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HLA Region (hla + region)
Selected AbstractsGenetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 1 2005G. Zai Schizophrenia (SCZ) is a neuropsychiatric disorder that affects approximately 1% of the general population. The human leukocyte antigen (HLA) system has been implicated in several genetic studies of SCZ. The myelin oligodendrocyte glycoprotein (MOG) gene, which is located close to the HLA region, is considered a candidate for SCZ due to its association with white matter abnormalities and its importance in mediating the complement cascade. Four polymorphisms in the MOG gene (CA)n (TAAA)n, and two intronic polymorphisms, C1334T and C10991T, were investigated for the possibility of association with SCZ using 111 SCZ proband and their families. We examined the transmission of the alleles of each of these polymorphisms with the transmission disequilibrium test. We did not observe significant evidence for biased transmission of alleles at the (CA)n (,2 = 2.430, 6 df, P = 0.876) (TAAA)n (,2 = 3.550, 5 df, P = 0.616), C1334T (,2 = 0.040, 1 df, P = 0.841) and C10991T (,2 = 0.154, 1 df, P = 0.695) polymorphisms. Overall haplotype analysis using the TRANSMIT program was also not significant (,2 = 7.954, 9 df, P = 0.539). Furthermore, our results comparing mean age at onset in the genotype groups using the Kruskal,Wallis Test were not significant. Our case-control analyses (182 cases age-, sex- and ethnicity-matched with healthy controls) and combined z -score [(CA)n: z -score =,1.126, P = 0.130; (TAAA)n: z -score = ,0.233, P = 0.408; C1334T: z -score = 0.703, P = 0.241; C10991T: z -score = 0.551, P = 0.291] were also not significant. Although our data are negative, the intriguing hypothesis for MOG in SCZ may warrant further investigation of this gene. [source] Multistage analysis strategies for genome-wide association studies: summary of group 3 contributions to Genetic Analysis Workshop 16GENETIC EPIDEMIOLOGY, Issue S1 2009Rosalind J. Neuman Abstract This contribution summarizes the work done by six independent teams of investigators to identify the genetic and non-genetic variants that work together or independently to predispose to disease. The theme addressed in these studies is multistage strategies in the context of genome-wide association studies (GWAS). The work performed comes from Group 3 of the Genetic Analysis Workshop 16 held in St. Louis, Missouri in September 2008. These six studies represent a diversity of multistage methods of which five are applied to the North American Rheumatoid Arthritis Consortium rheumatoid arthritis case-control data, and one method is applied to the low-density lipoprotein phenotype in the Framingham Heart Study simulated data. In the first stage of analyses, the majority of studies used a variety of screening techniques to reduce the noise of single-nucleotide polymorphisms purportedly not involved in the phenotype of interest. Three studies analyzed the data using penalized regression models, either LASSO or the elastic net. The main result was a reconfirmation of the involvement of variants in the HLA region on chromosome 6 with rheumatoid arthritis. The hope is that the intense computational methods highlighted in this group of papers will become useful tools in future GWAS. Genet. Epidemiol. 33 (Suppl. 1):S19,S23, 2009. © 2009 Wiley-Liss, Inc. [source] Heterogeneity testing in meta-analysis of genome searchesGENETIC EPIDEMIOLOGY, Issue 2 2005Elias Zintzaras Abstract Genome searches for identifying susceptibility loci for the same complex disease often give inconclusive or inconsistent results. Genome Search Meta-analysis (GSMA) is an established non-parametric method to identify genetic regions that rank high on average in terms of linkage statistics (e.g., lod scores) across studies. Meta-analysis typically aims not only to obtain average estimates, but also to quantify heterogeneity. However, heterogeneity testing between studies included in GSMA has not been developed yet. Heterogeneity may be produced by differences in study designs, study populations, and chance, and the extent of heterogeneity might influence the conclusions of a meta-analysis. Here, we propose and explore metrics that indicate the extent of heterogeneity for specific loci in GSMA based on Monte Carlo permutation tests. We have also developed software that performs both the GSMA and the heterogeneity testing. To illustrate the concept, the proposed methodology was applied to published data from meta-analyses of rheumatoid arthritis (4 scans) and schizophrenia (20 scans). In the first meta-analysis, we identified 11 bins with statistically low heterogeneity and 8 with statistically high heterogeneity. The respective numbers were 9 and 6 for the schizophrenia meta-analysis. For rheumatoid arthritis, bins 6.2 (the HLA region that is a well-documented susceptibility locus for the disease) and 16.3 (16q12.2-q23.1) had both high average ranks and low between-study heterogeneity. For schizophrenia, this was seen for bin 3.2 (3p25.3-p22.1) and heterogeneity was still significantly low after adjusting for its high average rank. Concordance was high between the proposed metrics and between weighted and unweighted analyses. Data from genome searches should be synthesized and interpreted considering both average ranks and heterogeneity between studies. Genet. Epidemiol. 28:123,137, 2005. © 2004 Wiley-Liss, Inc. [source] Genetic susceptibility to nasopharyngeal carcinoma within the HLA-A locus in TaiwaneseINTERNATIONAL JOURNAL OF CANCER, Issue 6 2003Cheng-Chan Lu Abstract NPC is an epithelial tumor that is highly prevalent among the southern Chinese. Numerous studies have indicated that specific HLA haplotypes and genes within the HLA complex are associated with NPC. As a first effort to localize the gene responsible for susceptibility, the HLA-A, -B, and -A2 subtypes were examined for their association to NPC. Consistent with previous reports, frequencies of HLA-A2 [OR = 2.50, pc = 0.020 (study population); OR = 3.73, pc = 0.0030 (,40 years old)] were significantly higher in patients with NPC than in healthy controls. Two-locus analysis indicated that A2+B46+ individuals are at greater risk for NPC than A2,B46, individuals in both the population studied and the ,40-year-old group. This, however, may be due to the close linkage of these 2 genes. Moreover, A2+B38+ individuals were at higher risk than A2,B38, individuals in both the population studied and the ,40-year-old group; A2 and B38 are not genetically linked. These findings suggest that B38 or B46 alone cannot confer a high risk of NPC but that, in conjunction with A2, B38 or B46 positivity greatly increases risk. None of 5 A2 subtypes identified from studied populations was significantly associated with NPC. Microsatellite marker D6S211, located 97 kb telomeric to HLA-A, was analyzed for its association with NPC. Allele 4 of D6S211 was significantly associated with NPC (OR = 3.97, pc = 0.0042). These results strongly support the hypothesis that genes associated with susceptibility to NPC in the HLA region are within the HLA-A locus. © 2002 Wiley-Liss, Inc. [source] Analysis of candidate genes on chromosome 19 in coeliac disease: an association study of the KIR and LILR gene clustersINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2002S. J. Moodie Summary Coeliac disease is strongly heritable, with more than half of the genetic susceptibility estimated to come from genes outside the HLA region. Several candidate regions have been suggested from genome-wide linkage studies including chromosome 19q13.4 where linkage has been replicated between populations. The natural killer (NK) cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptor (LILR, also known as ILT and LIR) gene clusters lie within this region in the leukocyte receptor cluster (LRC). KIR molecules are involved in cytotoxic lymphocyte function and expressed by intraepithelial T and NK cells in the duodenum. We studied 132 unrelated UK Caucasian coeliac patients and their parents together with a control group of 171 UK Caucasians. PCR-SSP for KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, LILRA3 (ILT6), LILRA3 deletion and an LILRA3 exon 3 single nucleotide polymorphism (SNP) allowed classification of KIR genotypes into five categories and determination of homozygosity or heterozygosity for the common A and B type KIR haplotypes (as defined in the text) and for the LILRA3 deletion. Case,control analysis found no association of the five KIR genotype categories, the A or B KIR haplotypes, the LILRA3 gene deletion or the LILRA3 exon 3 SNP with coeliac disease. A transmission disequilibrium test also found no association of the A and B KIR haplotypes or the LILRA3 gene deletion with coeliac disease. [source] Lack of association between HLA genotype and chronic fatigue syndromeINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2001J. A. Underhill Summary Although the aetiology of chronic fatigue syndrome is controversial, evidence that infective agents including viruses may have a role in the development of the condition has led to studies seeking an association with the immunomodulatory HLA genes. In the present study, we sought to extend previous work using a well-characterized patient group and modern HLA genotyping techniques. Fifty-eight patients were phenotyped for HLA A and B by microcytotoxicity and genotyped for HLA DRB, DQB and DPB by PCR oligoprobing, and the frequencies of antigens so assigned were compared with those from a control group of 134. No significant differences in HLA frequencies were found between patient and control groups. Thus, this study does not confirm previous findings of an HLA association with chronic fatigue syndrome, suggesting that neither presentation of viral antigen by HLA class I nor antigen processing genes in the HLA region is a major contributory factor in the development of the disease. [source] The genetics of inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2001T. Ahmad Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn's disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome-wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3,the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the ,positional' candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications. [source] Contribution of a haplotype in the HLA region to anti,cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA,DRB1ARTHRITIS & RHEUMATISM, Issue 12 2009Yukinori Okada Objective To examine the risk of anti,cyclic citrullinated peptide (anti-CCP) antibody positivity in rheumatoid arthritis (RA) patients carrying certain haplotypes in the HLA region. Methods A total of 1,389 Japanese patients with RA were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the HLA region using commercial oligonucleotide arrays (from Perlegen or Affymetrix) as well as for HLA,DRB1 alleles using a sequence-specific polymerase chain reaction method. Stepwise logistic regression was used to select from among the 30 SNPs the ones that represented a risk of anti-CCP antibody positivity. Haplotypes of the selected SNPs were inferred using an expectation-maximization algorithm. Associations of individual SNPs were evaluated with the Cochran-Armitage test for trend. DRB1 alleles and haplotypes were evaluated with the chi-square test. Heterogeneities of risks among the shared epitope (SE) and non-SE HLA,DRB1 alleles were examined using the exact test. Haplotype associations that were independent of individual HLA,DRB1 alleles were evaluated using the likelihood ratio test. Results Significant associations were found for 9 SNPs (smallest P value being 2.4 × 10,8) and in 4 HLA,DRB1 alleles (smallest P value being 2.0 × 10,10 in DRB1*0405). Stepwise logistic regression selected 4 SNPs (rs9262638, rs7775228, rs4713580, and rs9277359). Among the 16 inferred haplotypes of these 4 SNPs, 6 indicated significant associations (smallest P value being 1.9 × 10,11). Risks among SE and non-SE alleles were significantly heterogeneous (P = 0.0095 and P = 9.8 × 10,9, respectively), indicating the importance of stratification with individual DRB1 alleles rather than SE alleles. Conditional analysis of the risk associated with individual DRB1 alleles identified a risk haplotype that was independent of DRB1 (odds ratio 2.00 [95% confidence interval 1.44,2.79], P = 2.6 × 10,5). Conclusion Heterogeneous risks of anti-CCP antibody positivity were confirmed among SE and non-SE alleles in our patient population. A risk haplotype in the HLA region that is independent of HLA,DRB1 was confirmed. [source] Genetic risk factors for rheumatoid arthritis differ in caucasian and Korean populationsARTHRITIS & RHEUMATISM, Issue 2 2009Hye-Soon Lee Objective Recent studies have identified a number of novel rheumatoid arthritis (RA) susceptibility loci in Caucasian populations. The aim of this study was to determine whether the genetic variants at 4q27, 6q23, CCL21, TRAF1/C5, and CD40 identified in Caucasians are also associated with RA in a Korean case,control collection. We also comprehensively evaluated the genetic variation within PTPN22, a well-established autoimmune disease,associated gene. Methods We designed an experiment to thoroughly evaluate the PTPN22 linkage disequilibrium region, using tag single-nucleotide polymorphisms (SNPs) and disease-associated SNPs at 5 RA-associated loci recently identified in Caucasians, in 1,128 Korean patients with RA and 1,022 ethnically matched control subjects. We also resequenced the PTPN22 gene to seek novel coding variants that might be contributing to disease in this population. Results None of the susceptibility loci identified in Caucasian patients with RA contributed significantly to disease in Koreans. Although tag SNPs covering the PTPN22 linkage disequilibrium block were polymorphic, they did not reveal any disease association, and resequencing did not identify any new common coding region variants in this population. The 6q23 and 4q27 SNPs assayed were nonpolymorphic in this population, and the TRAF1/C5, CD40, and CCL21 SNPs did not show any evidence for association with RA in this population of Korean patients. Conclusion The genetic risk factors for RA are different in Caucasian and Korean patients. Although patients of different ethnic groups share the HLA region as a major genetic risk locus, most other genes shown to be significantly associated with disease in Caucasians appear not to play a role in Korean patients with RA. [source] Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysisARTHRITIS & RHEUMATISM, Issue 1 2009Anne Hinks Objective Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well-established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA. Methods A genome-wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single-nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine-mapping was performed (654 cases and 1,847 controls). Results Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine-mapping of that gene was performed, and 10 SNPs were found to be associated with JIA. Conclusion This study is the first to successfully apply a SNP-based genome-wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood. [source] Identification of previously unrecognized predisposing factors for ankylosing spondylitis from analysis of HLA,B27 extended haplotypes in sardiniaARTHRITIS & RHEUMATISM, Issue 8 2007Isabella Cascino Objective To define the contribution of HLA genes other than HLA,B27 in conferring susceptibility to ankylosing spondylitis (AS), through analysis of HLA,B27 haplotypes in Sardinian subjects. Methods Ninety-eight patients with AS, 133 HLA,B27,positive controls (of whom 33 were positive for HLA,B*2709), and 190 randomly selected controls were genotyped for microsatellites and single-nucleotide polymorphisms (SNPs) spanning the HLA region. Results Haplotypes carrying either the B*2705 or the B*2709 allele were found to share a conserved region downstream of the HLA,B gene and a functional polymorphism in the HLA,E gene (R128G), while differing in all other markers. Notably, the presence of an A at SNP rs1264457, encoding for Arg-128, was significantly increased in the cohort of patients (P = 6 × 10,6, corrected P = 3 × 10,5) but not in B*2705- or B*2709-positive controls. Comparing the alleles co-occurring at each HLA marker, we identified a region differentiating patients with AS and B*2705-matched controls. In particular, there was a markedly increased prevalence of heterozygosity at rs1264457 among B27-positive controls (74%, versus 47% in patients and 54% in random controls), suggesting a protective role of G128 in AS. Moreover, other markers around the HLA,B gene were also differentially represented. Conclusion These results demonstrate a significant difference in the frequency of some HLA markers between AS patients and B*2705-positive controls, which could be attributed to the opposite chromosome. In particular, the differential distribution of a functional polymorphism in the HLA,E gene suggests a possible role of natural killer function in AS pathogenesis. [source] Testicular carcinoma and HLA Class II genesCANCER, Issue 9 2002Dirk J. A. Sonneveld M.D., Ph.D. Abstract BACKGROUND The association with histocompatibility antigens (HLA), in particular Class II genes (DQB1, DRB1), has recently been suggested to be one of the genetic factors involved in testicular germ cell tumor (TGCT) development. The current study, which uses genotyping of microsatellite markers, was designed to replicate previous associations. METHODS In 151 patients, along with controls comprising parents or spouses, the HLA region (particularly Class II) on chromosome 6p21 was genotyped for a set of 15 closely linked microsatellite markers. RESULTS In both patients and controls, strong linkage disequilibrium was observed in the genotyped region, indicating that similar haplotypes are likely to be identical by descent. However, association analysis and the transmission disequilibrium test did not show significant results. Haplotype sharing statistics, a haplotype method that derives extra information from phase and single marker tests, did not show differences in haplotype sharing between patients and controls. CONCLUSION The current genotyping study did not confirm the previously reported association between HLA Class II genes and TGCT. As the HLA alleles for which associations were reported are also prevalent in the Dutch populations, these associations are likely to be nonexistent or much weaker than previously reported. Cancer 2002;95:1857,63. © 2002 American Cancer Society. DOI 10.1002/cncr.10903 [source] The influence of human leucocyte antigen (HLA) genes on autoimmune thyroid disease (AITD): results of studies in HLA-DR3 positive AITD familiesCLINICAL ENDOCRINOLOGY, Issue 1 2002Yoshiyuki Ban Summary objective Population-based, case,control studies have consistently shown association of Graves' disease (GD) with human leucocyte antigen (HLA)-DR3 in Caucasian populations. HLA association studies in Hashimoto's thyroiditis (HT) have also suggested an association with DR3, as well as with other HLA alleles. In contrast, HLA linkage studies in autoimmune thyroid disease (AITD) have been largely negative. The aim of the present study was to investigate the role of HLA in AITD and to explain the observed associations, but lack of linkage, by examining only AITD families with the associated allele, DR3. patients We studied 99 probands (60 with GD and 39 with HT) from 99 multiplex, multigenerational Caucasian AITD families, and 135 age- and sex-matched Caucasian controls in association studies. In addition, a dataset of 34 Caucasian AITD families (out of the 99 families) with HLA-DR3 positive probands were analysed in linkage studies. design HLA typing was performed using the technique of group-specific polymerase chain reaction-amplification with restriction enzyme digestion. Whole genome screening was performed using the ABI microsatellite panels. For fine mapping of the HLA region, we used the following markers: D6S276, D6S464, D6S439, D6S273, tumour necrosis factor , and D6S1610. LOD scores were calculated using the LIPED and GeneHunter programs. results Case,control association analyses using the probands from our 99 Caucasian families showed an association of GD with DRB1*03 [P = 0·00032, relative risk (RR) = 3·4]. Linkage analysis for the HLA region in the 34 DR3 positive AITD families showed negative LOD scores throughout the region. The two-point LOD score at marker D6S273 (the closest to HLA-DRB1) was ,3·0, and the multipoint LOD score was ,7·6, demonstrating strong evidence against linkage to the HLA region in the subset of DR3 positive families. Whole genome screening in the subset of 34 DR3 positive families revealed one locus showing evidence for linkage to AITD: D3S1580 on chromosome 3q27 with a maximum two-point LOD score of 2·1. conclusions The HLA locus did not cosegregate with disease in DR3 positive families, suggesting that HLA genes are not major genes for AITD expression even within DR3 positive families; Hence, although HLA-DR3 was associated with GD in the probands, it was most likely a modulating gene and not causative; and, as the DR3 positive families showed evidence for linkage with D3S1580, it may imply that the DR3 gene modulated the effect of a susceptibility gene within the D3S1580 locus. [source] | |||||||||||||