Noriko Sasaki

Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women

The Wnt-β-catenin signaling pathway that regulates bone density is also involved in cartilage development and homeostasis in vivo. Here, we assumed that genetic variation in Wnt-β-catenin signaling genes can affect the pathogenesis of cartilage related diseases, such as osteoarthritis. Wnt-1-induced secreted protein 1 (WISP1) is a target of the Wnt pathway and directly regulated by β-catenin. In the present study, we analyzed the association of a single nucleotide polymorphism (SNP) in the WISP1 3′-UTR region with the development of radiographically observable osteoarthritis of the spine. For this purpose, we evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 304 postmenopausal Japanese women. We compared those who carried the G allele (GG or GA, n = 184) with those who did not (AA, n = 120). We found that the subjects without the G allele (AA) were significantly over-represented in the subjects having higher endplate sclerosis score (P = 0.0069; odds ratio, 2.91; 95% confidence interval, 1.34–6.30 by logistic regression analysis). On the other hand, the occurrence of disc narrowing and osteophyte formation did not significantly differ between those with and without at least one G allele. Thus, we suggest that a genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis, in line with the involvement of the Wnt-β-catenin-regulated gene in bone and cartilage metabolism.

Q89r Polymorphism in the Ldl Receptor-related Protein 5 Gene Is Associated With Spinal Osteoarthritis in Postmenopausal Japanese Women

Study Design. An association study investigating the genetic etiology for spinal osteoarthritis. Objective. To determine the association of single-nucleotide polymorphism (SNP) causing an amino-acid change (Q89R) in the low-density lipoprotein receptor-related protein 5 (LRP5) coding region with spinal osteoarthritis. Summary of Background Data. Wnt/β-catenin signaling pathway regulates bone density through a Wnt coreceptor LRP5. This pathway is also involved in cartilage development and homeostasis, suggesting that genetic variation in LRP5 gene may affect the pathogenesis of cartilage-related diseases, such as osteoarthritis. Methods. We evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 357 Japanese postmenopausal women. Missense coding SNP for Q89R of LRP5 gene was determined using TaqMan polymerase chain reaction (PCR) method. Results. We found that subjects without the R allele (QQ; n = 321) had a significantly lower osteophyte formation score than did subjects bearing at least one R allele (QR + RR; n = 36) (7.80 vs. 10.89, P = 0.0019 by analysis of covariance). Conclusions. We suggest that a genetic variation at the LRP5 gene locus is associated with spinal osteoarthritis, in line with the involvement of the LRP5 gene in the bone and cartilage metabolism.

Association of a single nucleotide polymorphism in the insulin-like growth factor-1 receptor gene with spinal disc degeneration in postmenopausal Japanese women.

Study Design. An association study investigating the genetic etiology for spinal disc degeneration. Objective. To determine the association of single-nucleotide polymorphism (SNP) in the insulin-like growth factor-1 receptor (IGF1R) with spinal disc degeneration. Summary of Background Data. Insulin-like growth factor-1 (IGF-1) signaling pathway is involved in cartilage development and homeostasis, suggesting that genetic variations of genes involved in this pathway may affect the pathogenesis of cartilage-related diseases, such as disc degeneration. Methods. We evaluated the presence of endplate sclerosis, osteophytes, and narrowing of disc spaces in 434 Japanese postmenopausal women. A SNP in the IGF1R gene at intron 1 was determined using TaqMan polymerase chain reaction method. Results. We compared those who carried the G allele (GG or GC, n = 290) with those who did not (CC, n = 144). We found that the subjects with the G allele (GG or GC) were significantly over-represented in the subjects having higher disc narrowing score (P = 0.0033; odds ratio, 2.04; 95% confidence interval, 1.27–3.29 by logistic regression analysis). Conclusion. We suggest that a genetic variation at the IGF1R gene locus is associated with spinal disc degeneration, in line with the involvement of the IGF1R gene in the cartilage metabolism.

GPR98/Gpr98 Gene Is Involved in the Regulation of Human and Mouse Bone Mineral Density

CONTEXT Genetic factors are important in the development of osteoporosis. OBJECTIVE The aim of this study was to search for novel genes that regulate bone mineral density (BMD). DESIGN We performed a search for 57,244 single-nucleotide polymorphisms (SNP) associated with BMD using SNP arrays and a replication study. SETTING AND PATIENTS Baseline examinations were conducted in Japanese postmenopausal women. The mean (sd) age of the subjects was 66.5 (8.4) yr. We chose five SNP associated with BMD as those having lower combined P values between the first-stage (n = 251) and the second-stage (n = 499) analyses than the value determined by Bonferronis correction. We also analyzed the bone-related phenotypes in knockout mice of a candidate gene. RESULTS We focused on an SNP of G protein-coupled receptor 98 (GPR98) gene that showed a significant P value after the multiple-comparison tests in Japanese postmenopausal women. The subjects with one or two risk SNP (GG and AG genotype groups) had an increased risk of fractures (AA vs. GG + AG; P = 0.043). Femoral BMD was significantly lower in 12-wk-old Gpr98-knockout mice than in wild-type mice. A three-point bending test revealed that this morphological phenotype did in fact correlate with mechanical fragility in Gpr98-knockout mice. Compared with primary wild-type osteoblasts, primary Gpr98-deficient osteoblasts had increased Rankl expression and induced activity for osteoclastogenesis and osteoclastic function. CONCLUSIONS Genetic analyses in both human and mouse models uncovered the importance of the GPR98 gene in the regulation of bone metabolism.

Large‐scale analysis reveals a functional single‐nucleotide polymorphism in the 5′‐flanking region of PRDM16 gene associated with lean body mass

Genetic factors are important for the development of sarcopenia, a geriatric disorder characterized by low lean body mass. The aim of this study was to search for novel genes that regulate lean body mass in humans. We performed a large‐scale search for 250K single‐nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) using SNP arrays in 1081 Japanese postmenopausal women. We focused on an SNP (rs12409277) located in the 5′‐flanking region of the PRDM16 (PRD1‐BF‐1‐RIZ1 homologous domain containing protein 16) gene that showed a significant P value in our screening. We demonstrated that PRDM16 gene polymorphisms were significantly associated with total body BMD in 1081 postmenopausal Japanese women. The rs12409277 SNP affected the transcriptional activity of PRDM16. The subjects with one or two minor allele(s) had a higher lean body mass than the subjects with two major alleles. Genetic analyses uncovered the importance of the PRDM16 gene in the regulation of lean body mass.

Identification of non-synonymous polymorphisms in the WDSOF1 gene as novel susceptibility markers for low bone mineral density in Japanese postmenopausal women

Genetic factors are important for the development of osteoporosis. During the search for novel markers of single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) by performing a large-scale SNP screen with 251 Japanese postmenopausal women utilizing 50K SNP array, we here focused on the rs1370005 in the WD repeats and SOF1 domain-containing (WDSOF1) gene because we could found common non-synonymous variants in this WDSOF1 gene. The analysis of linkage disequilibrium (LD) in the WDSOF1 gene revealed that rs1370005 and 3 other non-synonymous SNPs (Arg47Ser, Pro108Leu and Ile194Val) lie in a 30-kb region of high LD. Quantitative real-time PCR (qRT-PCR) analysis showed that WDSOF1 mRNA was expressed in mouse primary osteoblasts and osteoclasts, suggesting that WDSOF1 plays some roles in the bone metabolism. We examined the 3 non-synonymous SNPs in WDSOF1 gene in 750 Japanese postmenopausal women. A trend test showed that Arg47Ser, Pro108Leu, and Ile194Val genotypes were significant associated with total body BMD (Arg47Ser; P=0.021, Pro108Leu; P=0.022 and Ile194Val; P=0.009). We also compared Z scores for total body BMD between the subjects bearing at least one minor allele and those lacking the minor allele using unpaired t test. Subjects with the one or two minor alleles had significantly lower Z scores for total body BMD (Arg47Ser; P=0.010, Pro108Leu; P=0.019 and Ile194Val; P=0.003). The present study suggests that these non-synonymous WDSOF1 polymorphisms play a role in the genetic susceptibility to osteoporosis.

Polymorphism of SLC25A32, the folate transporter gene, is associated with plasma folate levels and bone fractures in Japanese postmenopausal women

Elevation of homocysteine is associated with an increased risk for bone fractures. We previously reported that the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is associated with homocysteine levels and fracture. The association between the fracture and folate levels or their related gene polymorphisms is not completely clear. We speculated that the SLC25A32 gene, the mitochondrial inner membrane folate transporter, also could be implicated in the regulation of folate metabolism and fracture.

SLC25A24 as a Novel Susceptibility Gene for Low Fat Mass in Humans and Mice

CONTEXT Genetic factors contribute to the development of obesity. OBJECTIVE The aim of this study was to identify novel genes that regulate body fat mass. DESIGN We performed a search for single nucleotide polymorphisms (SNPs) associated with body fat percentage using SNP arrays and undertook a replication study and animal study. SETTING AND PATIENTS Baseline examinations were conducted in 251 (first-stage analysis), 499 (second-stage analysis), and 732 (additional analyses) Japanese postmenopausal women. The mean age (mean ± SD) of the subjects was 66.5 ± 9.4 years. We also analyzed the fat-related phenotypes of a candidate gene in knockout mice. RESULTS In the analysis of total body fat, we focused on an SNP of SLC25A24 that showed the lowest significant P value obtained from multiple comparison tests among Japanese postmenopausal women. A significant association was also found between SLC25A24 SNPs and body mass index in the 1482 Japanese postmenopausal women examined in the study. The SLC25A24 SNPs affected the mRNA expression of SLC25A24 in human preadipocytes. Compared with wild-type mice, Slc25a24-KO mice had significantly lower body weights and white adipose tissue weights. Adipocyte differentiation was inhibited in Slc25a24-KO adipose tissues and Slc25a24-knockdown adipocytes. CONCLUSIONS Genetic analyses in human and mouse models revealed the importance of SLC25A24/Slc25a24 in the regulation of body fat mass and adipogenesis.