Coronary Artery Disease–Associated and Longevity-Associated Polygenic Risk Scores for Prediction of Coronary Artery Disease Events in Persons Living With Human Immunodeficiency Virus: The Swiss HIV Cohort Study

Abstract

Background Coronary artery disease (CAD) is in part genetically determined. Aging is accentuated in people with HIV (PLWH). It is unknown whether genetic CAD event prediction in PLWH is improved by applying individual polygenic risk scores (PRS) and by considering genetic variants associated with successful aging and longevity. Methods In Swiss HIV Cohort Study participants of self-reported European descent, we determined univariable and multivariable odds ratios (OR) for CAD events, based on traditional CAD risk factors, adverse antiretroviral exposures, and different validated genome-wide PRS. PRS were built from CAD-associated single nucleotide polymorphisms (SNPs), longevity-associated SNPs, or both. Results We included 269 cases with CAD events between 2000-2017 (Median age 54 years, 87% male, 82% with suppressed HIV RNA) and 567 event-free controls. Clinical (i.e. traditional and HIV-related) risk factors, and PRS built from CAD-associated SNPs, longevity-associated SNPs, or both, each contributed independently to CAD events (p<0.001). Participants with the most unfavorable clinical risk factor profile (top quintile) had adjusted CAD-OR=17.82 (8.19-38.76), compared to participants in the bottom quintile. Participants with the most unfavorable CAD-PRS (top quintile) had adjusted CAD-OR=3.17 (1.74-5.79), compared to the bottom quintile. After adding longevity-associated SNPs to the CAD-PRS, participants with the most unfavorable genetic background (top quintile) had adjusted CAD-OR=3.67 (2.00-6.73), compared to the bottom quintile. Conclusions In Swiss PLWH, CAD prediction based on traditional and HIV-related risk factors was superior to genetic CAD prediction based on longevity- and CAD-associated PRS. Combining traditional, HIV-related and genetic risk factors provided the most powerful CAD prediction.

Leukocyte Count and Coronary Artery Disease Events in People With Human Immunodeficiency Virus: A Longitudinal Study

“…CAD events were defined per the Data Collection on Adverse events of Anti-HIV Drugs study and the World Health Organization's Monitoring Trends and Determinants in Cardiovascular Disease Project [ 20 ], as we have previously published [ 9 , 21 ]. CAD events included myocardial infarction, coronary angioplasty/stenting, coronary artery bypass grafting, and fatal cases (confirmed at autopsy or ascertained by the treating HIV physician as sudden death with no other likely cause plus evidence of CAD before death).…”

“…As in our previous CAD case-control studies [ 9 , 21 ], we used incidence density sampling [ 22 ], aiming to select 1 to 3 event-free controls for each case. We used risk-set sampling [ 23 (ie, we matched controls at the CAD event date of the corresponding cases [matching date] on similar observation duration, and their observation period was during similar calendar periods to account for differences in ART [with different CAD risk associations] [ 8 , 24 ]) in use during different periods and other differences.…”

“…Covariables were defined a priori based on their CAD association in the general population, as reported previously [ 9 , 21 , 25 ], and were ascertained at the latest SHCS visit before the matching date except for CD4 nadir (lowest CD4 value during the study period). Covariables included age (per 10 years older, added to detect any residual effect of suboptimal matching, as we have done previously [ 21 ]), family history of CAD, smoking, diabetes mellitus, hypertension, and dyslipidemia (total cholesterol >6.2 mmol/L or high-density lipoprotein < 1 mmol/L [men] and <1.2 mmol/L [women] or use of lipid-lowering drugs [ 25 ]).…”

“…Covariables included age (per 10 years older, added to detect any residual effect of suboptimal matching, as we have done previously [ 21 ]), family history of CAD, smoking, diabetes mellitus, hypertension, and dyslipidemia (total cholesterol >6.2 mmol/L or high-density lipoprotein < 1 mmol/L [men] and <1.2 mmol/L [women] or use of lipid-lowering drugs [ 25 ]). HIV-related covariables included HIV RNA < or ≥50 copies/mL, CD4 nadir, and ART exposures until the matching date, based on their CAD association in the Data Collection on Adverse events of Anti-HIV Drugs study [ 8 , 24 ], including recent (past 6 months) abacavir, didanosine, and integrase inhibitors; and cumulative (>1 year) exposure to lopinavir, indinavir, boosted darunavir, and stavudine [ 9 ]; hepatitis C [ 26 ]; and cytomegalovirus seropositivity [ 27 ].…”

“…People with human immunodeficiency virus (HIV; PWH), have an increased risk for coronary artery disease (CAD) events compared with the general population [ 1 , 2 ]. CAD risk in PWH is related to traditional CAD risk factors, HIV-related factors including chronic inflammation [ 3 , 4 ], immunosuppression [ 5 , 6 ], potential deleterious effects of certain antiretroviral therapy (ART) agents [ 7 , 8 ], and individual genetic background [ 9 ]. An increased CAD risk may persist in PWH with suppressed HIV viremia [ 1 , 2 ].…”