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Desbuquois dysplasia (DBQD) is a severe skeletal dysplasia of autosomal recessive inheritance. DBQD is classified into types 1 and 2 based on presence or absence of hand anomalies. In a previous study, we found a CANT1 (for calcium-activated nucleotidase 1) mutation, c.676G>A in five DBQD families. They were all East Asians (Japanese or Korean). The high prevalence of the same mutation among Japanese and Korean suggested that it is a common founder mutation in the two populations. To examine a possible common founder, we examined the region around CANT1 in chromosomes with c.676G>A mutation by genotyping polymorphic markers in the region for the families. We examined their haplotypes using the family data. We identified in all families a common haplotype containing the CANT1 mutation that ranged up to 550 kb. The two unrelated carriers of the mutation in general populations in Korea and Japan could also have the haplotype. We estimated the age of the founder mutation as ∼ 1420 years (95% CI=880-1940 years). The c.676G>A mutation of CANT1 commonly seen in Japanese and Korean DBQD should be derived from a common founder.

Osteoarthritis (OA) is a common disease that has a definite genetic component. Only a few OA susceptibility genes that have definite functional evidence and replication of association have been reported, however. Through a genome-wide association study and a replication using a total of approximately 4,800 Japanese subjects, we identified two single nucleotide polymorphisms (SNPs) (rs7775228 and rs10947262) associated with susceptibility to knee OA. The two SNPs were in a region containing HLA class II/III genes and their association reached genome-wide significance (combined P = 2.43x10(-8) for rs7775228 and 6.73x10(-8) for rs10947262). Our results suggest that immunologic mechanism is implicated in the etiology of OA.

Several genes have been implicated in the etiology of ankylosing spondylitis (AS); however, the significance of these genes except HLA-B27 remains to be elucidated. In this study, we examined the association of AS with novel candidate genes and previously reported genes other than HLA-B27. We examined a total of 45 single nucleotide polymorphisms (SNPs) in 15 genes by a sequential screening. We first genotyped 170 Japanese AS patients and 896 controls for the SNPs (first screen). Then, we genotyped eight SNPs with P < 0.05 in the first screen for 108 additional Japanese patients (second screen). We checked the replication of the association of the most significant SNP by genotyping 219 Taiwanese AS patients and 185 controls. When the first and second screens were combined, four SNPs showed nominal significance of P < 0.05. An intronic SNP (IVS1 + 996G > A) in MSX2, a novel candidate gene, showed the most significant association (P = 0.0030). The association was not replicated in our Taiwanese population; however, there was the same trend with the Japanese population in the allelic frequency distribution of the SNP. In the genes previously reported to have association with AS, only one synonymous SNP, c.963T > G in ANKH, showed a marginal association in the Japanese population (P = 0.045).