Synergistic effect of genetic polymorphisms in <em>TLR6</em> and <em>TLR10</em> genes on the risk of pulmonary tuberculosis in a Moldavian population.

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response (VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene-gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62-3.85; Fisher exact test P value = 1.5 × 10-5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility

Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population.

Toll-like receptors (TLRs) play a critical role in initiating an immune response to infections. In this study, we examined whether single nucleotide polymorphisms (SNPs) in TLR pathway genes are associated with pulmonary tuberculosis (PTB) in a Moldavian population. Thirty-four SNPs in genes associated with the TLR pathway and two SNPs in ASAP1 gene identified by GWAS were selected for genotyping in 272 patients and 251 community-matched healthy controls. Twenty-nine SNPs passed quality control and were statistically evaluated. SNPs TLR9 rs352139, TLR2 rs3804099 and MYD88 rs4988453 were associated with PTB in females (OR = 0.49, p = 0.0009; OR = 0.51, p = 0.0008; OR = 0.33, p = 0.027; here and below log-additive model with minor alleles assumed as effect associated alleles), while SNP TLR8 rs3764880 showed a significant association in males (OR = 0.44, p = 0.0087). Furthermore, SNPs TLR9 rs352139 and TLR8 rs3764880 were associated with PTB in the late-onset ( &gt;= 39-year-old) patient group (OR = 0.60, p = 0.0029 and OR = 0.70, p = 0.021, respectively) and SNPs TLR2 rs3804099, TLR4 rs4986790 and TLR4 rs1927906 in the early-onset (&lt;= 38-year-old) group (OR = 0.53, p = 0.0012; OR = 3.45, p = 0.013; OR = 2.31, p = 0.044, respectively). After correction for multiple testing, only SNPs TLR9 rs352139 and TLR2 rs3804099 in the female group and SNP TLR2 rs3804099 in the early-onset group remained significant. In summary, we show an association of SNP TLR8 rs3764880 with PTB in the Moldavian male population, providing support to previous studies conducted on other populations. Polymorphisms rs3804099 (TLR2) and rs352139 (TLR9) may also be associated with PTB risk in the Moldavian population but their effect is less consistent across different studies. Additional large-scale association studies along with functional tests are required to dissect the relevance of these associations

Analysis of the R1b-DF27 haplogroup shows that a large fraction of Iberian Y-chromosome lineages originated recently in situ

Haplogroup R1b-M269 comprises most Western European Y chromosomes; of its main branches, R1b-DF27 is by far the least known, and it appears to be highly prevalent only in Iberia. We have genotyped 1072 R1b-DF27 chromosomes for six additional SNPs and 17 Y-STRs in population samples from Spain, Portugal and France in order to further characterize this lineage and, in particular, to ascertain the time and place where it originated, as well as its subsequent dynamics. We found that R1b-DF27 is present in frequencies ~40% in Iberian populations and up to 70% in Basques, but it drops quickly to 6-20% in France. Overall, the age of R1b-DF27 is estimated at ~4,200 years ago, at the transition between the Neolithic and the Bronze Age, when the Y chromosome landscape of W Europe was thoroughly remodeled. In spite of its high frequency in Basques, Y-STR internal diversity of R1b-DF27 is lower there, and results in more recent age estimates; NE Iberia is the most likely place of origin of DF27. Subhaplogroup frequencies within R1b-DF27 are geographically structured, and show domains that are reminiscent of the pre-Roman Celtic/Iberian division, or of the medieval Christian kingdoms.Funding was provided by the Agencia Estatal de Investigación and Fondo Europeo de Desarollo Regional (FEDER) (grants CGL2013-44351-P, CGL2016-75389-P), by Agència de Gestió d’Ajuts Universitaris i de la Recerca (Generalitat de Catalunya) grant 2014 SGR 866, and by the Basque Government (IT-424-07). FT was supported by the ERC Advanced Grant Agreement No 295733, ‘LanGeLin’ projec

The phylogenetic and geographic structure of Y-chromosome haplogroup R1a.

International audience: R1a-M420 is one of the most widely spread Y-chromosome haplogroups; however, its substructure within Europe and Asia has remained poorly characterized. Using a panel of 16 244 male subjects from 126 populations sampled across Eurasia, we identified 2923 R1a-M420 Y-chromosomes and analyzed them to a highly granular phylogeographic resolution. Whole Y-chromosome sequence analysis of eight R1a and five R1b individuals suggests a divergence time of ∼25 000 (95% CI: 21 300-29 000) years ago and a coalescence time within R1a-M417 of ∼5800 (95% CI: 4800-6800) years. The spatial frequency distributions of R1a sub-haplogroups conclusively indicate two major groups, one found primarily in Europe and the other confined to Central and South Asia. Beyond the major European versus Asian dichotomy, we describe several younger sub-haplogroups. Based on spatial distributions and diversity patterns within the R1a-M420 clade, particularly rare basal branches detected primarily within Iran and eastern Turkey, we conclude that the initial episodes of haplogroup R1a diversification likely occurred in the vicinity of present-day Iran.European Journal of Human Genetics advance online publication, 26 March 2014; doi:10.1038/ejhg.2014.50