Exploration of associations between phospholipase A2 gene family polymorphisms and AIDS progression using the SNPlex method.

Members of the secreted phospholipase A2 (PLA2) protein family can inhibit HIV-1 virus replication in vitro. To evaluate the impact of PLA2 gene polymorphisms on AIDS disease development, we studied 12 family members using SNPlextrade mark technology that permitted simultaneous typing of 70 tagging Single Nucleotide Polymorphisms (tagSNPs). The study utilized HIV-1 seropositive donors with slow progressor (n=168) or rapid progressor (n=54) status, plus 355 control subjects. All donors were Caucasian (total 577 individuals). Genetic associations yielded mainly 0.01

Genomic approach of AIDS pathogenesis: exhaustive genotyping of the TNFR1 gene in a French AIDS cohort.

Large-scale genomic studies in cohorts have been made possible for the last few years thanks to the progress of molecular biology and bioinformatics. This systematic approach allows a better understanding of the molecular mechanisms of disease development and as a consequence can contribute to the rational design of new diagnostic and therapeutic tools. We present here the exhaustive genotyping of a candidate gene, tumor necrosis factor receptor 1 (TNFR1), in the genetic of resistance to immunodeficiency virus (GRIV) AIDS cohort. This gene was chosen because it is likely to be involved in the apoptosis pathways of CD4+ and CD8+ T-cells during human immunodeficiency virus 1 (HIV-1) infection. Seven frequent polymorphisms were characterized in 319 HIV-1 seropositive patients from the GRIV cohort with extreme disease progression phenotypes, slow progression or rapid progression, and in 427 healthy controls. The TNFR1 gene locus does not appear to be part of any haploblock and contains only a small haploblock of two successive SNPs. One promoter SNP (TNFR1_17444594, position -581) and one intronic SNP (TNFR1_27223241, position +11511) gave weak positive signals of association (resp. P=0.03 and P=0.04) as well as two haplotypes. To our knowledge, this is the first genetic association study dealing with the TNFR1 gene in AIDS and the putative associations identified will need to be validated through other AIDS cohort analyses or by further biological experimentation.

Associations of the IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFN (gamma) R1 cytokine receptor genes with AIDS progression in a French AIDS cohort.

We have performed an extensive analysis of Th1/Th2 cytokine receptors IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1 gene polymorphisms to evaluate their impact on AIDS progression. The coding regions and promoters of these genes were sequenced in the genetics of resistance to immunodeficiency virus cohort, composed of 327 HIV-1-positive patients with extreme progression phenotypes, slow and rapid progressors, and of 446 healthy control subjects, all of them of Caucasian descent. Overall, 104 single nucleotide polymorphisms and four insertions/deletions with a minor allelic frequency higher than 1% were identified, 21 of them being newly characterized. We observed weak associations for 13 polymorphisms of IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1, and 11 haplotypes of IL2Ralpha, IL4Ralpha, and IFNgammaR1. However, we could not relate these positive signals to any relevant biological information on the gene function. To affirm these putative associations in AIDS, further confirmation on other AIDS cohorts will be needed. This complete catalog of polymorphisms in IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1 cytokine receptor genes should also be useful for investigating associations in other immune-related diseases.

Exhaustive genotyping of the interleukin-1 family genes and associations with AIDS progression in a French cohort.

Interleukin (IL)-1 family members are key players in inflammatory processes but have been the subject of few studies of acquired immunodeficiency syndrome (AIDS). To better evaluate the impact of the IL-1 family on AIDS development, we genotyped the IL1 alpha , IL1 beta , IL1Ra, and IL1R1 genes in 245 slow progressor (SP) and 82 rapid progressor (RP) human immunodeficiency virus type 1-seropositive patients as well as in 446 control subjects, all of whom were of white ethnicity. One hundred sixteen frequent polymorphisms were identified, of which 23 were newly characterized by our study. Many putative associations were found between single-nucleotide polymorphism (SNP) or haplotype alleles and the extreme profiles of progression. Most of them corresponded to weak associations (.01

Exhaustive genotyping of the CEM15 (APOBEC3G) gene and absence of association with AIDS progression in a French cohort.

CEM15 (or APOBEC3G) has recently been identified as an inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. To evaluate the impact of its genetic variations on the progression of acquired immunodeficiency syndrome (AIDS), we have performed an extensive genetic analysis of CEM15. We have sequenced CEM15 in a cohort of 327 HIV-1-seropositive patients with extreme disease progression phenotypes--either slow progression or rapid progression--and in 446 healthy control subjects, all of white descent. We have identified 29 polymorphisms with allele frequencies >1%, 14 of which were newly characterized. There were no significant associations between the polymorphisms or haplotypes of CEM15 and a disease progression phenotype in our cohort.