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

Cortes, A., Maksymowych, W. P., Wordsworth, B. P., Inman, R. D., Danoy, P., Rahman, P., Stone, M. A., Corr, M., Gladman, D., Morgan, A., Marzo-Ortega, H., Ward, M. M., Learch, T. J., Reveille, J. D., Brown, M. A. and Weisman, M. H. (2014) Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Annals of the Rheumatic Diseases, 74 7: 1-7. doi:10.1136/annrheumdis-2013-204835


Author Cortes, A.
Maksymowych, W. P.
Wordsworth, B. P.
Inman, R. D.
Danoy, P.
Rahman, P.
Stone, M. A.
Corr, M.
Gladman, D.
Morgan, A.
Marzo-Ortega, H.
Ward, M. M.
Learch, T. J.
Reveille, J. D.
Brown, M. A.
Weisman, M. H.
Title Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis
Journal name Annals of the Rheumatic Diseases   Check publisher's open access policy
ISSN 0003-4967
1468-2060
Publication date 2014-03-20
Year available 2014
Sub-type Article (original research)
DOI 10.1136/annrheumdis-2013-204835
Open Access Status Not yet assessed
Volume 74
Issue 7
Start page 1
End page 7
Total pages 7
Place of publication London, United Kingdom
Publisher B M J Group
Language eng
Abstract To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS).

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.

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.

These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.
Formatted abstract
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 NF?B), 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.
Keyword Ankylosing spondylitis
genetic association study
x-ray
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 19536
U01 AI090909
19356
P01 AR052915
P01-052915
Institutional Status UQ
Additional Notes Available online ahead of print 20 March 2014.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
UQ Diamantina Institute Publications
 
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