We found a significant effect of the number of A alleles of the −1205G>A (rs3808627) in OPRK1 on CD4 count change (greater decline, P = 0.0224, Fig. 3A, Table 5) before HAART in Whites. Subjects bearing genotype AG of IVS2+7886A>G (rs12548098) in OPRK1 showed a lesser decline of CD4 count before HAART also in Whites (P = 0.0095, Fig. 3C). No subjects with the IVS2+7886GG genotype were observed in Whites. Subjects bearing genotype CT of −72C>T (rs9282806) in OPRK1 showed a lesser decline of CD4 count before HAART in African Americans (P = 0.0404, Fig. 3B). Four outliers were removed in the analysis of −72C>T in African Americans, including the only individual bearing the −72TT genotype; 2 outliers were removed in analysis of the influence of −1205G>A and IVS2+7886A>G on CD4 count change in Whites. No variants of PDYN showed an effect on CD4 count change before HAART.
After initiation of HAART, a significant effect of the number of A alleles of the IVS2+2225G>A (rs6985606) of the OPRK1 on VL change (greater decline) was found in Whites (P = 0.0033, Fig. 2B, Table 6). Also in Whites, a lesser decline of VL was found in individuals bearing genotypes TT and GT compared with GG genotype of IVS2+10658G>T (rs1365098, P = 0.0376, Fig. 2C) and in individuals bearing genotypes GG and AG compared with AA genotype of IVS2+10963A>G (rs997917, P = 0.0376, Fig. 2D). Genotypes of the polymorphism IVS2+10658G>T completely predict genotypes of IVS2+10963A>G.
In Hispanics, individuals with genotypes AA and GA of IVS2+2225G>A showed a lesser increase of CD4 count after initiation of HAART (P = 0.0401, Fig. 3D, Table 6). Two individuals were removed from this analysis as outliers. No variants of PDYN showed an effect on VL or CD4 count change after initiation of HAART.
Using logistic regression, in all controls and cases, we found that in African Americans, frequencies of the minor allele A of the OPRK1 promoter variant −1205G>A (rs3808627) and allele A of the possible PDYN promoter variant −11128G>A (rs1997794) are lower in the HIV+ group than in controls, indicating possible protection from infection (Table 7).
In this initial study, all findings in multiple regression analyses or logistic regression analyses were only pointwise significant and did not withstand multiple test correction. Further studies are needed to validate these genetic findings and the functionality of the variants.
LD analysis was performed in the group of HIV− controls only, separately for each ethnic group (see Figure S2, Supplemental Digital Content, http://links.lww.com/QAI/A390). In the OPRK1 gene, very high LD (r2 > 0.95) was found for the variant pair rs997917/rs1365098 in all 3 ethnicities; pairs rs3802281/rs3802282 and rs963549/rs702764 in Whites and African Americans; pair rs16918875/rs16918955 in Whites; and pair rs3802281/rs963549 in African Americans and Hispanics. Several pairs of OPRK1 variants, including rs3802282/rs702764, rs3802281/rs702764, and rs3802282/rs963549, were found to be in high LD (r2 > 0.75) in all 3 ethnicities.
Before the initiation of HAART, we found a significant effect of the number of T alleles of intronic PDYN IVS3+189C>T on the slope of VL decline in African Americans. This polymorphism has been found to be in association with alcohol dependence.36 No other variants of PDYN were found to have a significant effect on either VL or CD4 count change before or after HAART. However, a promoter allele PDYN −11128A (rs1997794) was found to be in association with HIV status (protection) also in African Americans. This variant might be involved in the regulation of promoter activity and might influence gene expression through formation of a noncanonical activator protein-1 binding site.37 This variant has been found to be in association with opioid dependence in Chinese women38 and with alcohol dependence in Whites.36 In tests of cognitive function, carriers of the minor allele of this variant and also variant 1508T>C (rs910080) had higher episodic memory scores than homozygote carriers of the major allele.39 Decline of cognitive function is one of the challenges of HIV+ patients. We did not find this polymorphism 1508T>C to be in association with either VL or CD4 count change in our study.
The large number of African Americans in this study allows interpreting associations found in this ethnicity with greater confidence. A limitation of this study is a relatively small number of Hispanic and White subjects.
The authors thank Susan Russo for editorial assistance. The authors acknowledge the National Institutes of Health–National Institute of Allergy and Infectious Diseases, which supported the WIHS and principal investigators of these studies (see the detailed acknowledgements provided below). The authors also acknowledge Susan Holman for facilitation and Judith Cook for help in our studies. The authors thank the women participating in the WIHS for their time, cooperation, and support. Data in the manuscript were collected by the WIHS Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Coordinating Center (Stephen Gange).
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