Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study

Abstract

The stromal-derived factor-1 (SDF-1) chemokine gene encodes the only natural ligand for CXCR4, the coreceptor for the pathogenic X4 HIV-1 strains. A single-nucleotide polymorphism (SNP) in the 3 0 untranslated region (SDF1-3 0 A ¼ rs1801157) of SDF-1 was reported to be protective against infection and progression in some, but not other, epidemiological studies. To identify additional alleles that may influence HIV-1 infection and progression to AIDS, nine SNPs (including rs1801157) spanning 20.2 kb in and around the SDF-1 gene were genotyped in over 3000 African American (AA) and European American (EA) participants enrolled in five longitudinal HIV-1/AIDS natural cohort studies. Six or five haplotypes were present at frequencies greater than 5% in AA or EA, respectively. Six of the nine SNPs occur on only one common haplotype (45%), while the remaining three SNPs were found on multiple haplotypes, suggesting a complex history of recombination. Among EA, rs754618 was associated with an increased risk of infection (OR ¼ 1.50, P ¼ 0.03), while rs1801157 ( ¼ SDF1-3 0 A) was associated with protection against infection (OR ¼ 0.63, P ¼ 0.01). In the MACS cohort, rs1801157 was associated with AIDS-87 (RH ¼ 0.31, P ¼ 0.02) and with death (RH ¼ 0.18, P ¼ 0.02). Significant associations to a single disease outcome were found for two SNPs and one haplotype in AA.

RANTES–28G Delays andDC-SIGN– 139C Enhances AIDS Progression in HIV Type 1-Infected Japanese Hemophiliacs

“…Our result was concordant with those of the reports denying the association, though Modi et al 32 recently reported its protective effect as haplotype.…”

CXCL12: A New Player in Coronary Disease Identified through Human Genetics

“…Until earlier this decade, CXCL12 was thought of mainly as an oncologic and immunologic mediator of disease in humans (Modi et al 2005; Mohle et al 1998; Zou et al 1998). Further, studies have shown that CXCL12 acts on lymphocytes and monocytes in vitro, and strongly attracts mononuclear cells in vivo.…”

CXCR4 as a Therapeutic Target

“…In line with this, it was demonstrated that the ligand of CCR5 (CCL3/MIP-1a, CCL4/MIP-1b, CCL5/RANTES) and CXCR4 (CXCL12) could effectively block the entry of R5 and X4 strains respectively [243,244]. Moreover, polymorphisms of CCR5 [245] or CXCL12 [246][247][248] that affect expression of the receptor at the cell membrane [245] or stability of the chemokine [249,250], respectively, are associated to resistance or higher susceptibility to HIV infection. Transmission and early progression of HIV infection mostly involve R5 viruses [240,251].…”