Genome-wide association study of high-sensitivity C-reactive protein, D-dimer, and interleukin-6 levels in multiethnic HIV+ cohorts

Abstract

Objectives: Elevated levels of interleukin-6 (IL-6), D-dimer, and C-reactive protein (hsCRP) are associated with increased incidence of comorbid disease and mortality among people living with HIV (PLWH). Prior studies suggest a genetic basis for these biomarker elevations in the general population. The study objectives are to identify the genetic basis for these biomarkers among PLWH. Methods: Baseline levels of hsCRP, D-dimer, and IL-6, and single nucleotide polymorphisms (SNPs) were determined for 7768 participants in three HIV treatment trials. Single variant analysis was performed for each biomarker on samples from each of three ethnic groups [African (AFR), Admixed American (AMR), European (EUR)] within each trial including covariates relevant to biomarker levels. For each ethnic group, the results were pooled across trials, then further pooled across ethnicities. Results: The transethnic analysis identified three, two, and one known loci associated with hsCRP, D-dimer, and IL-6 levels, respectively, and two novel loci, FGB and GCNT1, associated with D-dimer levels. Lead SNPs exhibited similar effects across ethnicities. Additionally, three novel, ethnic-specific loci were identified: CATSPERG associated with D-dimer in AFR and PROX1-AS1 and TRAPPC9 associated with IL-6 in AFR and AMR, respectively. Conclusion: Eleven loci associated with three biomarker levels were identified in PLWH from the three studies including six loci known in the general population and five novel loci associated with D-dimer and IL-6 levels. These findings support the hypothesis that host genetics may partially contribute to chronic inflammation in PLWH and help to identify potential targets for intervention of serious non-AIDS complications.

Long-term persistence of transcriptionally-active “defective” HIV-1 proviruses: Implications for persistent immune activation during antiretroviral therapy

“…Multiple processes are theorized to play a role; these include microbial translocation, chronic co-infection with other pathogens such as cytomegalovirus (CMV), host genetics, lifestyle factors (e.g. smoking), side effects of drugs, and persistence of low-level HIV-1 replication that is not 'detectable' via standard clinical assays [14][15][16][17]. We have hypothesized that another potential source of this chronic inflammation may be the persistence, expansion, and biologic activity of replication-incompetent, yet transcriptionally competent 'defective' HIV-1 proviruses [18,19].…”

Plasma sVCAM‐1, antiretroviral therapy and mortality in HIV‐1‐infected West African adults

“…In the START trial involving mainly patients from northern countries, sVCAM levels were not found to be associated with the risk of AIDS, serious non‐AIDS events or death [16]. A recently published genome‐wide association multi‐ethnic study showed that in people living with HIV, multiple single nucleotide polymorphisms were associated with levels of high‐sensitivity CRP, D‐dimer and IL‐6 and support the hypothesis that host genetics may partially contribute to chronic inflammation in HIV‐infected individuals [28]. The genetic basis for sVCAM elevations has not been studied so far and may differ according to ethnic origin.…”

Human Genetic Variation in F3 and Its Impact on Tissue Factor–Dependent Disease

“…In a multiethnic cohort of patients undergoing antiretroviral treatment for HIV, rs2022309 was associated with increased D-dimer levels (p ¼ 1.9 Â 10 À13 ). 60 Similarly, in the African American cohort in which rs2022030 was studied, rs2022309 was also found to be significantly associated with D-dimer levels (p < 10 À9 ) prior to conditioning on the lead SNP. 59 In a cohort of 2,128 European twins, rs2202309 was also associated with decreased D-dimer levels (β ¼ À 0.24, p ¼ 4.3 Â 10 À8 ); in this study, the SNP was reported to decrease D-dimer levels.…”

“…58 Because rs66841827 is an indel rather than a SNP, it was not directly interrogated in and not identified in two larger GWAS of Ddimer. 59,60 Nevertheless, with a minor allele frequency (MAF) of 0.52 in persons of European genetic ancestry, 61 it is unlikely to be very penetrant. rs610277 rs610277 is an A to G intronic polymorphism of F3.…”