Genetic variants in the HLA-DRB1 gene are associated with Kashin-Beck disease in the Tibetan population.

Objective To investigate the association between variants in the HLA–DRB1 gene and Kashin-Beck disease (KBD), as well as associations of selenium and iodine deficiencies with KBD in a Tibetan population. Methods Fourteen single-nucleotide polymorphisms (SNPs) were genotyped around the HLA–DRB1 gene, and HLA–DRB1 allele genotyping was performed in a discovery cohort, composed of 605 patients with KBD and 393 control subjects, and/or a replication cohort, composed of 290 patients with KBD and 295 controls. Plasma concentrations of selenium and iodine were measured and compared by t-test in 299 patients with KBD and 280 controls from the same villages. Results Four SNPs (rs6457617, rs6457620, rs9275295, and rs7745040) in the HLA–DRB1 gene locus were significantly associated with KBD in both the discovery cohort and replication cohort (combined cohort odds ratios [ORs] 1.307–1.402, P = 0.0039–0.0006). The protective haplotype GTCC and the risk haplotype ACGT, each generated by the 4 SNPs, showed a significant association with KBD (for GTCC, OR 0.77, P = 0.0031; for ACGT, OR 1.40, P = 0.0014). HLA–DRB1 allele genotyping revealed that the frequencies of HLA–DRB1*08 and *11 were significantly different between patients with KBD and controls (for HLA–DRB1*08, OR 0.731, P = 0.00564; for HLA–DRB1*11, OR 0.489, P = 0.000395). Moreover, plasma concentrations of selenium and iodine were significantly different between patients with KBD and controls from the same villages (P = 0.0013 and P = 1.84 × 10−12, respectively). Conclusion These findings, obtained in plasma samples from Tibetan patients with KBD and healthy control subjects from the same regions, confirm the role of selenium and iodine deficiencies in the development of KBD. Moreover, genetic variants in the HLA–DRB1 gene significantly increase the susceptibility to KBD in this population.