Vitamin-D pathway genes and HIV-1 disease progression in injection drug users

Abstract

Vitamin-D has pleiotropic effects on calcium and bone metabolism, cellular growth control, cell differentiation and modulation of both innate and acquired immune response. Previous studies revealed the association of vitamin-D receptor gene (VDR) polymorphism with infection diseases including HIV-1 infection. To assess for association between polymorphisms of vitamin-D pathway genes CYP27B1, vitamin-D binding protein (VDBP) and VDR with HIV-1 infection, disease progression to acquired immunodeficiency syndrome (AIDS) was analysed according to CDC93 criteria in a cohort of 185 HIV-1 seroprevalent patients belonging to the injection drug users. Genotype data was obtained from rs10877012, rs3782130 and rs4646536 markers at CYP27B1 locus; rs7041 and rs4588 at VDBP locus; and rs11568820, rs4516035, rs2228570, rs1544410 and rs17878969 at VDR locus. Distribution of genotypes between patients grouped by outcome was compared by contingency table analysis. Marker-marker interaction was assessed by a MDR analysis. Assuming an additive model for VDR markers, a Kaplan-Meier survival analysis was employed to evaluate association with disease progression. Among vitamin-D pathway genes, VDR locus reveals specific 5'UTR and 3'UTR diplotype combinations associated with both, slower and faster progression to AIDS. Marker-marker interaction analysis indicates a strong interaction between VDR markers and a redundant effect for CYP27B1 markers. According to our results, VDR locus association follows an additive model in which increased genetic risk score for the VDR is directly correlated with AIDS progression rates. Our data supports a role of vitamin-D pathway gene variability on HIV-1 disease progression.

Latitudinal Clines of the Human Vitamin D Receptor and Skin Color Genes

“…The inference of selection is not surprising, given that earlier studies have also indicated that positive natural selection has operated upon many of these candidate genes to result in a latitudinal cline in human skin pigmentation ( Jablonski and Chaplin 2010 , 2013 ; Beleza et al 2013a ). The skin color genes are well known to influence vitamin D generation by the capacity of melanin to absorb UVB energy, and once vitamin D is produced, its nuclear receptor VDR plays a central role in the signaling of vitamin D to influence a variety of important health-related traits ( Fang et al 2006 ; Uitterlinden et al 2006 ; Azad et al 2012 ; Bikle 2012 ; Disanto et al 2012 ; Jovicic et al 2012 ; Chaplin and Jablonski 2013 ; Christakos et al 2013 ; Mao and Huang 2013 ; Tiosano et al 2013 ; Abd-Allah et al 2014 ; Borella et al 2014 ; Cantorna and Waddell 2014 ; Cutolo et al 2014 ; Laplana et al 2014 ; Liu et al 2014 ; Mann et al 2014 ; Rolf et al 2014 ). Hence, there is also much potential for strong selection at the VDR locus.…”

Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC

“…Besides numerous observations emphasizing the regulation of calcium/phosphate homeostasis, the involvement of vitamin D status in immune response is widely evident. Furthermore, HIV+ subjects with vitamin D receptor variants showed a significantly increased risk of progression to AIDS [ 31 , 32 ].…”

Controversial Effects of Vitamin D and Related Genes on Viral Infections, Pathogenesis, and Treatment Outcomes

“…Three studies reported results regarding the potential effects of VDRG polymorphisms on HIV infection, pathogenesis, and treatment outcome. VDR diplotypes in 5 untranslated region (UTR) and 3 UTR locus combinations were associated with the pathogenesis of AIDS [154]. The VDR variant rs1544410_AA was also associated with the progression to AIDS and resistance to HIV-1 [155].…”