Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.cytokines ͉ human migration ͉ innate immunity ͉ Toll-like receptor 4 ͉ sepsis

The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 ¼ *0401 ¼ *0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that metaanalyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.

Background Osteopetrosis is a life-threatening, rare disorder typically resulting from osteoclast dysfunction and infrequently from failure to commitment to osteoclast lineage. Patients commonly present in infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, and bone marrow failure. In w70% of the patients there is a molecularly defined failure to maintain an acid pH at the osteoclast-bone interface (the ruffled border) which is necessary for the bone resorptive activity. Methods and resultsIn eight patients with infantile osteopetrosis which could be cured by bone marrow transplantation, the study identified by homozygosity mapping in distantly related consanguineous pedigrees a missense mutation in a highly conserved residue in the SNX10 gene. The mutation segregated with the disease in the families and was carried by one of 211 anonymous individuals of the same ethnicity. In the patients' osteoclasts, the mutant SNX10 protein was abnormally abundant and its distribution altered. The patients' osteoclasts were fewer and smaller than control cells, their resorptive capacity was markedly deranged, and the endosomal pathway was perturbed as evidenced by the distribution of internalised dextran. Conclusions SNX10 was recently shown to interact with vacuolar type H + -ATPase (V-ATPase) which pumps protons at the osteoclast-bone interface. Mutations in TCIRG1, the gene encoding a subunit of the V-ATPase complex, account for the majority of cases of osteopetrosis. It is speculated that SNX10 is responsible for the vesicular sorting of V-ATPase from Golgi or for its targeting to the ruffled border. A mutation in SNX10 may therefore result in 'secondary V-ATPase deficiency' with a failure to acidify the resorption lacuna. Determination of the sequence of the SNX10 gene is warranted in molecularly undefined patients with recessive 'pure' osteopetrosis of infancy.

This study, unlike previous ones, is the first to show a significant association between HLA class II alleles and MS in the Jewish population. The association with the HLA-DR2-related haplotype is similar to that among non-Jewish white patients with MS. Moreover, our data support the possibility that DRB1*1501 is the susceptibility allele responsible for the association between this haplotype and MS in the Jewish population. Our study also underscores differences in HLA profiles between Ashkenazi and non-Ashkenazi patients, and between the different clinical courses of the disease. The latter may indicate that the clinical courses of MS are influenced by the genetic background.

Objective: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase de®ciency (NC21-OHD) and to determine if genotype is related to ethnic origin. Design: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60 min 17-hydroxyprogesterone (17-OHP), 45±386 nmol/l) who were referred for evaluation of postnatal virilization or true precocious/ early puberty. Eleven siblings diagnosed through family screening were genotyped as well. Methods: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58±151 nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. Results: At diagnosis, group B tended to be younger (5.863.0 vs 8.164.3 years, P 0.09), had greater height SDS adjusted for mid-parental height SDS (1.661.1 vs 0.761.4, P 0.034), tended to have more advanced bone age SDS (2.961.5 vs 1.762.1, P 0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226692 vs 126662 nmol/l, P < 0.01). Group B also had pubarche and gonadarche at an earlier age (5.162.4 vs 7.462.2 years, P < 0.01 and 7.461.8 vs 9.961.4 years, P < 0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P 0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most signi®cant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. Conclusions: The ®ndings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.