A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease.
Martin Tammy M,Zhang Ge,Luo Jingchun,Jin Li,Doyle Trudy M,Rajska Barbara M,Coffman Jessica E,Smith Justine R,Becker Matthias D,Mackensen Friederike,Khan Muhammad A,Levinson Ralph D,Schumacher H Ralph,Wade N Kevin,Rosenbaum James T,Reveille John D
Arthritis and rheumatism
OBJECTIVE:Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS:Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS:As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION:This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
Jostins Luke,Ripke Stephan,Weersma Rinse K,Duerr Richard H,McGovern Dermot P,Hui Ken Y,Lee James C,Schumm L Philip,Sharma Yashoda,Anderson Carl A,Essers Jonah,Mitrovic Mitja,Ning Kaida,Cleynen Isabelle,Theatre Emilie,Spain Sarah L,Raychaudhuri Soumya,Goyette Philippe,Wei Zhi,Abraham Clara,Achkar Jean-Paul,Ahmad Tariq,Amininejad Leila,Ananthakrishnan Ashwin N,Andersen Vibeke,Andrews Jane M,Baidoo Leonard,Balschun Tobias,Bampton Peter A,Bitton Alain,Boucher Gabrielle,Brand Stephan,Büning Carsten,Cohain Ariella,Cichon Sven,D'Amato Mauro,De Jong Dirk,Devaney Kathy L,Dubinsky Marla,Edwards Cathryn,Ellinghaus David,Ferguson Lynnette R,Franchimont Denis,Fransen Karin,Gearry Richard,Georges Michel,Gieger Christian,Glas Jürgen,Haritunians Talin,Hart Ailsa,Hawkey Chris,Hedl Matija,Hu Xinli,Karlsen Tom H,Kupcinskas Limas,Kugathasan Subra,Latiano Anna,Laukens Debby,Lawrance Ian C,Lees Charlie W,Louis Edouard,Mahy Gillian,Mansfield John,Morgan Angharad R,Mowat Craig,Newman William,Palmieri Orazio,Ponsioen Cyriel Y,Potocnik Uros,Prescott Natalie J,Regueiro Miguel,Rotter Jerome I,Russell Richard K,Sanderson Jeremy D,Sans Miquel,Satsangi Jack,Schreiber Stefan,Simms Lisa A,Sventoraityte Jurgita,Targan Stephan R,Taylor Kent D,Tremelling Mark,Verspaget Hein W,De Vos Martine,Wijmenga Cisca,Wilson David C,Winkelmann Juliane,Xavier Ramnik J,Zeissig Sebastian,Zhang Bin,Zhang Clarence K,Zhao Hongyu, ,Silverberg Mark S,Annese Vito,Hakonarson Hakon,Brant Steven R,Radford-Smith Graham,Mathew Christopher G,Rioux John D,Schadt Eric E,Daly Mark J,Franke Andre,Parkes Miles,Vermeire Severine,Barrett Jeffrey C,Cho Judy H
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
Whole-genome single nucleotide polymorphism-based linkage analysis in spondyloarthritis multiplex families reveals a new susceptibility locus in 13q13.
Costantino Félicie,Chaplais Emmanuel,Leturcq Tifenn,Said-Nahal Roula,Leboime Ariane,Zinovieva Elena,Zelenika Diana,Gut Ivo,Charon Céline,Chiocchia Gilles,Breban Maxime,Garchon Henri-Jean
Annals of the rheumatic diseases
OBJECTIVE:Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Apart from HLA-B27, most of the underlying genetic components remain to be identified. We conducted a whole-genome high-density non-parametric linkage analysis to identify new genetic factors of susceptibility to SpA. METHODS:914 subjects including 462 with SpA from 143 multiplex families were genotyped using Affymetrix 250K microarrays. After quality control, 189 368 single nucleotide polymorphisms (SNPs) were kept for further analyses. Both non-parametric and parametric linkage analyses were performed using Merlin software. Association was tested with Unphased. RESULTS:Non-parametric linkage analysis identified two regions significantly linked to SpA: the major histocompatibility complex (LODmax=24.77) and a new 13q13 locus (LODmax=5.03). Additionally, eight loci achieved suggestive LOD scores, including the previously identified SPA2 locus at 9q33 (LODmax=3.51). Parametric analysis supported a codominant model in 13q13 with a maximum heterogeneity LOD, 'HLOD' score of 3.084 (α=0.28). Identification of meiotic recombination events around the 13q13 linkage peak in affected subjects from the 43 best-linked families allowed us to map the disease interval between 38.753 and 40.040 Mb. Family-based association analysis of the SNPs inside this interval in the best-linked families identified a SNP near FREM2 (rs1945502) which reached a p value close to statistical significance (corrected p=0.08). CONCLUSION:We report here for the first time a significant linkage between 13q13 and SpA. Identification of susceptibility factor inside this chromosomal region through targeted sequencing in linked families is underway.
Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.
Ellinghaus David,Jostins Luke,Spain Sarah L,Cortes Adrian,Bethune Jörn,Han Buhm,Park Yu Rang,Raychaudhuri Soumya,Pouget Jennie G,Hübenthal Matthias,Folseraas Trine,Wang Yunpeng,Esko Tonu,Metspalu Andres,Westra Harm-Jan,Franke Lude,Pers Tune H,Weersma Rinse K,Collij Valerie,D'Amato Mauro,Halfvarson Jonas,Jensen Anders Boeck,Lieb Wolfgang,Degenhardt Franziska,Forstner Andreas J,Hofmann Andrea, , , , , ,Schreiber Stefan,Mrowietz Ulrich,Juran Brian D,Lazaridis Konstantinos N,Brunak Søren,Dale Anders M,Trembath Richard C,Weidinger Stephan,Weichenthal Michael,Ellinghaus Eva,Elder James T,Barker Jonathan N W N,Andreassen Ole A,McGovern Dermot P,Karlsen Tom H,Barrett Jeffrey C,Parkes Miles,Brown Matthew A,Franke Andre
We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease.
Robinson Philip C,Leo Paul J,Pointon Jennifer J,Harris Jessica,Cremin Katie,Bradbury Linda A,Stebbings Simon,Harrison Andrew A, , , , , , ,Duncan Emma L,Evans David M,Wordsworth Paul B,Brown Matthew A
NPJ genomic medicine
Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with 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 . Suggestive associations were demonstrated with common variants in , and and with a low-frequency variant in Two of the variants have been previously associated with inflammatory bowel disease (IBD; and ). 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.
Phenome-wide association study maps new diseases to the human major histocompatibility complex region.
Liu Jixia,Ye Zhan,Mayer John G,Hoch Brian A,Green Clayton,Rolak Loren,Cold Christopher,Khor Seik-Soon,Zheng Xiuwen,Miyagawa Taku,Tokunaga Katsushi,Brilliant Murray H,Hebbring Scott J
Journal of medical genetics
BACKGROUND:Over 160 disease phenotypes have been mapped to the major histocompatibility complex (MHC) region on chromosome 6 by genome-wide association study (GWAS), suggesting that the MHC region as a whole may be involved in the aetiology of many phenotypes, including unstudied diseases. The phenome-wide association study (PheWAS), a powerful and complementary approach to GWAS, has demonstrated its ability to discover and rediscover genetic associations. The objective of this study is to comprehensively investigate the MHC region by PheWAS to identify new phenotypes mapped to this genetically important region. METHODS:In the current study, we systematically explored the MHC region using PheWAS to associate 2692 MHC-linked variants (minor allele frequency ≥0.01) with 6221 phenotypes in a cohort of 7481 subjects from the Marshfield Clinic Personalized Medicine Research Project. RESULTS:Findings showed that expected associations previously identified by GWAS could be identified by PheWAS (eg, psoriasis, ankylosing spondylitis, type I diabetes and coeliac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with eight diseases not previously assessed by GWAS (eg, lichen planus) were also identified and replicated in an independent population. Many of these associated diseases appear to be immune-related disorders. Further assessment of these diseases in 16 484 Marshfield Clinic twins suggests that some of these diseases, including lichen planus, may have genetic aetiologies. CONCLUSIONS:These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP-disease associations, and is ideal when characterising cross-phenotype associations, and further emphasise the importance of the MHC region in human health and disease.
MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions.
Wang Geng,Kim Tae-Hwan,Li Zhixiu,Cortes Adrian,Kim Kwangwoo,Bang So-Young,Leo Paul,Brown Matthew A,Xu Huji
Arthritis research & therapy
BACKGROUND:The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort. METHODS:A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects. RESULTS:A strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians. CONCLUSIONS:This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.
Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis.
Momenzadeh Parisa,Mahmoudi Mahdi,Beigy Maani,Garshasbi Masoud,Vodjdanian Mahdi,Farazmand Ali,Jamshidi Ahmad Reza
Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin, while both genetic and environmental factors have been demonstrated to be etiologically involved. Recent genome-wide association and replication studies have suggested that anthrax toxin receptor 2 (ANTXR2), interleukin-1 receptor 2 (IL1R2), caspase recruitment domain-containing protein 9 (CARD9), and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) seem to be associated with AS pathogenesis. This case-control study was performed on 349 unrelated AS patients and 469 age- and gender-matched healthy controls, to investigate whether these non-MHC genes (IL1R2 rs2310173, ANTXR2 rs4333130, CARD9 rs4077515, and SNAPC4 rs3812571) influence the AS risk in Iranian population. ANTXR2 rs4333130 allele C (p = 0.0328; OR 0.744, 95% CI 0.598-0.927) and genotype CC (p = 0.0108; OR 0.273, 95% CI 0.123-0.605) were found to be significantly protective against AS. No other associations were found between AS and studied genes. The association between ANTXR2 rs4333130 and AS was independent of HLA-B27 status. Moreover, we found clinical disease severity scores (BASDAI and BASFI) and pain score were higher in ANTXR2 rs4333130 CT genotype. However, we observed that CARD9 allele C (p = 0.012) and genotype CC (p = 0.012) were significant protective factors against AS only in HLA-B27-negative patients, and IL1R2 rs2310173 genotype GT was mildly protective against AS only in HLA-B27-negative status. These findings support the role of non-MHC pathogenic pathways in susceptibility to AS and warrants more comprehensive studies focusing on these non-MHC pathways for developing novel therapeutic strategies.
An HLA-C amino-acid variant in addition to HLA-B*27 confers risk for ankylosing spondylitis in the Korean population.
Kim Kwangwoo,Bang So-Young,Lee Seunghun,Lee Hye-Soon,Shim Seung-Cheol,Kang Young Mo,Suh Chang-Hee,Sun Celi,Nath Swapan K,Bae Sang-Cheol,Kim Tae-Hwan
Arthritis research & therapy
INTRODUCTION:The presence of the HLA-B*27 allele is a major risk factor for the development of ankylosing spondylitis (AS), which causes chronic inflammation of the spine and other sites. We investigated residual effects outside HLA-B within the major histocompatibility complex (MHC) region in the Korean population. METHODS:Using the Korean HLA reference panel, we inferred the classic HLA alleles and amino-acid residues of the six HLA genes (HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1) and MHC single-nucleotide polymorphisms in 3820 Korean subjects, including 654 Korean cases of AS and 3166 controls, who were genotyped by using Immunochip. Logistic regression and log-likelihood ratio tests were used in AS association tests for imputed markers. RESULTS:The most significant associations were identified at amino-acid positions in the epitope-binding site of HLA-B (P = 1.71 × 10(-481) at position 70, P = 7.20 × 10(-479) at position 97, and P = 2.54 × 10(-484) at positions 114), highlighting the risk effect of the HLA-B*27 allele and the protective effects of other classic alleles. A secondary effect was located at the leucine at amino-acid position 116 in the epitope-binding site of HLA-C (P = 1.69 × 10(-14)), completely tagging the HLA-C*15:02 allele. This residue had a large effect in HLA-B*27-negative patients (odds ratio = 6.6, 95 % confidence interval = 3.8 to 11.4). CONCLUSIONS:The four amino-acid positions of HLA-B and -C account for most of the associations between AS and MHC in the Korean population. This finding updates the list of AS susceptibility loci and provides new insight into AS pathogenesis mediated by MHC class I molecules.
Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.
Evans David M,Spencer Chris C A,Pointon Jennifer J,Su Zhan,Harvey David,Kochan Grazyna,Oppermann Udo,Opperman Udo,Dilthey Alexander,Pirinen Matti,Stone Millicent A,Appleton Louise,Moutsianas Loukas,Moutsianis Loukas,Leslie Stephen,Wordsworth Tom,Kenna Tony J,Karaderi Tugce,Thomas Gethin P,Ward Michael M,Weisman Michael H,Farrar Claire,Bradbury Linda A,Danoy Patrick,Inman Robert D,Maksymowych Walter,Gladman Dafna,Rahman Proton, ,Morgan Ann,Marzo-Ortega Helena,Bowness Paul,Gaffney Karl,Gaston J S Hill,Smith Malcolm,Bruges-Armas Jacome,Couto Ana-Rita,Sorrentino Rosa,Paladini Fabiana,Ferreira Manuel A,Xu Huji,Liu Yu,Jiang Lei,Lopez-Larrea Carlos,Díaz-Peña Roberto,López-Vázquez Antonio,Zayats Tetyana,Band Gavin,Bellenguez Céline,Blackburn Hannah,Blackwell Jenefer M,Bramon Elvira,Bumpstead Suzannah J,Casas Juan P,Corvin Aiden,Craddock Nicholas,Deloukas Panos,Dronov Serge,Duncanson Audrey,Edkins Sarah,Freeman Colin,Gillman Matthew,Gray Emma,Gwilliam Rhian,Hammond Naomi,Hunt Sarah E,Jankowski Janusz,Jayakumar Alagurevathi,Langford Cordelia,Liddle Jennifer,Markus Hugh S,Mathew Christopher G,McCann Owen T,McCarthy Mark I,Palmer Colin N A,Peltonen Leena,Plomin Robert,Potter Simon C,Rautanen Anna,Ravindrarajah Radhi,Ricketts Michelle,Samani Nilesh,Sawcer Stephen J,Strange Amy,Trembath Richard C,Viswanathan Ananth C,Waller Matthew,Weston Paul,Whittaker Pamela,Widaa Sara,Wood Nicholas W,McVean Gilean,Reveille John D,Wordsworth B Paul,Brown Matthew A,Donnelly Peter, ,
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 histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis.
Pointon J J,Harvey D,Karaderi T,Appleton L H,Farrar C,Wordsworth B P
Genes and immunity
Associations with disease identified by genome-wide association studies (GWAS) must be replicated and refined to validate causative variants. In the Wellcome Trust Case Control Consortium (WTCCC) GWAS using 14 500 non-synonymous single nucleotide polymorphisms (nsSNP), rs11062385 (a nsSNP in JARID1A) showed nominal association with ankylosing spondylitis (AS) (P=0.0006, odds ratio (OR)=1.26, 95% confidence interval (95% CI)=1.1-1.4). To replicate and refine the association of JARID1A, rs11062385 was genotyped in 730 further cases and compared with allele frequencies in non-AS disease cohorts typed by WTCCC. We replicated the initial association (P=0.04, OR=1.16, 95% CI=1.01-1.34) and identified a strengthened association with AS in a meta-analysis of this new study combined with the original WTCCC study (P=0.0001, OR=1.21, 95% CI=1.10-1.33). We also genotyped nine further intronic tagging SNPs in JARID1A in 1604 AS cases and 1020 new control samples, but none was associated with AS. JARID1A or a locus in strong linkage disequilibrium with it is a positional candidate for susceptibility to AS.
Variants in RUNX3 contribute to susceptibility to psoriatic arthritis, exhibiting further common ground with ankylosing spondylitis.
Apel Maria,Uebe Steffen,Bowes John,Giardina Emiliano,Korendowych Eleanor,Juneblad Kristina,Pasutto Francesca,Ekici Arif B,McManus Ross,Ho Pauline,Bruce Ian N,Ryan Anthony W,Behrens Frank,Böhm Beate,Traupe Heiko,Lohmann Jörg,Gieger Christian,Wichmann Heinz-Erich,Padyukov Leonid,Fitzgerald Oliver,Alenius Gerd-Marie,McHugh Neil J,Novelli Giuseppe,Burkhardt Harald,Barton Anne,Reis André,Hüffmeier Ulrike
Arthritis and rheumatism
OBJECTIVE:Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. METHODS:Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. RESULTS:Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 × 10(-8) by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.15-1.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 × 10(-2) ; OR 1.13 [95% CI 1.00-1.28]), indicating a role in the skin manifestations of psoriasis. CONCLUSION:Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cell-mediated diseases.
Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.
,Cortes Adrian,Hadler Johanna,Pointon Jenny P,Robinson Philip C,Karaderi Tugce,Leo Paul,Cremin Katie,Pryce Karena,Harris Jessica,Lee Seunghun,Joo Kyung Bin,Shim Seung-Cheol,Weisman Michael,Ward Michael,Zhou Xiaodong,Garchon Henri-Jean,Chiocchia Gilles,Nossent Johannes,Lie Benedicte A,Førre Øystein,Tuomilehto Jaakko,Laiho Kari,Jiang Lei,Liu Yu,Wu Xin,Bradbury Linda A,Elewaut Dirk,Burgos-Vargas Ruben,Stebbings Simon,Appleton Louise,Farrah Claire,Lau Jonathan,Kenna Tony J,Haroon Nigil,Ferreira Manuel A,Yang Jian,Mulero Juan,Fernandez-Sueiro Jose Luis,Gonzalez-Gay Miguel A,Lopez-Larrea Carlos,Deloukas Panos,Donnelly Peter, , , , , ,Bowness Paul,Gafney Karl,Gaston Hill,Gladman Dafna D,Rahman Proton,Maksymowych Walter P,Xu Huji,Crusius J Bart A,van der Horst-Bruinsma Irene E,Chou Chung-Tei,Valle-Oñate Raphael,Romero-Sánchez Consuelo,Hansen Inger Myrnes,Pimentel-Santos Fernando M,Inman Robert D,Videm Vibeke,Martin Javier,Breban Maxime,Reveille John D,Evans David M,Kim Tae-Hwan,Wordsworth Bryan Paul,Brown Matthew A
Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.
Association between vitamin D receptor gene polymorphism and ankylosing spondylitis in Han Chinese.
Zhang Pingping,Li Qiuxia,Qi Jun,Lv Qing,Zheng Xuqi,Wu Xinyu,Gu Jieruo
International journal of rheumatic diseases
OBJECTIVES:To investigate whether vitamin D receptor (VDR) gene polymorphisms confer susceptibility to aankylosing spondylitis (AS) and study its polymorphisms in Han Chinese. METHODS:We screened single nucleotide polymorphisms (SNPs) in the VDR region through genome-wide genotyping chips in AS cases and healthy controls, then used the exome sequencing result to analyze all the potential AS-associated SNPs in the VDR gene. RESULTS:Thirty-two SNPs were found in the VDR gene in the genome-wide genotyping chips and the logistic regression result showed no significant difference between AS cases and controls. A total of 46 SNPs in the VDR region were genotyped through exome sequencing, including four functional SNPs (rs731236 [TaqI], rs2228570 [FokI], rs7975232 [ApaI], rs1544410 [BsmI]) and two newly discovered SNPs (12:48259222 and 12:48276730). To note, rs731236 and rs2228570 locate in the exons of VDR, which cause synonymous and missense mutation. The association test showed there was no significant difference between AS cases and controls in the allele frequency distribution, but haplotype analysis of rs11168266-rs11168267 show nominal significance (P = 0.01268). CONCLUSION:Our preliminary study indicates the haplotypes (TG) of rs11168266-rs11168267 in the VDR gene confers susceptibility to AS, which is worth further research.
Genome-wide copy number variation analysis identifies deletion variants associated with ankylosing spondylitis.
Jung Seung-Hyun,Yim Seon-Hee,Hu Hae-Jin,Lee Kyu Hoon,Lee Joo-Hyun,Sheen Dong-Hyuk,Lim Mi-Kyoung,Kim Soon-Young,Park Sung-Won,Kim So-Hee,Han Kyudong,Kim Tae-Hwan,Shim Seung-Cheol,Chung Yeun-Jun
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:To identify ankylosing spondylitis (AS)-associated copy number variations (CNVs) in Korean subjects and their synergistic roles in the development of AS. METHODS:A genome-wide association study (GWAS) was performed in 309 patients with AS and 309 control subjects, using a copy number variant (CNV) microarray. AS-associated CNV regions were replicated in 2 independent sets (625 patients and 891 control subjects) by quantitative polymerase chain reaction (PCR) and deletion-typing PCR. RESULTS:In the CNV GWAS, 227 CNV regions were shown to be significantly associated with the risk of AS. Of the candidate CNV regions, 9 were successfully replicated in the first replication analysis: 1q32.2 (HHAT), 1p34.2 (BMP8A), 2q31.2 (PRKRA), 6p21.32 (HLA-DPB1), 11q22.1 (CNTN5), 13q13.1 (EEF1DP3), 14q24.2 (RGS6), 16p13.3, and 22q11.1 (IL17RA). The 5 deletion-type CNV regions, in 1q32.2, 2q31.2, 6p21.32, 13q13.1, and 16p13.3, were associated with an increased risk of AS, and the other 4 CNV regions were protective. In the second replication analysis, 4 CNV regions in 1q32.2, 2q31.2, 6p21.32, and 16p13.3 were replicated. Among patients with CNV regions in ≥4 risk-increasing loci, the risk was 18.0 times higher than that in patients without any deletions (odds ratio [OR] 17.98, P = 2.3 × 10(-7) ). Among patients with CNV regions in ≥2 protective loci, the risk was 5.2 times lower than that in those without any deletions (OR 0.19, P = 4.0 × 10(-10) ). The additive effects of simultaneous events were shown to be dependent on the frequency of CNV regions. Through deletion-typing PCR and sequencing, the exact sizes and breakpoint sequences were defined in 4 CNV regions. The mechanism of all 3 deletions was shown to be microhomology-based nonhomologous end joining. CONCLUSION:The results of this study can help to identify pathogenic mechanisms of AS and can easily be applied in the development of algorithms estimating the risk of AS.
A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14.
Costantino Félicie,Talpin Alice,Said-Nahal Roula,Leboime Ariane,Zinovieva Elena,Zelenika Diana,Gut Ivo,Charon Céline,Izac Brigitte,Weissman Michael,Chiocchia Gilles,Reveille John,Breban Maxime,Garchon Henri-Jean
Annals of the rheumatic diseases
OBJECTIVE:More than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA. METHODS:906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations. RESULTS:43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10). Such association appeared to be independent of HLA-B27. CONCLUSIONS:We report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.
Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.
,Reveille John D,Sims Anne-Marie,Danoy Patrick,Evans David M,Leo Paul,Pointon Jennifer J,Jin Rui,Zhou Xiaodong,Bradbury Linda A,Appleton Louise H,Davis John C,Diekman Laura,Doan Tracey,Dowling Alison,Duan Ran,Duncan Emma L,Farrar Claire,Hadler Johanna,Harvey David,Karaderi Tugce,Mogg Rebecca,Pomeroy Emma,Pryce Karena,Taylor Jacqueline,Savage Laurie,Deloukas Panos,Kumanduri Vasudev,Peltonen Leena,Ring Sue M,Whittaker Pamela,Glazov Evgeny,Thomas Gethin P,Maksymowych Walter P,Inman Robert D,Ward Michael M,Stone Millicent A,Weisman Michael H,Wordsworth B Paul,Brown Matthew A
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 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 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.
A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis.
Lin Zhiming,Bei Jin-Xin,Shen Meixin,Li Qiuxia,Liao Zetao,Zhang Yanli,Lv Qing,Wei Qiujing,Low Hui-Qi,Guo Yun-Miao,Cao Shuangyan,Yang Mingcan,Hu Zaiying,Xu Manlong,Wang Xinwei,Wei Yanlin,Li Li,Li Chao,Li Tianwang,Huang Jianlin,Pan Yunfeng,Jin Ou,Wu Yuqiong,Wu Jing,Guo Zishi,He Peigen,Hu Shaoxian,Wu Husheng,Song Hui,Zhan Feng,Liu Shengyun,Gao Guanmin,Liu Zhangsuo,Li Yinong,Xiao Changhong,Li Juan,Ye Zhizhong,He Weizhen,Liu Dongzhou,Shen Lingxun,Huang Anbin,Wu Henglian,Tao Yi,Pan Xieping,Yu Buyun,Tai E Shyong,Zeng Yi-Xin,Ren Ee Chee,Shen Yan,Liu Jianjun,Gu Jieruo
To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.