The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

Abstract

We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

Polymorphisms in the interleukin-7 receptor α gene and mortality in untreated HIV-infected individuals

“…In agreement with the present data, a significant correlation between the rs6897932 C-allele and faster CD4 þ T-cell recovery after initiation of ART was found in an HIV-infected Ugandan cohort [3]. However, in another study conducted in a predominantly white cohort rs6897932 C-allele carriers seemed to have a slower CD4 þ T-cell recovery after initiation of ART [7].…”

“…In agreement, higher levels of sIL-7Ra have been found to be associated with rs6897932 C-allele homozygosity [3,7]. Furthermore, the rs987106 A-allele has been associated with lower level of sIL-7Ra [3].…”

“…DNA samples were not available from 44 HIV-infected individuals. On the basis of existing literature five SNPs were chosen as our primary target of investigation (rs6897932, rs987106, rs3194051, rs1494555, and rs11567685) [3,4,[7][8][9][10][11] (Table 2, Supplementary Material, http://links.lww.com/QAD/ A328). Furthermore, five SNPs were examined as explorative variables (rs11567762, rs1494565, rs10053847, rs11567714, and rs2229232).…”

“…Recently, polymorphisms in the gene encoding the IL-7 receptor a (IL7Ra) have been shown to be associated with CD4 cell counts in HIV-infected individuals, as the rs6897932 T-allele was found to be a significant predictor of faster immune recovery after initiation of ART [3,4]. Furthermore, rs987106 T-allele homozygosity has been found to be associated with lower rate of decline in the CD4 cell count in untreated HIVinfected individuals [4].…”

Current situation of the Pharmacogenetics of Immune Recovery in Treated HIV-Infected Patients

“…In fact, the therapeutic use of IL7 in poor recoverers is currently being explored. Some significant associations with genetic variation in other cytokines (IL2, IL6, IL10, IL15) have been reported, but the data arises from single studies and results need further replication [7,[12][13][14]. Regarding apoptosis parameters and molecular changes in mitochondrial DNA, the little data available at present is inconsistent, and this therefore requires more investigation [7,[15][16][17].…”