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United States Department of Agriculture

Agricultural Research Service

Research Project: MUSCULOSKELETAL HEALTH IN THE ELDERLY

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: Common genetic determinants of vitamin D insufficiency: the sunlight consortium)

Author
item Wang, Thomas J
item Feng, Zhang
item Richards, Brent
item Kestenbaum, Bryan
item Van Meurs, Joyce B
item Berry, Diane
item Kiel, Douglas
item Streeten, Elizabeth A
item Ohlsson, Claes
item Koller, Daniel L
item Jarvelin, Marjo-riitta
item Cooper, Jason D
item O'reilly, Paul F
item Houston, Denise K
item Glazer, Nicole L
item Vandenput, Liesbeth
item Peacock, Munro
item Shi, Julia
item Rivadeneira, Fernando
item Mccarthy, Mark I
item Anneli, Pouta
item De Boer, Ian H
item Mangino, Massimo
item Kato, Bernet
item Smyth, Deborah J
item Booth, Sarah L
item Jacques, Paul F
item Burke, Greg L
item Goodarzi, Mark
item Cheung, Ching-lung
item Wolf, Myles
item Rice, Kenneth
item Goltzman, David
item Hidiroglou, Nick
item Ladouceur, Martin
item Hui, Siu L
item Wareham, Nicholas J
item Hocking, Lynne J
item Hart, Deborah
item Arden, Nigel K
item Copper, Cyrus
item Malik, Suneil
item Fraser, William D
item Hartikainen, Anna-lisa
item Zhai, Guangju
item Macdonald, Helen
item Forouhi, Nita G
item Loos, Ruth J F
item Reid, David M
item Hakim, Alan
item Dennison, Elaine
item Liu, Yongmei
item Power, Chris
item Stevens, Helen E
item Jaana, Laitinen
item Vasan, Ramachandran S
item Soranzo, Nicole
item Bojunga, Joerg
item Pstay, Bruce M
item Lorentzon, Mattias
item Foroud, Tatiana
item Harris, Tamara B
item Hofman, Albert
item Jansson, John-olov
item Cauley, Jane A
item Uitterlinden, Andre G
item Gibson, Quince
item Palotie, Leena
item Karasik, David S
item Econs, Michael J
item Kritchevsky, Stephen B
item Florez, Jose C
item Todd, John A
item Dupuis, Josee
item Hypponen, Elina
item Spector, Timothy D

Submitted to: Lancet
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/2010
Publication Date: 7/20/2010
Citation: Wang, T., Feng, Z., Richards, B., Kestenbaum, B., Van Meurs, J., Berry, D., Kiel, D., Streeten, E., Ohlsson, C., Koller, D., Jarvelin, M., Cooper, J., O'Reilly, P., Houston, D., Glazer, N., Vandenput, L., Peacock, M., Shi, J., Rivadeneira, F., Mccarthky, M., Anneli, P., De Boer, I., Mangino, M., Kato, B., Smyth, D., Booth, S., Jacques, P., Burke, G., Goodarzi, M., Cheung, C., Wolf, M., Rice, K., Goltzman, D., Hidiroglou, N., Ladouceur, M., Hui, S., Wareham, N., Hocking, L., Hart, D., Arden, N., Copper, C., Malik, S., Fraser, W., Hartikainen, A., Zhai, G., Macdonald, H., Forouhinita G, Loos, R., Reid, D., Hakim, A., Dennison, E., Liu, Y., Power, C., Stevens, H., Jaana, L., Vasan, R., Soranzo, N., Bojunga, J., Pstay, B., Lorentzon, M., Foroud, T., Harris, T., Hofman, A., Jansson, J., Cauley, J., Uitterlinden, A., Gibson, Q., Palotie, L., Karasik, D., Econs, M., Kritchevskyk, S., Florez, J., Todd, J., Dupuis, J., Hypponen, E., Spector, T. 2010. Common genetic determinants of vitamin D insufficiency: the sunlight consortium. Lancet. 376(9736):180-188.

Interpretive Summary: Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D deficiency has been linked to a number of other disorders , including diabetes, cancer, and cardiovascular disease. In humans, vitamin D concentrations are determined by sun exposure and dietary intake, but there is also evidence suggesting that genetic factors may also play a role. We performed a genome-wide association study of vitamin D concentrations among ~30,000 individuals of European descent from 15 different studies. Five studies were designated as discovery studies (studying 16,125 individuals), in which the genetic factors influencing vitamin D concentrations were identified. There were 10 additional studies (studying 17,744 individuals) used to replicate the findings from the discovery studies. Vitamin D insufficiency was defined as vitamin D concentrations below 75 nmol/L. Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1 and CYP24A1), and vitamin D transport (GC) were found to influence vitamin D concentrations. These variants were significant in the discovery cohorts and confirmed in the replication cohorts. A genotype score was constructed using these three confirmed variants. Those with the highest genotype scores had a 2.5-fold greater likelihood of vitamin D insufficiency. In conclusion, genetic variation identifies individuals of European descent who have substantially elevated risk of vitamin D deficiency. The results are valuable for human nutrition managements.

Technical Abstract: Background: Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role. Methods: We performed a genome-wide association study of 25-OH D among ~30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L. Findings: Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 x 10-109 for rs2282679, in GC); 11q12 (P=2.1 x 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 x 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 x 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2.5-fold elevated odds of vitamin D insufficiency (P=2.3 x 10-48). Interpretation: Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1 and CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency.

Last Modified: 05/23/2017
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