Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

Abstract

Background: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection.

Methods: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort.

Results: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD.

Conclusions: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Keywords: HIV infection; antiretroviral therapy; coronary artery disease; genetics; traditional risk factors.

Figure 1.

Summary of the models applied and sensitivity analyses performed. Abbreviations: CAD, coronary artery disease; HIV, human immunodeficiency virus.

Figure 2.

Contribution of traditional coronary artery disease (CAD) risk factors, HIV-related factors and weighted genetic score to CAD risk in multivariable analysis. Results are represented as the estimated effect and 95% confidence interval on the odds ratio of a first CAD event for genetic risk score quartile (black dots), HIV-related variables (gray triangles), and traditional CAD risk factors (gray squares). Results for the final, fully adjusted model (Supplementary Table 1A) and for the weighted genetic risk score (see Methods section) are shown. Abbreviations: ART, antiretroviral therapy; CAD, coronary artery disease; CI, confidence interval; HDL, high-density lipoprotein; HIV, human immunodeficiency virus.

Figure 3.

Coronary artery disease (CAD) risk according to genetic score quartile and number of non-genetic CAD risk factors (odds ratio and 95% confidence interval). Participants are stratified into 12 groups by weighted genetic score quartile (quartile 1, 2, 3, and 4) and by the number of nongenetic risk factors (0–2, 3–4, or >4 nongenetic CAD risk factors). The first group is the reference group (odds ratio = 1), ie, participants with 0–2 nongenetic risk factors who are in genetic risk score quartile 1. The sum of all nongenetic CAD risk factors is considered (presence of risk factor = 1, absence of risk factor = 0), including traditional risk factors and additional factors that contributed significantly to CAD risk in the D:A:D study [25], ie, age, past smoking, exposure ≥1 year to lopinavir, exposure ≥1 year to indinavir, current exposure to abacavir. Abbreviations: CAD, coronary artery disease; CI, confidence interval; HIV, human immunodeficiency virus; Q, quartile.

Figure 4.

Coronary artery disease (CAD) variability explained by traditional risk factors, human immunodeficiency virus–related factors and genetic background. Variability in the CAD odds ratio explained by the final model: 21.1%. Of this, age: 7.5%, current smoking: 3.1%, past smoking: 0.4%, high total cholesterol: 0.7%, hypertension: 0.5%, diabetes: 0.5%, low high-density lipoprotein cholesterol: 0.1%, family history of CAD: 1.9%, genetic risk score: 0.9%, current antiretroviral therapy: 0.2%, current abacavir: 0.7%, lopinavir (≥1 year): 0.7%, indinavir (≥1 year): 0.3%, HIV load: 0%, CD4⁺ count: 0%. Abbreviations: ABC, abacavir; CAD, coronary artery disease; HDL, high-density lipoprotein; IDV, indinavir; LPV, lopinavir.