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DBP rs16846876 and rs12512631 polymorphisms are associated with progression to AIDS naive HIV-infected patients: a retrospective study.

ABSTRACT: BACKGROUND:Most of the circulating Vitamin D (VitD) is transported bound to vitamin D-binding protein (DBP), and several DBP single nucleotide polymorphisms (SNPs) have been related to circulating VitD concentration and disease. In this study, we evaluated the association among DBP SNPs and AIDS progression in antiretroviral treatment (ART)-naïve-HIV-infected patients. METHODS:We performed a retrospective study in 667 patients who were classified according to their pattern of AIDS progression (183 long-term non-progressors (LTNPs), 334 moderate progressors (MPs), and 150 rapid progressors (RPs)) and 113 healthy blood donors (HIV, HCV, and HBV negative subjects). We genotyped seven DBP SNPs (rs16846876, rs12512631, rs2070741, rs2282679, rs7041, rs1155563, rs2298849) using Agena Bioscience's MassARRAY platform. The genetic association was evaluated by Generalized Linear Models adjusted by age at the moment of HIV diagnosis, gender, risk group, and VDR rs2228570 SNP. Multiple testing correction was performed by the false discovery rate (Benjamini and Hochberg procedure; q-value). RESULTS:All SNPs were in HWE (p?>?0.05) and had similar genotypic frequencies for DBP SNPs in healthy-controls and HIV-infected patients. In unadjusted GLMs, we only found significant association with AIDS progression in rs16846876 and rs12512631 SNPs. In adjusted GLMs, DBP rs16846876 SNP showed significant association under the recessive inheritance model [LTNPs vs. RPs (adjusted odds ratio (aOR)?=?3.53; q-value?=?0.044) and LTNPs vs. MPs (aOR?=?3.28; q-value?=?0.030)] and codominant [LTNPs vs. RPs (aOR?=?4.92; q-value?=?0.030) and LTNPs vs. MPs (aOR?=?3.15; q-value?=?0.030)]. Also, we found DBP rs12512631 SNP showed significant association in the inheritance model dominant [LTNPs vs. RPs (aOR?=?0.49; q-value?=?0.031) and LTNPs vs. MPs (aOR?=?0.6; q-value?=?0.047)], additive [LTNPs vs. RPs (aOR?=?0.61; q-value?=?0.031)], overdominant [LTNPs vs. MPs (aOR?=?0.55; q-value?=?0.032)], and codominant [LTNPs vs. RPs (aOR?=?0.52; q-value?=?0.036) and LTNPs vs. MPs (aOR?=?0.55; q-value?=?0.032)]. Additionally, we found a significant association between DBP haplotypes (composed by rs16846876 and rs12512631) and AIDS progression (LTNPs vs RPs): DBP haplotype AC (aOR?=?0.63; q-value?=?0.028) and the DBP haplotype TT (aOR?=?1.64; q-value?=?0.028). CONCLUSIONS:DBP rs16846876 and rs12512631 SNPs are related to the patterns of clinical AIDS progression (LTNP, MP, and RP) in ART-naïve HIV-infected patients. Our findings provide new knowledge about AIDS progression that may be relevant to understanding the pathogenesis of HIV infection.

SUBMITTER: Jimenez-Sousa MA

PROVIDER: S-EPMC6806573 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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DBP rs16846876 and rs12512631 polymorphisms are associated with progression to AIDS naïve HIV-infected patients: a retrospective study.

Jiménez-Sousa María Ángeles MÁ Jiménez José Luis JL Fernández-Rodríguez Amanda A Bellón José María JM Rodríguez Carmen C Riera Melchor M Portilla Joaquín J Castro Ángeles Á Muñoz-Fernández María Ángeles MÁ Resino Salvador S

Journal of biomedical science 20191023 1

<h4>Background</h4>Most of the circulating Vitamin D (VitD) is transported bound to vitamin D-binding protein (DBP), and several DBP single nucleotide polymorphisms (SNPs) have been related to circulating VitD concentration and disease. In this study, we evaluated the association among DBP SNPs and AIDS progression in antiretroviral treatment (ART)-naïve-HIV-infected patients.<h4>Methods</h4>We performed a retrospective study in 667 patients who were classified according to their pattern of AIDS ...[more]

PMID: 31640710

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Project description:BACKGROUND:The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. RESULTS:Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. CONCLUSIONS:These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.

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DBP rs16846876 and rs12512631 polymorphisms are associated with progression to AIDS naive HIV-infected patients: a retrospective study.

Publications

DBP rs16846876 and rs12512631 polymorphisms are associated with progression to AIDS naïve HIV-infected patients: a retrospective study.

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