A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each ). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls () and were highly significant in the combined dataset (). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set , replication set , combined ). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P combined = 2.76 × 10 -17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. © 2013 Nature America, Inc. All rights reserved.

The Genetics of Ankylosing Spondylitis and Axial Spondyloarthritis

Ankylosing spondylitis (AS) and spondyloarthritis are strongly genetically determined. The long-standing association with HLA-B27 is well described, although the mechanism by which that association induces AS remains uncertain. Recent developments include the description of HLA-B27 tag single nucleotide polymorphisms in European and Asian populations. An increasing number of non-MHC genetic associations have been reported, which provided amongst other things the first evidence of the involvement of the IL-23 pathway in AS. The association with ERAP1 is now known to be restricted to HLA-B27 positive disease. Preliminary studies on the genetics of axial spondyloarthritis demonstrate a lower HLA-B27 carriage rate compared with AS. Studies with larger samples and including non-European ethnic groups are likely to further advance the understanding of the genetics of AS and spondyloarthritis. © 2012.

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients

The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study...

Genetics of ankylosing spondylitis and rheumatoid arthritis: Where are we at currently, and how do they compare?

Both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are common, highly heritable conditions, the pathogenesis of which are incompletely understood. Gene-mapping studies in both conditions have over the last couple of years made major breakthroughs in identifying the mechanisms by which these diseases occur. Considering RA, there is an over-representation of genes involved in TNF signalling and the NFκB pathway that have been shown to influence the disease risk. There is also considerable sharing of susceptibility genes between RA and other autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes, autoimmune thyroid disease and celiac disease, with thus far little overlap with AS. In AS, genes involved in response to IL12/IL23, and in endoplasmic reticulum peptide presentation, have been identified, but a full genomewide association study has not yet been reported.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis

Objective. Ankylosing spondylitis (AS) is a debilitating chronic inflammatory condition with a high degree of familiality (λs=82) and heritability (>90%) that primarily affects spinal and sacroiliac joints. Whole genome scans for linkage to AS phenotypes have been conducted, although results have been inconsistent between studies and all have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis. Methods: The International Genetics of Ankylosing Spondylitis Consortium combined data from three whole genome linkage scans for AS (n=3744 subjects) to determine chromosomal markers that show evidence of linkage with disease. Linkage markers typed in different centres were integrated into a consensus map to facilitate effective data pooling. We performed a weighted meta-analysis to combine the linkage results, and compared them with the three individual scans and a combined pooled scan. Results: In addition to the expected region surrounding the HLA-B27 gene on chromosome 6, we determined that several marker regions showed significant evidence of linkage with disease status. Regions on chromosome 10q and 16q achieved 'suggestive' evidence of linkage, and regions on chromosomes 1q, 3q, 5q, 6q, 9q, 17q and 19q showed at least nominal linkage in two or more scans and in the weighted meta-analysis. Regions previously associated with AS on chromosome 2q (the IL-1 gene cluster) and 22q (CYP2D6) exhibited nominal linkage in the meta-analysis, providing further statistical support for their involvement in susceptibility to AS. Conclusion: These findings provide a useful guide for future studies aiming to identify the genes involved in this highly heritable condition. . Published by on behalf of the British Society for Rheumatology.

Haemochromatosis and HLA--H

The recently identified can didate gene, HLA-H, for haemochromatosis (HH) by Feder et al. generated considerable scientific interest coupled with a degree of uncertainty about the likely involvement of this gene in this common iron metabolism disorder, Feder et al. found a single point mutation resulting in an amino acid substitution (C282Y) that was homozygous in 148 (83%) of their patients, heterozygous in 9 patients (5%) but completely absent in 21 patients (12%). They proposed that the lack of a causative mutation in HLA-H in 12% of their patients was because these cases were not linked to chromosome 6p. A significant weakness in this argument is that all familial studies of the disorder so far have concluded that HH is due to a single major HLA-linked gene5-7. The ultimate test for a candidate gene is the clear segregation of a mutation with the disorder in all patients. Thus, some of the uncertainty surrounding the role of HLA-H in HH may be resolved by the identification of complete concordance of the C282Y mutation (or some other mutation) in HLA H with disease status in HH families. One potential problem in the design of such an experimental analysis is that a number of studies have shown the presence of a predominant ancestral haplotype in all HH populations examined: Australian, French, Italian, UK and US Thus in the analysis of a putative causative mutation, it is important to include families with...

Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10-8) and three variants reported as suggestive (P<5×10-7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10-9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10-9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10-8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma. © 2012 Ramasamy et al.

The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis

Ankylosing spondylitis (AS) is a common and highly heritable inflammatory arthropathy. Although the gene HLA-B27 is almost essential for the inheritance of the condition, it alone is not sufficient to explain the pattern of familial recurrence of the disease. We have previously demonstrated suggestive linkage of AS to chromosome 2q13, a region containing the interleukin 1 (IL-1) family gene cluster, which includes several strong candidates for involvement in the disease. In the current study, we describe strong association and transmission of IL-1 family gene cluster single-nucleotide polymorphisms and haplotypes with AS.

Matters Arising: Zhu et al, "A novel gene variation of TNFα associated with ankylosing spondylitis: A reconfirmed study"

In a recently published study1 involving 79 ankylosing spondylitis (AS) patients and 132 unrelated healthy blood donors, Zhu et al report association of a tumour necrosis factor α (TNFα) single nucleotide polymorphism (SNP), rs1799724, with AS.1 I have many concerns with this paper and its conclusions...

Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese

Objective: To test the association of interleukin 1 (IL1) gene family members with ankylosing spondylitis (AS), previously reported in Europid subjects, in an ethnically remote population. Methods: 200 Taiwanese Chinese AS patients and 200 ethnically matched healthy controls were genotyped for five single nucleotide polymorphisms (SNPs) and the IL1RN.VNTR, markers previously associated with AS. Allele, genotype, and haplotype frequencies were compared between cases and controls. Results: Association of alleles and genotypes of the markers IL1F10.3, IL1RN.4, and IL1RN.VNTR was observed with AS (p<0.05). Haplotypes of pairs of these markers and of the markers IL1RN.6/1 and IL1RN.6/2 were also significantly associated with AS. The strongest associations observed were with the marker IL1RN.4, and with the two-marker haplotype IL1RN.4-IL1RN.VNTR (both p = 0.004). Strong linkage disequilibrium was observed between all marker pairs except those involving IL1B-511 (D′ 0.4 to 0.9, p<0.01). Conclusions: The IL1 gene cluster is associated with AS in Taiwanese Chinese. This finding provides strong statistical support that the previously observed association of this gene cluster with AS is a true positive finding.

Matters Arising: HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis

We read with great interest the paper by Laivoranta-Nyman et al.1 They studied Finnish patients with rheumatoid arthritis (RA) and controls, and suggested that there exist susceptibility, neutral and protective HLA-DR-DQ haplotypes that do not match the predictions of current hypotheses for the mechanism of association of the HLA class II region and RA...

Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis

Objective: To determine the influence of HLA-B27 homozygosity and HLA-DRB1 alleles in the susceptibility to, and severity of, ankylosing spondylitis in a Finnish population. Methods: 673 individuals from 261 families with ankylosing spondylitis were genotyped for HLA-DRB1 alleles and HLA-B27 heterozygosity/ homozygosity. The frequencies of HLA-B27 homozygotes in probands from these families were compared with the expected number of HLA-B27 homozygotes in controls under Hardy-Weinberg equilibrium (HWE). The effect of HLA-DRB1 alleles was assessed using a logistic regression procedure conditioned on HLA-B27 and case-control analysis. Results: HLA-B27 was detected in 93% of cases of ankylosing spondylitis. An overrepresentation of HLA-B27 homozygotes was noted in ankylosing spondylitis (11%) compared with the expected number of HLA-B27 homozygotes under HWE (4%) (odds ratio (OR) = 3.3 (95% confidence interval, 1.6 to 6.8), p = 0.002). HLA-B27 homozygosity was marginally associated with reduced BASDAI (HLA-B27 homozygotes, 4.5 (1.6); HLA-B27 heterozygotes, 5.4 (1.8) (mean (SD)), p = 0.05). Acute anterior uveitis (AAU) was present in significantly more HLA-B27 positive cases (50%) than HLA-B27 negative cases (16%) (OR = 5.4 (1.7 to 17), p<0.004). HLA-B27 positive cases had a lower average age of symptom onset (26.7 (8.0) years) compared with HLA-B27 negative cases (35.7 (11.2) years) (p<0.0001). Conclusions: HLA-627 homozygosity is associated with a moderately increased risk of ankylosing spondylitis compared with HLA-β27 heterozygosity. HLA-B27 positive cases had an earlier age of onset of ankylosing spondylitis than HLA-B27 negative cases and were more likely to develop AAU. HLA-DRB1 alleles may influence the age of symptom onset of ankylosing spondylitis.