IBMS BoneKEy | BoneKEy Watch
Novel susceptibility genes for ankylosing spondylitis identified
DOI:10.1038/bonekey.2014.118
Jung et al. report the first genome-wide association study (GWAS) to explore the DNA copy number variations (CNVs) associated with ankylosing spondylitis (AS) using samples from 309 patients and 309 healthy controls, all of whom had Korean ancestry.
A total of 619 186 CNVs were identified; 227 were significantly associated with AS susceptibility. The ten most significant occurred at these loci (the gene, if known, is shown in brackets): 1q32.2 (HHAT), 2q31.2 (PRKRA), 6p21.32 (HLA–DPB1), 13q13.1 (EEF1DP3), 16p13.3, 1p34.2 (BMP8A), 6p24.3 (BMP6), 11q22.1 (CNTN5), 14q24.2 (RGS6) and 22q11.1 (IL17RA). All were deletion-type CNV regions except for 22q11.1, which was a gain-type CNV region. The first five loci listed were associated with a significantly higher risk of developing AS while the rest were protective.
Two separate replication sets confirmed that four CNV regions were consistently significant: 1q32.2 (HHAT), 2q31.2 (PRKRA), 6p21.32 (HLA–DPB1) and 16p13.3. Patients with deletions in four or more risk-associated loci had an 18 times higher risk of developing AS.
Further experiments revealed the deletion breakpoints and the mechanism of formation for three of the CNV regions identified. Notably, the variance within the HHAT gene is suggested as potentially important in promoting osteoblastic activity and to the abnormalities in anabolic and catabolic joint remodeling in arthritis.
Editor’s comment: This study highlights several interesting genes that may be involved in the pathogenesis of AS or in the inflammation process underlying inflammatory arthritis.
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