Table 1.
Selected biomarkers (B) and genetic instruments (G) that may have utility for evaluation in an MR study for HIV-associated outcomes.
| Category | Biomarker (B) | Genetic instruments (G) | Genetic consequence on biomarkers (G→B) | Genetic Effect on HIV disease outcome (G→D) | References |
|---|---|---|---|---|---|
| Chemokine receptor | CCR5 | CCR5 −Δ32 (rs333) CCR5 haplotypes (e.g. P1/HHE) | Altered CCR5 surface expression | Associations with HIV-AIDS susceptibility [including surrogates of disease (CD4, VL)] and immune reconstitution during HAART. | [15–19,48,57,58] |
| Chemokines | CCL3L, CCL4L | CCL3L and CCL4L various gene copy number. | Increased gene dose of CCL3L1-containing segmental duplication associates with increased protein levels (the relationship is not linear, reaching a plateau at high gene dose) | Associations of CCL3L1-containing segmental duplications with HIV-AIDS susceptibility and immune reconstitution. Specific combinatorial content of CCL3L and CCL4L genes associate with HIV-AIDS outcomes. CCL4L gene copy number associates with HIV susceptibility. | [28–30,42,59–61] |
| CCL5 | CCL5 −471G>A (rs2107538) CCL5 In1.1T>C (rs2280789) | Altered transcription and possibly protein levels | Associations with HIV-AIDS susceptibility | [62–66] | |
| CCL2 | CCL2 −2578 A>G (rs4795895) | Altered protein expression | Associations with HIV susceptibility and disease progression including HIV-associated dementia | [67,68] | |
| CCL2, CCL5 | DARC Asp42Gly (rs12075) | Altered serum level of CCL2 (MCP-1), CCL5 (RANTES) and IL-8; SNP accounts for ~20% of the variability in serum CCL2 levels | Not studied | [69] | |
| CCL4 | CCL4L2 rs4796217 C>T | Minor allele significantly associates with a low plasma level of CCL4 (MIPβ) | Not studied | [70] | |
| Peripheral blood cell counts | CD4+ T cell counts | MHC locus rs2524054 C>A | Altered CD4 levels and CD4/CD8 ratio in HIV negative individuals. Explains ~5.7% variation of CD4/CD8 ratio | The A allele of rs2524054 strongly associates with viremia when HIV controllers were compared to a group of HIV-1 progressors | [71] |
| WBC, neutrophils | DARC −46T>C (rs2814778) | Low WBC and neutrophil counts, and at the population level, explains ~27% and ~20% of the variation in neutrophil and WBC counts, respectively. | African-specific DARC −46C/C associates with an increased risk of acquiring HIV but slow disease progression. The latter association occurs mainly in those African Americans who are also leukopenic. | [72–75] | |
| Platelet counts | ATXN2 rs11065987 A>G | Minor allele associates with altered platelet counts | Not studied | [76] | |
| Cytokines/inflammatory markers | IL-6 | IL-6 −174 G>C (rs1800795) | Associates with altered IL-6 and CRP levels | Altered risk of KS development and variable recovery of CD4 cells during HAART | [77–80] |
| IL-6sR | IL-6R rs4129267 C>T | Associates with plasma levels of IL-6sR | Not studied | [70] | |
| IL-10 | IL-10 −592C>A (rs1800872) | Decreased IL-10 levels | Increased HIV-AIDS susceptibility | [81–84] | |
| IL-18 | IL-18 rs2250417 A>G | Minor allele associates with low plasma IL-18 | Not studied | [70] | |
| TNFα | ABO rs505922 T>C | Minor allele associates with low levels of TNFα | Not studied | [70] | |
| CRP | CRP rs7553007 G>A | Minor allele associates lower CRP levels | Not studied | [14] | |
| Fibrinogen | FGB rs1800789 G>A | Minor allele associates with high fibrinogen and explains less than 2% of variations in levels | Not studied | [85] |
Abbreviations: CCR5, CC chemokine receptor 5; CCL, CC ligand; DARC, Duffy Antigen Receptor for Chemokines; WBC, white blood cells; VL, viral load; IL, interleukin; KS, Kaposi sarcoma, and CRP, C-reactive protein. CCL3L denotes CCL3L-1, -2, and -3 genes; CCL4L denotes CCL4L-1 and CCL4L-2 genes.