Polygenic Risk Scores for Prediction of Subclinical Coronary Artery Disease in Persons With Human Immunodeficiency Virus (HIV): The Swiss HIV Cohort Study

Abstract

Background In people living with HIV (PLWH), individual polygenic risk scores (PRSs) are associated with coronary artery disease (CAD) events. Whether PRSs are associated with subclinical CAD is unknown. Methods In Swiss HIV Cohort Study participants of European descent, we defined subclinical CAD as presence of soft, mixed, or high risk plaque (SMHRP) on coronary CT angiography, or as participants in the top tertile of the study population’s coronary artery calcium (CAC) score, using non-contrast CT. We obtained uni-/multivariable odds ratios (OR) for subclinical CAD endpoints based on non-genetic risk factors, and validated genome-wide PRSs built from single nucleotide polymorphisms (SNPs) associated with CAD, carotid intima-media thickness (IMT), or longevity in the general population. Results We included 345 genotyped participants (median age 53 years, 89% male, 96% suppressed HIV RNA); 172 and 127 participants had SMHRP and CAC, respectively. CAD-associated PRS and IMT-associated PRS were associated with SMHRP and CAC (all p < 0.01), but longevity-PRS was not. Participants with unfavorable CAD-PRS (top quintile) had adjusted SMHRP-OR = 2.58 (95% confidence interval [CI], 1.18-5.67), and CAC-OR = 3.95 (95% CI, 1.45-10.77), vs. bottom quintile. Unfavorable non-genetic risk (top vs. bottom quintile) was associated with adjusted SMHRP-OR = 24.01 (95% CI, 9.75-59.11), and CAC-OR = 65.07 (95% CI, 18.48-229.15). Area under the ROC curve increased when we added CAD-PRS to non-genetic risk factors (SMHRP: 0.75, 0.78, respectively; CAC: 0.80, 0.83, respectively). Conclusions In Swiss PLWH, subclinical CAD is independently associated with an individual CAD-associated PRS. Combining non-genetic and genetic cardiovascular risk factors provided the most powerful subclinical CAD prediction.

Polygenic Scores and Preclinical Cardiovascular Disease in Individuals With HIV: Insights From the REPRIEVE Trial

“…This is comparable with studies in cohorts without HIV; genome‐wide CAD PRSs with known CVD risk factors in a French‐Canadian cohort of over 11 000 participants yielded C‐statistic of 0.72–0.89 for prevalent CAD, 50 and in the ARIC (Atherosclerosis Risk in Communities) and MESA (Multiethnic Study of Atherosclerosis) cohorts (7237 total participants), yielded C‐statistics of 0.701 and 0.660, respectively. 51 Our results were also comparable with studies in PWH; genome‐wide CAD PRSs in the aforementioned Swiss HIV Cohort Study 48 , 49 yielded a C‐statistic of 0.75 for subclinical CAD plaques using nongenetic risk factors alone, which increased to 0.78 with inclusion of CAD PRSs. 48 …”

“… 47 Another study in 345 PWH from the Swiss HIV cohort study found CAD PRSs to be associated with subclinical CAD presence alone from CCTA but restricted to a cohort of exclusively European ancestry. 48 , 49 To our knowledge, our study is the first to demonstrate that a new multiancestry PRS 26 can reliably predict multiple measures of subclinical CAD, especially high‐risk plaque phenotypes, among PWH from diverse ancestries.…”

Telomere Length Declines in Persons With Human Immunodeficiency Virus Before Antiretroviral Therapy Start but Not After Viral Suppression: A Longitudinal Study Over >17 Years

“…Our finding that TL-PRS was associated with TL decline particularly during untreated HIV infection is interesting, and might suggest that suppressive ART is a strong environmental factor with a larger effect on TL dynamics than genetic background. Because we assessed the TL-PRS in a convenience sample of previously assembled study populations [3,32], our genetic findings should be interpreted cautiously.…”

“…First, we analyze TL change pre-ART and on-suppressive-ART in a highly selected population of participants (final n=107). Second, because of limited study population size, we investigated the potential effects of genetic background and of ARVs on longitudinal TL change in 798 additional participants from our previous longitudinal studies [3,32] who had >2 TL measurements available.…”

“…To increase power, we investigated the association of TL change with TL-PRS and with exposure to particular ARVs in our participants plus participants of our previous longitudinal studies [3,32]. The majority of these participants contributed two data points which were unrelated to the ART start date.…”