Genetic polymorphisms inside and outside the MHC improve prediction of AS radiographic severity in addition to clinical variables

Bartolomé, Nerea; Szczypiorska, Magdalena; Sánchez, Alejandra; Sanz, Jesús; Juanola-Roura, X.; Gratacós, Jordi; Zarco-Montejo, Pedro; Collantes, Eduardo; Martínez, Antonio; Tejedor, Diego; Artieda, Marta; Mulero, Juan

doi:10.1093/rheumatology/kes056

Cited by 18 publications

(11 citation statements)

References 42 publications

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“…This study compared the polymorphisms of genes between patients with at least one syndesmophyte vs those with no syndesmophytes. Two studies have suggested that prediction of radiographic severity was improved by genetic variants by showing prediction model of radiographic severity using the bath ankylosing spondylitis radiology index (BASRI) [10], [30].…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein 6 Polymorphisms Are Associated with Radiographic Progression in Ankylosing Spondylitis

et al. 2014

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Background and ObjectNearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS.MethodsA total of 417 Korean AS patients were classified into two groups based on the radiographic severity as defined by the modified Stoke’ Ankylosing Spondylitis Spinal Score (mSASSS) system. Severe AS was defined by the presence of syndesmophytes and/or fusion in the lumbar or cervical spine (n = 195). Mild AS was defined by the absence of any syndesmophyte or fusion (n = 170). A total of 251 single nucleotide polymorphisms (SNPs) within 52 genes related to bone formation were selected and genotyped. Odds ratios (OR) and 95% confidence interval (95% CI) were analysed by multivariate logistic regression controlling for age at onset of symptoms, sex, disease duration, and smoking status as covariates.ResultsWe identified new loci of bone morphogenetic protein 6 (BMP6) associated with radiographic severity in patients with AS that passed false discovery rate threshold. Two SNPs in BMP6 were significantly associated with radiologic severity [rs270378 (OR 1.97, p = 6.74×10−4) and rs1235192 [OR 1.92, p = 1.17×10−3]) adjusted by covariates.ConclusionThis is the first study to demonstrate that BMP6 is associated with radiographic severity in AS, supporting the role wingless-type like/BMP pathway on radiographic progression in AS.

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Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein 6 Polymorphisms Are Associated with Radiographic Progression in Ankylosing Spondylitis

et al. 2014

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“…The functional severity, radiographic severity and activity of the AS, respectively measured with the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Radiology Index (BASRI) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), can help us study the pathogenesis of the disease. Recently, several studies have associated some biomarkers with the functional and radiographic severity status of the patient[ 19 , 20 ] and with their BASDAI score[ 21 ].…”

Section: Introductionmentioning

confidence: 99%

A Single Nucleotide Polymorphism in the Il17ra Promoter Is Associated with Functional Severity of Ankylosing Spondylitis

et al. 2016

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The aim of this study was to identify new genetic variants associated with the severity of ankylosing spondylitis (AS). We sequenced the exome of eight patients diagnosed with AS, selected on the basis of the severity of their clinical parameters. We identified 27 variants in exons and regulatory regions. The contribution of candidate variants found to AS severity was validated by genotyping two Spanish cohorts consisting of 180 cases/300 controls and 419 cases/656 controls. Relationships of SNPs and clinical variables with the Bath Ankylosing Spondylitis Disease Activity and Functional Indices BASDAI and BASFI were analyzed. BASFI was standardized by adjusting for the duration of the disease since the appearance of the first symptoms. Refining the analysis of SNPs in the two cohorts, we found that the rs4819554 minor allele G in the promoter of the IL17RA gene was associated with AS (p<0.005). This variant was also associated with the BASFI score. Classifying AS patients by the severity of their functional status with respect to BASFI/disease duration of the 60th, 65th, 70th and 75th percentiles, we found the association increased from p60 to p75 (cohort 1: p<0.05 to p<0.01; cohort 2: p<0.01 to p<0.005). Our findings indicate a genetic role for the IL17/ILRA axis in the development of severe forms of AS.

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“…Only polymorphisms in the MHC and in ERAP1 have so far been reported in more than one study to affect clinical or radiographic severity. [9][10][11][12][13] Several other studies have reported other genetic polymorphisms that correlate with disease or radiographic severity, but none have been replicated to date.…”

Section: Introductionmentioning

confidence: 99%

Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis

et al. 2014

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Objective To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). Method We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon–intron boundaries, and 5 kb flanking DNA in the 5′ and 3′ UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into ‘mild’ and ‘severe’ groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. Results Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10−5), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10−3). There was no observed association between radiographic severity and HLA-B*27. Conclusions These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

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Genetic polymorphisms inside and outside the MHC improve prediction of AS radiographic severity in addition to clinical variables

Abstract: Prediction of radiographic severity in AS based on clinical variables can be significantly improved by including SNPs both inside and outside the MHC region.

Cited by 18 publications

References 42 publications

Bone Morphogenetic Protein 6 Polymorphisms Are Associated with Radiographic Progression in Ankylosing Spondylitis

Bone Morphogenetic Protein 6 Polymorphisms Are Associated with Radiographic Progression in Ankylosing Spondylitis

A Single Nucleotide Polymorphism in the Il17ra Promoter Is Associated with Functional Severity of Ankylosing Spondylitis

Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis

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