A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Consanguinity and susceptibility to infectious diseases in humans.

Studies of animal populations suggest that low genetic heterozygosity is an important risk factor for infection by a diverse range of pathogens, but relatively little research has looked to see whether similar patterns exist in humans. We have used microsatellite genome screen data for tuberculosis (TB), hepatitis and leprosy to test the hypothesis that inbreeding depression increases risk of infection. Our results indicate that inbred individuals are more common among our infected cases for TB and hepatitis, but only in populations where consanguineous marriages are common. No effect was found either for leprosy, which is thought to be oligogenic, or for hepatitis in Italy where consanguineous marriages are rare. Our results suggest that consanguinity is an important risk factor in susceptibility to infectious diseases in humans.

Online genetic databases informing human genome epidemiology.

BACKGROUND: With the advent of high throughput genotyping technology and the information available via projects such as the human genome sequencing and the HapMap project, more and more data relevant to the study of genetics and disease risk will be produced. Systematic reviews and meta-analyses of human genome epidemiology studies rely on the ability to identify relevant studies and to obtain suitable data from these studies. A first port of call for most such reviews is a search of MEDLINE. We examined whether this could be usefully supplemented by identifying databases on the World Wide Web that contain genetic epidemiological information. METHODS: We conducted a systematic search for online databases containing genetic epidemiological information on gene prevalence or gene-disease association. In those containing information on genetic association studies, we examined what additional information could be obtained to supplement a MEDLINE literature search. RESULTS: We identified 111 databases containing prevalence data, 67 databases specific to a single gene and only 13 that contained information on gene-disease associations. Most of the latter 13 databases were linked to MEDLINE, although five contained information that may not be available from other sources. CONCLUSION: There is no single resource of structured data from genetic association studies covering multiple diseases, and in relation to the number of studies being conducted there is very little information specific to gene-disease association studies currently available on the World Wide Web. Until comprehensive data repositories are created and utilized regularly, new data will remain largely inaccessible to many systematic review authors and meta-analysts.

Host genetics and the outcome of hepatitis B viral infection.

Hepatitis B Virus (HBV) infection can result in numerous different clinical outcomes. A complex combination of environment, and viral and host genetic factors play a critical role in determining both susceptibility to HBV persistence and the course of infection. Evidence is presented that suggests that host genetic factors play an important role in determining the outcome of HBV infection. This data from various groups demonstrates that multiple genes play a role in determining hepatitis B viral clearance or persistence. However, to identify all the relevant variants that affect the outcome of infection, alternative strategies such as genome-wide association studies with large sample sizes will be required to define the majority of the relevant polygenes.

Influence of IL-10RA and IL-22 polymorphisms on outcome of hepatitis C virus infection.

BACKGROUND: Two receptor chains, IL-10RA and IL-10RB, are known to mediate the functions of interleukin-10 (IL-10), which has been shown to be involved in the progression of persistent hepatitis C virus (HCV) infection. Little information is available on the role of host genetic variation in IL-10 receptor genes and outcome of HCV infection. IL-22, an IL-10 homologue, shares the IL-10RB receptor chain with IL-10 and has antiviral properties. We investigated the possible role of polymorphisms in the IL-10RA and IL-22 genes in hepatitis C disease pathogenesis. METHODS: This study population consisted of 631 HCV patients, recruited from several hepatology clinics across Europe. We genotyped four single-nucleotide polymorphisms (SNPs) in the IL-10RA and six SNPs in the IL-22 gene by ligation detection reaction or restriction fragment length polymorphism. Outcome of HCV infection was assessed according to viral clearance, treatment response, severity of fibrosis and overall inflammation. CONCLUSIONS: Variation in IL-10RA appeared to be correlated with response to treatment and inflammation. Two SNPs in IL-22 affected treatment response and viral clearance respectively. We furthermore report on allele and haplotype frequencies and linkage disequilibrium for IL-10RA and IL-22. Our results indicate that genetic variation in these genes may play a modulatory role in the outcome of hepatitis C infection.

Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence.

Persistent hepatitis B virus infection is a major risk factor for hepatocellular carcinoma, the most frequent cancer in some developing countries. Up to 95% of those infected at birth and 15% of those infected after the neonatal period fail to clear hepatitis B virus, together resulting in approximately 350 million persistent carriers worldwide. Via a whole genome scan in Gambian families, we have identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22. Coding changes in two of these genes, the type I IFN receptor gene, IFN-AR2, and the IL-10RB gene that encodes a receptor chain for IL-10-related cytokines including the IFN-lambdas, are associated with viral clearance (haplotype P value = 0.0003), and in vitro assays support functional roles for these variants in receptor signaling.

Genetics of infectious diseases.

Infectious diseases represent a major health problem worldwide, both in terms of morbidity and mortality. A complex combination of environmental, pathogen and host genetic factors plays a role in determining both susceptibility to particular microbes and the course of infection. Numerous studies have now mapped and identified relevant genes using a variety of both family-based and population-based approaches. Much interest has been focused on susceptibility to malaria, HIV/AIDS and mycobacterial infection, but other bacterial, viral and parasitic diseases are receiving increasing attention. Some major genes have been identified by genome scans of multi-case families, and mouse genetics has contributed to mapping and identification of a few genes. However, the great majority of known susceptibility loci emerged from screening of likely candidate genes. The emerging picture is of highly polygenic diseases, with occasional major genes, along with significant inter-population heterogeneity. This genetic architecture likely reflects the role that evolutionary selection has played in generating and maintaining a diverse repertoire of susceptibility/resistance loci, most with individually small effects. Genome-wide association studies with large sample sizes will be required to define the majority of the relevant polygenes.

Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection.

The natural outcome and response to treatment in hepatitis C virus (HCV) infection varies between individuals. Whereas some variation may be attributable to viral and environmental variables, it is probable that host genetic background also plays a significant role. Interleukin (IL)-10 has a key function in the regulation of cellular immune responses and in the suppression of pro-inflammatory cytokine secretion. Functional polymorphisms in the IL-10 gene have been described. We investigated the role of these polymorphisms in the outcome of HCV infection, treatment response and development of fibrosis in a case-control association study. Self-limiting infection was associated with the IL-10 (-592) AA genotype (OR=2.05; P=0.028). Persistent infection was associated with the IL-10 (-1082) GG genotype (OR=0.48; P=0.018). Sustained response to interferon therapy was associated with the IL-10 (-1082) GG genotype (OR=2.28; P=0.005) and the haplotype GCC (OR=2.27; P=0.020). The IL-10 (-1082) AA genotype and the ATA/ATA and ACC/ACC homozygous haplotypes were more frequent among patients with rapid fibrosis. Furthermore, the microsatellites IL-10.R and IL-10.G were associated with interferon response with IL-10R.2 conveying susceptibility (OR=1.80; P=0.034), and IL-10R.3 and IL-10.G13 being protective (OR=0.47; P=0.003 and OR=0.59; P=0.042, respectively). We conclude that polymorphisms in the IL-10 promoter appear to have some influence on the outcome of HCV infection, treatment and development of fibrosis.

Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection.

The effect of host genetic variation on the outcome of hepatitis C virus (HCV) infection and its treatment is poorly understood. The chemokine receptors CCR5, CCR2, and CCR3 and their ligands, RANTES, MCP-1, MCP-2, and MIP-1alpha, are involved in the immune responses and the selective recruitment of lymphocytes to the liver in HCV infection. We studied 20 polymorphisms within these genes and investigated their association with persistent carriage of HCV, severity of liver disease, hepatic inflammation, and response to treatment in a large European cohort. Significant associations were found between CCR5-delta32 and reduced portal inflammation (P =.011, odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.09-4.84) and milder fibrosis (P =.015, OR: 1.97, 95% CI: 1.13-3.42). A promoter polymorphism at position -403 in the RANTES gene was associated with less severe portal inflammation (P =.004). An amino acid change in MCP2, Q46K, was associated with severity of fibrosis (P =.018, OR: 2.29, 95% CI: 1.14-4.58). In conclusion, our study suggests a possible role of the polymorphisms CCR5-delta32, RANTES -403, and MCP-2 Q46K in the outcome of HCV infection.