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Matthew Brown, John Reveille and colleagues report a genome-wide association study for ankylosing spondylitis. They identify four genetic loci outside of the MHC newly associated to AS susceptibility. To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10 −800 ), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10 −19 ) and 21q22 (rs2242944; P = 8.3 × 10 −20 ), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10 −8 ) and IL1R2 (rs2310173; P = 4.8 × 10 −7 ). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10 −14 ) and ERAP1 (rs27434; P = 5.3 × 10 −12 ). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Objective To replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1. Methods Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls. Results The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified. Conclusions The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.

Matthew Brown, Peter Donnelly and colleagues report results of a genome-wide association meta-analysis and follow-up study of ankylosing spondylitis. They identify three new risk variants and report a genetic interaction between ERAP1 and HLA-B27, implicating aberrant peptide handling in the pathophysiology of this disease. Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3 , LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis ( P < 5 × 10 −8 in the combined discovery and replication datasets) and a further four loci at PTGER4 , TBKBP1 , ANTXR2 and CARD9 that show strong association across all our datasets ( P < 5 × 10 −6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1 , which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.

Diabetes The MHC complex, occupying a sizeable section of human chromosome 6, is linked to almost all known autoimmune disorders. A new study uses a large data set from the Wellcome Trust Case Control Consortium to focus more closely on the MHC genes linked to a specific disease, childhood diabetes. Two susceptibility genes emerge: HLA-A and HLA-B . The discovery clarifies the aetiology of type 1 diabetes and points to a class of peptides worth studying in the search for vaccination strategies. New methods and larger sample groups are used to precisely determine the alleles in the HLA complex which contribute susceptibility to type 1 diabetes. The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3 ), but these genes cannot completely explain the association between type 1 diabetes and the MHC region 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . Owing to the region’s extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression—to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P combined = 2.01 × 10 -19 and 2.35 × 10 -13 , respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies 4 , 5 , 6 , 7 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , we conclude that MHC-class-I-mediated events, principally involving HLA-B*39 , contribute to the aetiology of type 1 diabetes.

Ankylosing spondylitis (AS) is polygenic with contributions from the immunologically relevant genes HLA-B*27 , ERAP1 and IL23R . A recent genome-wide association screen (GWAS) identified associations ( P ∼0.005) with the non-synonymous single-nucleotide polymorphisms (nsSNPs), rs4077515 and rs3812571, in caspase recruitment domain-containing protein 9 ( CARD9 ) and small nuclear RNA-activating complex polypeptide 4 ( SNAPC4 ) on chromosome 9q that had previously been linked to AS. We replicated these associations in a study of 730 AS patients compared with 2879 historic disease controls (rs4077515 P= 0.0004, odds ratio (OR)=1.2, 95% confidence interval (CI)=1.1–1.4; rs3812571 P= 0.0003, OR=1.2, 95% CI=1.1–1.4). Meta-analysis revealed strong associations of both SNPs with AS, rs4077515 P= 0.000005, OR=1.2, 95% CI=1.1–1.3 and rs3812571 P= 0.000006, OR=1.2, 95% CI=1.1–1.3. We then typed 1604 AS cases and 1020 controls for 13 tagging SNPs; 6 showed at least nominal association, 5 of which were in CARD9 . We imputed genotypes for 13 additional SNPs but none was more strongly associated with AS than the tagging SNPs. Finally, interrogation of an mRNA expression database revealed that the SNPs most strongly associated with AS (or in strong linkage disequilibrium) were those most associated with CARD9 expression. CARD9 is a plausible candidate for AS given its central role in the innate immune response.

We have retrospectively analyzed 837 random anonymized dried blood spot (DBS) samples from neonatal screening programs in Scandinavia for mutations in HFE, the candidate gene for hemochromatosis. We have found C282Y allele frequencies of 2.3% +2.0%–1.3% in Greenland, 4.5%± 1.9% in Iceland, 5.1%± 2.3% in the Faeroe Islands, and 8.2%± 2.7% in Denmark. The high prevalence of HFE mutations in Denmark suggests that population screening for the C282Y mutation could be highly advantageous in terms of preventive health care. Long‐term follow‐up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes will give an indication of the penetrance of the mutations. Hum Mutat 13:154–159, 1999. © 1999 Wiley‐Liss, Inc.

Haemochromatosis is a genetic disease associated with progressive iron overload, and is common among populations of northern European origin. HLA-H is a recently reported candidate gene for this condition. Two mutations have been identified, a substitution of cysteine for tyrosine at amino acid 282 (C282Y, nucleotide 845) and of histidine for aspartate at amino acid 63 (H63D, nucleotide 187). Over 90% of UK haemochromatosis patients are homozygous for the C282Y mutation. We have examined 5956 chromosomes (2978 people) for the presence of HLA-H C282Y and H63D by PCR followed by restriction enzyme analysis. We have found world wide allele frequencies of 1.9% for C282Y and 8.1% for H63D. The highest frequencies were 10% for C282Y in 90 Irish chromosomes and 30.4% for H63D in 56 Basque chromosomes. C282Y was most frequent in northern European populations and absent from 1042 African chromosomes, 484 Asian chromosomes, and 644 Australasian chromosomes. The distribution of the C282Y mutation coincides with that of populations in which haemochromatosis has been reported and is consistent with the theory of a north European origin for the mutation. The H63D polymorphism is more widely distributed and its connection with haemochromatosis remains unclear.

Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with HLA-B*27 as well as other human leukocyte antigen variants and at least 47 individual non-MHC-associated variants. However, substantial additional heritability remains as yet unexplained. To identify further genetic variants associated with the disease, we undertook an association study of AS in 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. A novel association achieving genome-wide significance was noted at CDKAL1 . Suggestive associations were demonstrated with common variants in FAM118A , C7orf72 and FAM114A1 and with a low-frequency variant in PNPLA1. Two of the variants have been previously associated with inflammatory bowel disease (IBD; CDKAL1 and C7orf72 ). These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having similar aetiopathogenesis. Inflammatory disease: Joint and gut disorders share genes Newly discovered genes linked to an inflammatory disease of the spinal joints confirm a common underpinning with Crohn’s and colitis. Philip Robinson from the University of Queensland, Australia, and colleagues searched for genetic variants associated with ankylosing spondylitis, an inflammatory disease that can cause vertebrae to fuse together. They analyzed the entire protein-coding DNA of 5,040 people with the spinal joint disorder and 21,133 healthy controls. They found strong evidence that a variant of the CDKAL1 gene is a risk factor for ankylosing spondylitis, and weaker evidence for a handful of other variants. Two of these have previously been implicated in the development of Crohn’s disease and colitis, suggesting that these inflammatory bowel diseases and ankylosing spondylitis have a common genetic basis. As such, people with both diseases might respond to the same therapies.