TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis.

Sensitivity of T4 effector-memory (T4EM) lymphocytes to radiation-induced apoptosis shows heritability compatible with a Mendelian mode of transmission. Using gene expression studies and flow cytometry, we show a higher TNF-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10)mRNA level and a higher level of membrane bound TRAIL (mTRAIL) on radiosensitive compared to radioresistant T4EM lymphocytes. Functionally, we show that mTRAIL mediates a pro-apoptotic autocrine signaling after irradiation of T4EM lymphocytes linking mTRAIL expression to T4EM radiosensitivity. Using single marker and multimarker Family-Based Association Testing, we identified 3 SNPs in the TRAIL gene that are significantly associated with T4EM lymphocytes radiosensitivity. Among these 3 SNPs, two are also associated with acute and subacute dermatitis after radiotherapy in breast cancer indicating that T4EM lymphocytes radiosensitivity may be used to predict response to radiotherapy. Altogether, these results show that mTRAIL level regulates the response of T4EM lymphocytes to ionizing radiation and suggest that TRAIL/TNFSF10 genetic variants hold promise as markers of individual radiosensitivity.

C-Nap1 mutation affects centriole cohesion and is associated with a Seckel-like syndrome in cattle.

Caprine-like Generalized Hypoplasia Syndrome (SHGC) is an autosomal-recessive disorder in Montbéliarde cattle. Affected animals present a wide range of clinical features that include the following: delayed development with low birth weight, hind limb muscular hypoplasia, caprine-like thin head and partial coat depigmentation. Here we show that SHGC is caused by a truncating mutation in the CEP250 gene that encodes the centrosomal protein C-Nap1. This mutation results in centrosome splitting, which neither affects centriole ultrastructure and duplication in dividing cells nor centriole function in cilium assembly and mitotic spindle organization. Loss of C-Nap1-mediated centriole cohesion leads to an altered cell migration phenotype. This discovery extends the range of loci that constitute the spectrum of autosomal primary recessive microcephaly (MCPH) and Seckel-like syndromes.

A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations.

Rheumatoid arthritis (RA) is a common systemic autoimmune disease and its onset and prognosis are controlled by genetic, immunological, and environmental factors. The HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. However, they cover only a part of its genetic components and their relative contribution is different between populations. To identify novel genetic determinants, we took a candidate gene approach in a trans-ethnic manner. After critical selection of 169 genes based on their immunological function, we performed SNP discovery of these genes by the resequencing of exons and surrounding areas using European and Japanese DNAs. We then generated a panel of 1,509 SNPs for case-control association study in both populations. The DerSimonian-Laird test for meta-analysis, using the combined results of the two populations, identified rs7551957 at the 5'-flanking region of the low-affinity Fc-gamma receptor IIa (FCGR2A) gene as the strongest candidate for the association (p = 8.6 × 10(-5), odds ratio = 1.58 with 95%CI 1.25-1.99). Suggestive signals were also obtained for three SNPs in the dihydropyrimidine dehydrogenase (DPYD) gene (rs6685859; p = 1.3 × 10(-4), rs7550959; p = 1.5 × 10(-4) and rs7531138; p = 1.7 × 10(-4)) and an intronic SNP, rs2269310, of the erythrocytic spectrin beta (SPTB) gene (p = 7.9 × 10(-4)).

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

A major susceptibility locus for HTLV-1 infection in childhood maps to chromosome 6q27.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a human oncoretrovirus causing adult T-cell leukemia/lymphoma and chronic neuromyelopathy. We previously showed by segregation analysis that a dominant gene controls HTLV-1 infection through breast-feeding in children of African origin. Here, we report the mapping of this locus by a genome-wide linkage analysis based on the genetic model provided by segregation analysis. Five pedigrees of African origin with HTLV-1 seropositive children were included in the study. Significant evidence for linkage (LOD score of 3.36, P=0.00004) was obtained for chomosomal region 6q27 when using the robust analysis including only HTLV-1-infected subjects. When HTLV-1 seronegative children born to infected mothers were added in the analysis, a maximum LOD score of 2.79 (P=0.0002) was obtained for chomosome 2p25. This result was mostly due to the largest pedigree of our sample, which alone gave a LOD score of 2.90 (P=0.00013). We further excluded the role of exonic variants of two candidate genes located in the linked regions, CCR6 (chemokine receptor 6) in 6q27 and ID2 (inhibitor of DNA binding 2) in 2p25. Our results, mapping a major susceptibility locus to chromosome 6q27 and suggesting genetic heterogeneity with another locus at 2p25, pave the way to the determination of the molecular basis of predisposition to HTLV-1 infection in children.

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.

Comprehensive search for intra- and inter-specific sequence polymorphisms among coding envelope genes of retroviral origin found in the human genome: genes and pseudogenes.

BACKGROUND: The human genome carries a high load of proviral-like sequences, called Human Endogenous Retroviruses (HERVs), which are the genomic traces of ancient infections by active retroviruses. These elements are in most cases defective, but open reading frames can still be found for the retroviral envelope gene, with sixteen such genes identified so far. Several of them are conserved during primate evolution, having possibly been co-opted by their host for a physiological role. RESULTS: To characterize further their status, we presently sequenced 12 of these genes from a panel of 91 Caucasian individuals. Genomic analyses reveal strong sequence conservation (only two non synonymous Single Nucleotide Polymorphisms [SNPs]) for the two HERV-W and HERV-FRD envelope genes, i.e. for the two genes specifically expressed in the placenta and possibly involved in syncytiotrophoblast formation. We further show--using an ex vivo fusion assay for each allelic form--that none of these SNPs impairs the fusogenic function. The other envelope proteins disclose variable polymorphisms, with the occurrence of a stop codon and/or frameshift for most--but not all--of them. Moreover, the sequence conservation analysis of the orthologous genes that can be found in primates shows that three env genes have been maintained in a fully coding state throughout evolution including envW and envFRD. CONCLUSION: Altogether, the present study strongly suggests that some but not all envelope encoding sequences are bona fide genes. It also provides new tools to elucidate the possible role of endogenous envelope proteins as susceptibility factors in a number of pathologies where HERVs have been suspected to be involved.

Analysis of IGG and IGG4 in HIV-1 seropositive patients and correlation with biological and genetic markers.

We have compared the levels of immunoglobulins G (IgG) and G4 (IgG4) in extreme seropositive patients from the GRIV cohort consisting of 168 patients with slow progression (SP) and 60 with rapid progression (RP) as well as in 173 healthy controls. IgG levels were significantly higher in SP patients than in RP patients (P = 0.008), both higher than in seronegative individuals. IgG4 levels were significantly lower in SP patients than in RP patients (P = 0.001), both lower than in seronegative individuals. We tried to correlate these levels with biological parameters (CD4(+) and CD8(+) cells, total lymphocytes, white blood cell counts, percentage of CD4(+) cells, and viral load) as well as with genetic markers from Th1/Th2 cytokines (IL2, IL4, IL6, IL10, IL13, and IFNgamma). IgG levels were correlated with the percentage of CD4(+) cells in SP while IgG4 levels were correlated with CD8(+) cell count in SP and with percentage of CD4(+) cells in RP patients. Among the parameters measured in SP patients at the time of inclusion in the study, the best predictor of progression towards AIDS was the viral load, the best predictor for stability was CD4(+) cell count, but overall, the best predictor for SP evolution (stability vs. progression) appeared to be the percentage of CD4(+) cells. Interestingly, correlations between the levels of IgG or IgG4 and the cytokine gene polymorphisms were found, notably in the IL10 gene.

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.

Dominant effects of CCR2-CCR5 haplotypes in HIV-1 disease progression.

Three haplotypes for the CCR2-CCR5 region previously have been shown to affect AIDS progression; however, it is not known if the protective and accelerating effects of the haplotypes are relatively constant throughout infection or exert their effects early or late in HIV type 1 infection. The authors report the relative contributions to AIDS progression of CCR2 64I, CCR5 Delta32, and the CCR5 promoter haplotype +.P1.+ in the GRIV cohort, which included patients representing the extremes of the distribution for AIDS progression: rapid progressors (RP) who developed CD4 T-cell counts of <300/ mm within 3 years after the last HIV-1-seronegative test and slow progressors (SP) who were HIV-1 infected for > or =8 years with CD4 T-cell counts of >500/mm. Comparing the RP with a seroconverter control group including intermediate progressors to AIDS, we observed the early protective effect of CCR5 Delta32 (odds ratio = 0.25; P = 0.007) was similar in strength to the early susceptible effect of CCR5 +.P1.+ (odds ratio = 2.1, P = 0.01). Comparison of the intermediate control group to the SP showed weaker and less significant odd ratios, suggesting that the effect of these factors tended to be stronger on early progression; the tendency towards a disproportionately early effect was significant for CCR5 Delta32 (P = 0.04) but not for CCR5 +.P1.+ (P = 0.12). Follow-up of SP demonstrated that these polymorphisms have little effect after 8 years, because the subset of SP who had progression after study entry had the same genotype distribution as the global population of SP, suggesting that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression.

Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122