title: 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.
abstract: 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.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham Birmingham, AL, USA.
authors.forename: Travis R
authors.initials: TR
authors.lastname: Porter
authors.forename: Xuelin
authors.initials: X
authors.lastname: Li
authors.forename: Charles B
authors.initials: CB
authors.lastname: Stephensen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mulligan
authors.forename: Brandy
authors.initials: B
authors.lastname: Rutledge
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Flynn
authors.forename: Jorge
authors.initials: J
authors.lastname: Lujan-Zilbermann
authors.forename: Rohan
authors.initials: R
authors.lastname: Hazra
authors.forename: Craig M
authors.initials: CM
authors.lastname: Wilson
authors.forename: Peter L
authors.initials: PL
authors.lastname: Havens
authors.forename: Jianming
authors.initials: J
authors.lastname: Tang
keywords: HIV-1; antiretroviral; genetics; race; vitamin D; youth