Genetic associations with 25-hydroxyvitamin D deficiency in HIV-1-infected youth: fine-mapping for the GC/DBP gene that encodes the vitamin D-binding protein.

TitleGenetic associations with 25-hydroxyvitamin D deficiency in HIV-1-infected youth: fine-mapping for the GC/DBP gene that encodes the vitamin D-binding protein.
Publication TypePublication
Year of Publication2013
AuthorsPorter TR, Li X, Stephensen CB, Mulligan K, Rutledge B, Flynn PM, Lujan-Zilbermann J, Hazra R, Wilson CM, Havens PL, Tang J
Corporate AuthorsAdolescent MedicineTrials Network for HIV/AIDS Interventions(ATN) 063 study team
JournalFront Genet
Volume4
Pagination234
Date Published2013
ISSN1664-8021
Abstract

<p>Serum 25-hydroxyvitamin D [25(OH)D] is often deficient (<12 ng/ml) or insufficient (<20 ng/ml) in youth living with human immunodeficiency virus type 1 infection (YLH). Based on evidence from multiple genome-wide association studies, we hypothesized that genetic factors associated with 25(OH)D deficiency should be readily detectable in YLH even when controlling for other known factors, including use of the antiretroviral drug efavirenz (EFV). Genotyping by bi-directional sequencing targeted 15 single nucleotide polymorphisms (SNPs) at the GC/DBP locus, with a focus on coding and regulatory variants, as well as those repeatedly reported in the literature. Three intronic SNPs (rs222016, rs222020, and rs222029) in a conserved haplotype block had unequivocal association signals (false discovery rate ≤ 0.006). In particular, the minor allele G for rs222020 was highly unfavorable among 192 YLH (99 African-Americans and 93 others), as gauged by relatively low likelihood for 25(OH)D sufficiency at enrollment (odds ratio = 0.31, p = 9.0 × 10(-4)). In a reduced multivariable model, race, season, latitude, body mass index, exposure to EFV, and rs222020-G were independent factors that collectively accounted for 38% of variance in the log10-transformed 25(OH)D concentration (p < 0.0001). Interaction terms were evident for rs222020-G × season (p < 0.001), latitude × season (especially fall and winter; p < 0.01), and race × EFV use (p = 0.024). Overall, variance in serum 25(OH)D is substantially attributable to multiple factors, but the exact contribution of genetic and non-genetic factors can be obscured by partial overlaps and frequent interactions. </p>

DOI10.3389/fgene.2013.00234
Alternate JournalFront Genet
PubMed ID24294218
PubMed Central IDPMC3827582
Grant ListU01 HD040474 / HD / NICHD NIH HHS / United States
U01 HD040497 / HD / NICHD NIH HHS / United States
U01 HD040533 / HD / NICHD NIH HHS / United States
UL1 TR001082 / TR / NCATS NIH HHS / United States