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Ossification of the posterior longitudinal ligament (OPLL) of the spine is a subset of 'bone-forming' diseases, characterized by ectopic ossification in the spinal ligaments. OPLL is a common disorder among elderly populations in eastern Asia and is the leading cause of spinal myelopathy in Japan. We performed a genomewide linkage study with 142 affected sib pairs, to identify genetic loci related to OPLL. In multipoint linkage analysis using GENE- HUNTER-PLUS, evidence of linkage to OPLL was detected on chromosomes 1p, 6p, 11q, 14q, 16q, and 21q. The best evidence of linkage was detected near D21S1903 on chromosome 21q22.3 (maximum Z[SUBlr] = 3.97); therefore, the linkage region was extensively investigated for linkage disequilibrium with single-nucleotidepolymorphisms (SNPs) covering 20 Mb. One hundred fifty positional candidate genes lie in the region, and 600 gene-based SNPs were genotyped. There were positive allelic associations with seven genes (P < .01 ) in 280 patients and 210 controls, and four of the seven genes were clustered within a region of 750 kb, ∼1.2 Mb telomeric to D21S1903. Extensive linkage disequilibrium and association studies of the four genes indicated that SNPs in the collagen 6A1 gene (COL6A1) were strongly associated with OPLL (P = .000003 for the SNP in intron 32 [-29]). Haplotype analysis with three SNPs in COL6A1 gave a single-point P value of .0000007. Identification of the locus of susceptibility to OPLL by genomewide linkage and linkage disequilibrium studies permits us to investigate the pathogenesis of the disease, which may lead to the development of novel therapeutic tools. [ABSTRACT FROM AUTHOR]

Presents information on a study which examined the role of genetic variants of interleukin-3 (IL-3) in the pathophysiology of rheumatoid arthritis (RA) in Japan. Association between RA and a single-nucleotide polymorphism in the IL-3 promoter region; Methodology; Results and discussion.

Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR. [ABSTRACT FROM AUTHOR]

Lumbar-disc herniation (LDH), one of the most common musculoskeletal diseases, has strong genetic determinants. Recently, several genes that encode extracellular matrix (ECM) proteins in the intervertebral disc have been reported to associate with LDH. Thrombospondins (THBSs) 1 and 2 are good candidates for the LDI-I susceptibility gene: They are intervertebral disc ECM proteins that regulate the effective levels of matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling. Here, we report that THBS2 is associated with LDH in Japanese populations. An intronic SNP in THBS2 (IVS10-8C → T; rs9406328) showed significant association (p = 0.0000028) with LDH in two independent Japanese populations. This SNP, located in a polypyrimidine tract upstream of the 3' splice site of intron 10, exerts allelic differences on exon 11 skipping rates in vivo, with the susceptibility allele showing increased skipping. Skipping of exon 11 results in decreased THBS2 interaction with MMP2 and MMP9. Further, a missense SNP in MMP9 (Q279R; rs17576) is also strongly associated with LDH in the Japanese population (p = 0.00049) and shows a combinatorial effect with THBS2 (odds ratio 3.03, 95% confidence interval 1.58-5.77). Thus, a splicing-affecting SNP in THBS2 and a missense SNP in MMP9 are associated with susceptibility to LDH. Our data indicate that regulation of intervertebral disc ECM metabolism by the THBS2MMP system plays an essential role in the etiology and pathogenesis of LDH. [ABSTRACT FROM AUTHOR]

Lumbar disc herniation (LDH), degeneration and herniation of the nucleus pulposus of the intervertebral disc (IVD) of the lumbar spine, is one of the most common musculoskeletal diseases. Its etiology and pathogenesis, however, remain unclear. Type XI collagen is important for cartilage collagen formation and for organization of the extracellular matrix. We identified an association between one of the type XI collagen genes, COL11A1, and LDH in Japanese populations. COL11A1, which encodes the a1 chain of type XI collagen, was highly expressed in IVD, but its expression was decreased in the IVD of patients with LDH. The expression level was inversely correlated with the severity of disc degeneration. A single-nucleotide polymorphism (c.4603C→T [rs1676486]) had the most significant association with LDH (P = 3.3 x 10-6), and the transcript containing the disease-associated allele was decreased because of its decreased stability. These observations indicate that type XI collagen is critical for IVD metabolism and that its decrease is related to LDH. [ABSTRACT FROM AUTHOR]

Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A ne-phropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-nucleotide polymorphisms (SNPs) in the selectin gene cluster on chromosome 1q24-25, and we found two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11) that were significantly associated with IgAN in Japanese patients. All eight SNPs were in almost complete linkage disequilibrium. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser (x² = 9.02, P = .0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38 - 5.38] for His-to-Tyr substitutions; x² = 17.4, P = .000031, odds ratio = 3.61 [95% CI 1.91 - 6.83] for Pro-to-Ser substitutions), and SELL1 could affect promoter activity of the L-selectin gene (x² = 19.5, P = .000010, odds ratio = 3.77 [95% CI 2.02 - 7.05].) The TGT haplotype at these three loci was associated significantly with IgAN (x² = 18.67, P = .000016, odds ratio = 1.88 [95% CI 1.41-2.51]). Our results suggest that these eight SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype that involves interstitial infiltration. [ABSTRACT FROM AUTHOR]

Examines the localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1 in Japan. Factors influencing the occurrence of epilepsy; Use of genetic mapping to identify the pathogenic mechanisms involved in epilepsy; Clinical manifestations of the disease.