Genome-wide association study identifies ITPR2 as a susceptibility gene for Kashin-Beck disease in Han Chinese

Kashin-Beck disease (KBD) is a chronic osteochondropathy, the pathogenesis of which remains elusive. The aim of this study was to identify susceptibility genes for KBD by conducting a 2-stage genome-wide association study (GWAS). Ninety patients with grade II or grade III KBD with extreme KBD phenotypes and 1,627 healthy control subjects were enrolled in the initial GWAS. Affymetrix Genome-Wide Human SNP Array 6.0 was used for genotyping. For the replication study, 9 single-nucleotide polymorphisms (SNPs) of the significant gene identified by the GWAS (ITPR2) were tested in an independent validation sample composed of 559 patients with KBD and 467 healthy control subjects. The GWAS identified significant association (P = 1.58 × 10(-8) ) between KBD and a novel locus, ITPR2 SNP rs10842750. The replication study showed significant associations with KBD at 9 ITPR2 SNPs, including rs10842750 (P = 5.97 × 10(-3) ), rs16931011 (P = 1.29 × 10(-3) ), rs1531928 (P = 4.95 × 10(-3) ), rs4414322 (P = 4.40 × 10(-3) ), rs11048570 (P = 4.53 × 10(-3) ), rs11048572 (P = 4.43 × 10(-3) ), rs2017510 (P = 4.58 × 10(-3) ), rs9669395 (P = 5.77 × 10(-3) ), and rs1002835 (P = 4.85 × 10(-3) ). In patients with KBD, the genotype score for rs10842750 was also correlated with KBD clinical severity grades (P = 0.013). Our results strongly suggest that ITPR2 is a novel susceptibility gene for KBD in Han Chinese. This study may provide new insights into the pathogenesis and rationale for treatment of KBD as well as other osteoarthritides with similar articular cartilage lesions.