Helen; Jaana, Laitinen; Vasan, Ramachandran S.; Soranzo, Nicole; Bojunga, Jörg; Psaty, Bruce M.; Lorentzon, Mattias; Foroud, Tatiana; Harris, Tamara B.; Hofman, Albert; Jansson, John Olov; Cauley, Jane A.; Uitterlinden, André G.; Gibson, Quince; Järvelin, Marjo Riitta; Karasik, David; Siscovick, David S.; Econs, Michael J.; Kritchevsky, Stephen B.; Florez, José C.; Todd, John A.; Dupuis, Josée; Hyppönen, Elina; Spector, Timothy D.

doi:10.1016/s0140-6736(10)60588-0

Cited by 1,387 publications

(1,333 citation statements)

References 33 publications

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“…rs4588 in GC , rs10741657 in CYP2R1 and rs6013897 in CYP24A1 have been used in genetic instruments for 25OHD in MR studies before. rs4423214 near DHCR7 is in perfect LD with rs12785878, identified in the original SUNLIGHT consortium 25OHD GWAS 22. Finally, rs116970203 near CYP2R1 is a low frequency variant identified in the most recent GWAS of 25OHD and has been shown to act independently of rs10741657 23…”

Section: Methodsmentioning

confidence: 88%

“…Common genetic variants have been identified in Genome Wide Association Studies (GWAS)21, 22 of 25OHD, only variants that passed a genome wide association threshold ( p < 5 × 10 −8 ) and had been replicated were selected. These genetic proxies or instruments are located in or near four 25OHD related genes: Group‐specific component ( GC ), cytochrome P450 family 2, subfamily R, polypeptide 1 ( CYP2R1 ), 7‐dehydrocholesterol reductase ( DHCR7 ) and cytochrome P450, family 24, polypeptide 1 ( CYP24A1 ).…”

Section: Methodsmentioning

confidence: 99%

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Assessing the causal association between 25‐hydroxyvitamin D and the risk of oral and oropharyngeal cancer using Mendelian randomization

Dudding

Johansson

Thomas

et al. 2018

Intl Journal of Cancer

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Circulating 25‐hydroxyvitamin D (25OHD) is an appealing potential intervention for cancer risk and has been associated with oral and oropharyngeal cancer risk but evidence is inconsistent. The availability of genetic variants, uncorrelated with known confounders, but predictive of 25OHD and genetic data in a large oral and oropharyngeal cancer collaboration aids causal inference when assessing this association. A total of 5,133 oral and oropharyngeal cancer cases and 5,984 controls with genetic data were included in the study. Participants were based in Europe, North America and South America and were part of the Genetic Associations and Mechanisms in Oncology (GAME‐ON) Network. Five genetic variants reliably associated with circulating 25OHD were used to create a relative genetic measure of 25OHD. In the absence of measured 25OHD, two‐sample Mendelian randomization using individual level outcome data were used to estimate causal odds ratios (OR) for cancer case status per standard deviation increase in log25OHD. Analyses were replicated in an independent population‐based cohort (UK Biobank). In the GAME‐ON study, there was little evidence of a causal association between circulating 25OHD and oral cancer (OR = 0.86 [0.68;1.09], p = 0.22), oropharyngeal cancer (OR = 1.28 [0.72;2.26], p = 0.40) or when sites were combined (OR = 1.01 [0.74;1.40], p = 0.93). Replication in UK Biobank and pooled estimates produced similar results. Our study suggests that a clinically relevant protective effect of 25OHD on oral and oropharyngeal cancer risk is unlikely and supplementation of the general population with 25OHD is unlikely to be beneficial in preventing these cancers.

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Section: Methodsmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Assessing the causal association between 25‐hydroxyvitamin D and the risk of oral and oropharyngeal cancer using Mendelian randomization

Dudding

Johansson

Thomas

et al. 2018

Intl Journal of Cancer

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“…Recently, the result of a large genome wide association study on 33,996 individuals demonstrated the association of variants at three loci with lower 25-OH vitamin D concentrations [23]. However, as pointed out in an accompanying editorial, the "battle" against vitamin D deficiency is not likely to be affected by these findings [24].…”

Section: Discussionmentioning

confidence: 99%

Relationship between body mass index and serum 25-hydroxyvitamin D stronger among Caucasians than African Americans in NHANES adults 2001-2006

Arab¹,

Adams²,

Kim³

et al. 2012

OJEpi

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“…Recent advances in genetic testing have permitted, via genome-wide association studies (GWAS), the identification of various single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in vitamin D synthesis, transport and metabolism, that are associated with circulating levels of 25(OH)D (75,76). Genes included in the results of the GWAS were 7-dehydrocholesterol reductase (DHCR7), CYP2R1, 1,25-dihydroxyvitamin D-24-hydroxylase (CYP24A1), and vitamin D binding protein (GC).…”

Section: Novel Perspectives I Genetic Variants In Vitamin D Homeostamentioning

confidence: 99%

Vitamin D Deficiency and Cardiovascular Disease: Potential Mechanisms and Novel Perspectives

Maaty

2013

J Nutr Sci Vitaminol

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Summary Interest in contemporary vitamin D research has been sparked in recent years, stemming from the identification of vitamin D receptors in virtually all cells as well as the enzymatic machinery necessary to produce its active form. Both epidemiological and invitro studies have linked vitamin D deficiency to enigmatic diseases including cardiovascular disease; however, a clear mechanistic link remains missing. This review highlights conclusions of observational studies, in-vitro experiments and randomized-controlled trials that aimed to link deficiency of the sunshine vitamin to one of the leading causes of death in the world, cardiovascular disease. Furthermore, putative mechanisms viewed from a novel perspective are also discussed.

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Common genetic determinants of vitamin D insufficiency: a genome-wide association study

Cited by 1,387 publications

References 33 publications

Assessing the causal association between 25‐hydroxyvitamin D and the risk of oral and oropharyngeal cancer using Mendelian randomization

Assessing the causal association between 25‐hydroxyvitamin D and the risk of oral and oropharyngeal cancer using Mendelian randomization

Relationship between body mass index and serum 25-hydroxyvitamin D stronger among Caucasians than African Americans in NHANES adults 2001-2006

Vitamin D Deficiency and Cardiovascular Disease: Potential Mechanisms and Novel Perspectives

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