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

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 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.

Determinants of radiographic severity in ankylosing spondylitis

“…Syndesmophyte formation is not consistently preceded by observed erosion, sclerosis or squaring, making their biological relevance unclear. A recent study found that use of the cmSASSS rather than mSASSS increased complete agreement of scores from 69.7% to 81.4% (116). This study also found that cmSASSS remained highly correlated with mSASSS (r 2 > 0.96).…”

“…Consistent with mSASSS validation studies, if less than four corners were lacking scores, they were given the mean score for that vertebral segment (cervical or lumbar) (51). A 'contracted mSASSS' (cmSASSS) was used, scoring 0 for normal vertebral corners, erosion, sclerosis or squaring, 1 for a definite syndesmophyte, and 2 for each corner with a total bony bridge (116). Scores for erosion, and squaring were removed as they reduce inter-rater reliability (55,56).…”

“…If this finding were replicated on a larger scale it would be an indication that the processes that affect BMD over a lifetime differ to the processes that contribute to syndesmophyte formation. This is unlikely given the involvement of inflammatory mediators such as RANK in both BMD and AS, and the connection between TNF and the bone forming Wnt pathway by DKK-1 (27,116,176 Osteoproliferation related alleles in the height score may be diluted beyond significance by alleles related to height only. Despite the relationship between bone metabolism and human height, the role of height loci in the dysfunctional bone metabolism of AS remains to be established.…”

Inflammation-driven bone formation in ankylosing spondylitis: characterisation of the proteoglycan-induced spondylitis mouse model

“…Many of them are involved in the regulation of immune responses suggesting these single nucleotide polymorphisms (SNP) might augment the auto-immunity (Table 1-1). Genes associated with radiographic progression include several MHC molecules, such as HLA-DRB1, HLA-B and HLA-DQA1, as well as other genes mainly involved in bone anabolic and catabolic pathways (Table 1-2) [7][8][9].…”

“…[7][8][9] ... 8 arthritis, enteropathy-related spondylitis and arthritis, and undifferentiated SpA [2].…”