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Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).

ABSTRACT: Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples.

SUBMITTER: Shendre A

PROVIDER: S-EPMC5714351 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).

Shendre Aditi A Wiener Howard W HW Irvin Marguerite R MR Aouizerat Bradley E BE Overton Edgar T ET Lazar Jason J Liu Chenglong C Hodis Howard N HN Limdi Nita A NA Weber Kathleen M KM Gange Stephen J SJ Zhi Degui D Floris-Moore Michelle A MA Ofotokun Ighovwerha I Qi Qibin Q Hanna David B DB Kaplan Robert C RC Shrestha Sadeep S

PloS one 20171204 12

Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associ ...[more]

PMID: 29206233

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Project description:AIMS:To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women. METHODS AND RESULTS:sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into four sets (n?=?23 each) by HIV and sCVD status (HIV-/sCVD-, HIV-/sCVD+, HIV+/sCVD-, and HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometry was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the four groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression [median fluorescence intensity (MFI)] in non-classical monocytes was highest among HIV-/CVD- [628, interquartile range (IQR) (295-1389)], followed by HIV+/CVD- [486, IQR (248-699)], HIV-/CVD+ (398, IQR (89-901)), and lowest in HIV+/CVD+ women [226, IQR (73-519)), P?=?0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV-/CVD- vs. HIV+/CVD+ remained significant with P?=?0.005 (HIV-/CVD- vs. HIV+/CVD- P?=?0.04, HIV-/CVD- vs. HIV-/CVD+ P?=?0.06, HIV+/CVD+ vs. HIV+/CVD- P?=?0.88, HIV+/CVD+ vs. HIV-/CVD+ P?=?0.81, HIV+/CVD- vs. HIV-/CVD+, P?=?0.99). All pairwise comparisons with HIV-/CVD- were individually significant (P?=?0.050 vs. HIV-/CVD+, P?=?0.028 vs. HIV+/CVD-, P?=?0.009 vs. HIV+/CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD- (501.5, IQR (249.5-887.3)) vs. CVD+ (297, IQR (81.75-626.8) individuals (P?=?0.028, n?=?46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV-related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P?<?0.05). In regression analyses, adjusted for education level, study site, and injection drug use, presence of HIV infection and sCVD remained significantly associated with lower CXCR4 expression on non-classical monocytes (P?=?0.003), but did not differ in classical or intermediate monocytes. CONCLUSION:CXCR4 expression in non-classical monocytes was significantly lower among women with both HIV infection and sCVD, suggesting a potential atheroprotective role of CXCR4 in non-classical monocytes.

Dataset Information

Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).

Publications

Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).

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