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Genetic polymorphisms and sex differences are suggested to affect muscle fiber composition; however, no study has investigated the effects of genetic polymorphisms on muscle fiber composition with respect to sex differences. Therefore, the present study examined the effects of genetic polymorphisms on muscle fiber composition with respect to sex differences in the Japanese population. The present study included 211 healthy Japanese individuals (102 men and 109 women). Muscle biopsies were obtained from the vastus lateralis to determine the proportion of myosin heavy chain (MHC) isoforms (MHC-I, MHC-IIa, and MHC-IIx). Moreover, we analyzed polymorphisms in α-actinin-3 gene ( ACTN3; rs1815739 ), angiotensin-converting enzyme gene ( ACE; rs4341 ), hypoxia-inducible factor 1 α gene ( rs11549465 ), vascular endothelial growth factor receptor 2 gene ( rs1870377 ), and angiotensin II receptor, type 2 gene ( rs11091046 ), by TaqMan single-nucleotide polymorphism genotyping assays. The proportion of MHC-I was 9.8% lower in men than in women, whereas the proportion of MHC-IIa and MHC-IIx was higher in men than in women (5.0 and 4.6%, respectively). Men with the ACTN3 RR + RX genotype had a 4.8% higher proportion of MHC-IIx than those with the ACTN3 XX genotype. Moreover, men with the ACE ID + DD genotype had a 4.7% higher proportion of MHC-I than those with the ACE II genotype. Furthermore, a combined genotype of ACTN3 R577X and ACE insertion/deletion (I/D) was significantly correlated with the proportion of MHC-I ( r = -0.23) and MHC-IIx ( r = 0.27) in men. In contrast, no significant correlation was observed between the examined polymorphisms and muscle fiber composition in women. These results suggest that the ACTN3 R577X and ACE I/D polymorphisms independently affect the proportion of human skeletal muscle fibers MHC-I and MHC-IIx in men but not in women. NEW & NOTEWORTHY In men, the RR + RX genotype of the α-actinin-3 gene ( ACTN3) R577X polymorphism was associated with a higher proportion of myosin heavy chain (MHC)-IIx. The ID + DD genotype of the angiotensin-converting enzyme gene ( ACE) insertion/deletion (I/D) polymorphism, in contrast to a previous finding, was associated with a higher proportion of MHC-I in men. In addition, the combined genotype of these polymorphisms was correlated with the proportion of MHC-I and MHC-IIx in men. Thus ACTN3 R577X and ACE I/D polymorphisms influence the muscle fiber composition in Japanese men.

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at -420 (rs1862513) and -358 (rs3219175) located in the human resistin gene ( RETN ) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP -358 G>A, followed by rs1423096 C>T, SNP -420 C>G, and rs10401670 C>T ( P = 5.39×10 -47 , 1.81×10 -22 , 2.09×10 -16 , and 9.25×10 -15 , respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3'-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population., (Copyright © 2016 the American Physiological Society.)

Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping., (Copyright © 2016. Published by Elsevier Inc.)

Introduction: Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA., Method: We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed., Results: Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10(-8)), followed by rs6986423 in CSMD1 (p = 2.4 × 10(-6)) and rs17727339 in FCRL3 (p = 1.4 × 10(-5)). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations., Conclusion: Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

Objective: While antinuclear antibodies (ANAs) are observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), the detailed genetic background of ANAs has remained unclear. We undertook this study to identify the genetic determinants of ANAs in the general population in order to elucidate the underlying mechanisms of ANA production and to distinguish disease susceptibility genes from ANA production genes., Methods: A total of 9,575 Japanese volunteers were registered, and their ANA levels were quantified using indirect immunofluorescence to analyze correlates of ANA positivity. Genetic studies were performed using 7,148 of the 9,575 subjects. We performed a genome-wide association study using 3,185 subjects genotyped for 303,506 single-nucleotide polymorphisms (SNPs), followed by a replication study of 3,963 subjects. HLA-DRB1 and HLA-DQB1 alleles were imputed, and associations between ANA positivity and the SNPs or the HLA alleles associated with SLE were analyzed., Results: Female sex and old age were associated with ANA positivity, except for the nucleolar pattern. The T allele of rs2395185 in the HLA locus, which was in moderate linkage disequilibrium with HLA-DRB1*0405, was significantly associated with ANA positivity (P = 1.3 × 10(-11) ). The T allele of rs2395185 displayed increasing effects on the frequency of speckled and homogeneous patterns (P = 7.5 × 10(-12) and P = 2.2 × 10(-11) , respectively) but decreasing effects on the frequency of the nucleolar pattern (P = 0.0045). The 7 SNPs and 4 HLA-DRB1 alleles associated with SLE did not display strong associations with ANA positivity., Conclusion: SNP rs2395185 linked with HLA-DRB1*0405 is a genetic determinant of ANA production in the Japanese population. Overlapping of loci for susceptibility to SLE and to ANA positivity was limited. The nucleolar pattern showed different associations from other staining patterns, both with correlates of ANA positivity and with the HLA locus., (Copyright © 2014 by the American College of Rheumatology.)

Background: Prostate-specific antigen (PSA) is a useful marker for prostate cancer (PCa) and is widely used for screening of PCa. Previous studies have shown that genetic components influence the levels of PSA, and some of these genetic components would lead to better diagnostic sensitivity and specificity to PCa. However, genetic studies for PSA from Asian countries are limited. Our aim was to identify genetic components influencing PSA levels in the Japanese population using genome-wide association study (GWAS) and to analyse whether genetic components would lead to better screening abilities of PCa., Methods: We performed a GWAS comprising 1086 male subjects using 303 283 single nucleotide proteins, followed by a replication study of 1302 subjects. PSA levels were quantified by chemiluminescence immunoassay method. Quantitative linear regression analysis was performed to assess genetic components of PSA levels. A total of 413 subjects with prostate biopsies were analysed to examine whether genetic determinants would improve diagnostic ability., Results: Rs16856139 in SLC45A3, the same region as the previous Chinese study, showed an overall significant association with PSA levels (p=2.4×10(-11)) along with rs1058205 in KLK3. In silico analysis revealed significant association between rs16856139 and expression of SLC45A3. Genetic scores of PSA showed a dose-dependent decrease of area under curve (AUC) of PCa and successfully subgrouped the individuals with significantly different AUC (p≤0.0097)., Conclusions: Rs16856139, associated with the expression of SLC45A3, is significantly associated with the levels of PSA in the Japanese population. Classification of subjects based on PSA genetic determinants would improve screening ability of PSA to detect PCa., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective. To re-evaluate the roles of HLA-DRB1 alleles in susceptibility to SLE and RA and their effects on autoantibody status in large-scale Japanese cohorts. Methods. A total of 656 SLE, 2410 RA and 911 control subjects, who were all Japanese, were genotyped for HLA-DRB1 alleles using sequence-specific oligonucleotide probes. The association of alleles with disease susceptibility was tested by logistic regression analysis and by the relative predispositional effect method. The association with autoantibody status was examined by the standard χ(2) test. Results. HLA-DRB1*15:01, *09:01, *08:02 and *04:01 were significantly associated with SLE susceptibility, while shared epitope (SE) alleles and DRB1*09:01 were associated with RA susceptibility. The compound heterozygote of DRB1*09:01/*15:01 conferred an increased risk for SLE compared with the homozygotes for DRB1*09:01 and *15:01 and was associated with earlier onset of disease, whereas the compound effect of DRB1-SE/*09:01 was not clear in RA. DRB1*09:01 was significantly associated with the appearance of anti-Sm antibody in SLE as well as ACPA in RA, while protectively associated with anti-dsDNA antibody in SLE. No significant interaction was observed between DRB1*09:01 and smoking status for the appearance of ACPA, unlike that observed in SE alleles in RA. Conclusion. We identified HLA-DRB1 alleles associated with SLE and RA in a Japanese population and demonstrated a shared susceptibility of DRB1*09:01 between the diseases as well as its effect on autoantibody production.

Purpose: To investigate whether genetic variations in the insulin-like growth factor 1 (IGF-1) gene are associated with high myopia in Japanese., Methods: A total of 1,339 unrelated Japanese patients with high myopia (axial length ≥26 mm in both eyes) and two independent control groups were evaluated (334 cataract patients without high myopia and 1,194 healthy Japanese individuals). The mean axial length (mm±SD) in the case group was 29.18±1.85 mm, and the mean spherical equivalent (D±SD) of the phakic eyes was -12.69±4.54 D. We genotyped five tagging single nucleotide polymorphisms (SNPs) in IGF-1: rs6214, rs978458, rs5742632, rs12423791, and rs2162679. Chi-square tests for trend, multivariable logistic regression, and haplotype regression analysis were conducted., Results: We found no significant association between the IGF-1 SNPs and high or extreme myopia (axial length ≥28 mm in both eyes, 837 subjects) in the additive model, even when compared with the cataract and general population controls, with or without adjustments for age and sex. The evaluation using dominant and recessive models also did not reveal any significant associations. The haplotype analysis with a variable-sized sliding-window strategy also showed a lack of association of IGF-1 SNPs with high or extreme myopia., Conclusions: The results of the present study using a Japanese subset do not support the proposal that the IGF-1 gene determines susceptibility to high or extreme myopia in Caucasians and Chinese. Further studies are needed to confirm our reports in other populations and to identify the underlying genetic determinants of these ocular pathological conditions.

Aims: To investigate whether objective cardiovascular parameters have an independent association with nocturnal voiding in women., Methods: Thirty-two parameters derived from questionnaires, and anthropometric, physiological and biochemical measures of 5,980 women were applied for analysis. Nocturnal voiding was assessed by the International Prostate Symptom Score and the Overactive Bladder Symptom Score. We measured variables including previously reported correlates of nocturnal voiding, such as age, a history of hypertension, and a history of diabetes, as well as those focusing on cardiovascular function, such as the cardio-ankle vascular index, the augmentation index, the ankle-brachial index, plasma B-type natriuretic peptide (BNP), and C-reactive protein (CRP)., Results: Age [odds ratio (OR): 1.058, P < 0.001], length of sleep (OR: 1.194, P < 0.001), sleeplessness (OR: 2.841, P < 0.001), urgency (OR: 1.528, P < 0.001), log(BNP) (OR: 2.031, P < 0.001), waist circumference (OR: 1.037, P = 0.002), body mass index (OR: 0.935, P = 0.007), menopause (OR: 1.503, P = 0.043), and history of hypertension (OR: 1.225, P = 0.029) were independently associated with nocturnal voiding ≥2 times. Age (β = 0.256, P < 0.001), urgency (β = 0.195, P < 0.001), sleeplessness (β = 0.181, P < 0.001), length of sleep (β = 0.088, P < 0.001), log(BNP) (β = 0.072, P < 0.001), waist circumference (β = 0.086, P < 0.001), and low-density lipoprotein-cholesterol (β = -0.038, P = 0.003) were significantly correlated with the severity of nocturnal voiding., Conclusions: Plasma BNP, which represents cardiac load, is strongly associated with the prevalence and severity of nocturnal voiding in Japanese women, as well as previously known correlates including age, urgency, quality and quantity of sleep, and obesity., (Copyright © 2012 Wiley Periodicals, Inc.)

HLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA). However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated peptide/protein antibody (ACPA). We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes. Here, we attempted to detect genetically different subsets of ACPA-negative RA by classifying ACPA-negative RA patients into two groups based on their positivity for rheumatoid factor (RF). HLA-DRB1 genotyping data for totally 954 ACPA-negative RA patients and 2,008 healthy individuals in two independent sets were used. HLA-DRB1 allele and diplotype frequencies were compared among the ACPA-negative RF-positive RA patients, ACPA-negative RF-negative RA patients, and controls in each set. Combined results were also analyzed. A similar analysis was performed in 685 ACPA-positive RA patients classified according to their RF positivity. As a result, HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-negative RF-positive RA in the combined analysis (p = 8.8×10(-6) and 0.0011, OR: 1.57 (1.28-1.91) and 1.37 (1.13-1.65), respectively). We also found that HLA-DR14 and the HLA-DR8 homozygote were associated with ACPA-negative RF-negative RA (p = 0.00022 and 0.00013, OR: 1.52 (1.21-1.89) and 3.08 (1.68-5.64), respectively). These association tendencies were found in each set. On the contrary, we could not detect any significant differences between ACPA-positive RA subsets. As a conclusion, ACPA-negative RA includes two genetically distinct subsets according to RF positivity in Japan, which display different associations with HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with HLA-DRB1*04:05 and *09:01. ACPA-negative RF-negative RA is associated with DR14 and the HLA-DR8 homozygote.

Purpose: The objective of this study was to investigate whether genetic variations in the paired box 6 (PAX6) gene are associated with high myopia in Japanese subjects., Methods: A total of 1,307 unrelated Japanese patients with high myopia (axial length ≥26 mm in both eyes) and two independent control groups were evaluated (333 cataract patients without high myopia and 923 age-matched healthy Japanese individuals). We genotyped three tag single-nucleotide polymorphisms (SNPs) in PAX6: rs2071754, rs644242, and rs3026354. These SNPs provided 100% coverage of all phase II HapMap SNPs within the PAX6 region (minor allele frequency ≥0.10; r(2) threshold: 0.90). Chi-square tests for trend and multivariable logistic regression were conducted., Results: Genotype distributions in the three SNPs were in accordance with the Hardy-Weinberg equilibrium. After adjusting for age and sex, evaluation of cataract control showed a marginal association with high myopia in rs644242 (odds ratio [95% confidence interval]=0.69 [0.49-0.96], p=0.026), and a significant association was observed in healthy Japanese controls (0.79 [0.66-0.96], p=0.015). We pooled two control cohorts to evaluate the association. This analysis revealed a strong association between rs644242 and high myopia (0.78 [0.65-0.92], p=0.0045). The rs644242 A allele was a protective allele for development of high myopia. Subanalysis also revealed that rs644242 was significantly associated with extreme high myopia (0.78 [0.64-0.95], p=0.0165). The other two SNPs did not show a significant association with this condition., Conclusions: The current study showed a significant association of PAX6 with high and extreme myopia in Japanese participants. The A allele of rs644242 is a protective allele.

Background: FOXE1 and NKX2-1 are two known genetic risk factors for the predisposition to sporadic papillary thyroid carcinoma (PTC) in Europeans, but their association in other ethnicities is still unknown., Objective: We aim to examine the association of the two genes with Japanese sporadic PTC, which exhibits high BRAF(V600E) mutation rate., Methods: 507 Japanese sporadic PTC cases and 2766 controls were genotyped for rs965513 (FOXE1) and rs944289 (NKX2-1). PTC cases were also examined for their BRAF(V600E) mutational status., Results: The association of both rs965513 (p=1.27×10(-4), OR=1.69, 95% CI 1.29 to 2.21) and rs944289 (p=0.0121, OR=1.21, 95% CI 1.04 to 1.39) with the risk of sporadic PTC was confirmed. Subgroup analysis based on the BRAF mutational status showed strong association of rs965513 with BRAF(V600E)-positive cases (p=2.26×10(-4), OR=1.72, 95% CI 1.29 to 2.29), but not with BRAF(V600E)-negative cases (p=0.143, OR=1.52, 95% CI 0.87 to 2.65). However, there was no difference in the observed effect size between both subgroups. For rs944289, both subgroups showed marginal association (p=0.0585, OR=1.17, 95% CI 0.99 to 1.37 for BRAF(V600E)-positive cases; p=0.0492, OR=1.35, 95% CI 1.00 to 1.81 for BRAF(V600E)-negative cases)., Conclusions: Both FOXE1 and NKX2-1 were associated with the increased risk of sporadic Japanese PTC. No clear associations were observed for either SNP with BRAF(V600E) status.

Rheumatoid arthritis (RA) is a typical complex trait and the major cause of chronic inflammation worldwide. Although multiple genetic loci have been shown for their association with the onset of RA, they cover only a part of its genetic components and are largely ethnicity-specific. To identify novel genetic factors related to the predisposition and prognosis of RA in Japanese, we conducted a large-scale genome-wide association (GWA) study. We performed a GWA analysis by scanning the genome of 1247 RA cases and 1486 controls for 277 420 single nucleotide polymorphisms (SNPs), followed by replication analysis using two independent sample sets consisting of 1865 cases and 1623 controls, and 2303 cases and 3380 controls. We identified two SNPs, rs2075876 and rs760426, in intron of the autoimmune regulator AIRE gene at chromosome 21q22 that showed strong associations with the disease (P= 3.6 × 10(-9) and P= 4.4 × 10(-8), respectively). Rs1800250, in exon7 of AIRE, was in strong linkage disequilibrium (r(2)= 0.94) with rs2075876 and introduced an amino acid alteration (S278R) in the SAND domain of the AIRE protein. In silico analysis showed the decreased transcription of AIRE by the risk allele of rs2075876 compared with the alternative allele (P= 6.8 × 10(-5)). No correlation was observed between the rs2075876 genotype and quantitative traits reflecting the progression of RA. As AIRE is a key molecule which regulates the expression and presentation of self-antigens in thymic negative selection, its downregulation by genetic polymorphisms may result in the survival of auto-reactive T cells to trigger auto-inflammation in RA.

Purpose: To investigate whether there are associations of genetic variations in chromosome 15q14 and 15q25, recently shown to confer risk of refractive error and myopia in Caucasians, with high myopia in Japanese., Methods: A total of 1125 unrelated Japanese patients with high myopia and two independent control groups were evaluated (366 cataract patients without high myopia and 929 healthy Japanese patients). The four single nucleotide polymorphisms (SNPs) rs634990 and rs524952 at 15q14 and rs8027411 and rs17175798 at 15q25 were genotyped., Results: A significant association with high myopia was observed in 15q14 (P = 0.0035 for rs634990 and P = 0.0017 for rs524952 when evaluated with cataract controls and P = 1.91 × 10(-6) for rs634990 and P = 8.78 × 10(-7) for rs524952 with healthy Japanese controls). When evaluated with cataract controls, the odds ratios (95% confidence intervals) were 1.30 (1.10-1.53) for rs634990 C allele and 1.32 (1.11-1.56) for rs524952 A allele. The population attributable risks were 0.29 and 0.30, respectively. The SNPs in 15q25 did not show a significant association with high myopia when evaluated with cataract control (P > 0.42), while it showed a weak association when evaluated with healthy Japanese controls (P = 0.031 for rs8027411 and P = 0.047 for rs17175798) with odds ratios of 1.17 (1.03-1.33) for rs8027411 T allele and 1.15 (1.02-1.31) for rs17175798 C allele., Conclusions: These findings suggest that a region in 15q14 is susceptibility loci for high myopia. This locus harbor susceptibility genes for not only common myopia but also for high myopia. The 15q25 locus might also have association to myopia.

Purpose: Recently, a complement component 1 inhibitor (SERPING1) gene polymorphism was identified as a novel risk factor for age-related macular degeneration (AMD) in Caucasians. We aimed to investigate whether variations in SERPING1 are associated with typical AMD or with polypoidal choroidal vasculopathy (PCV) in a Japanese population., Methods: We performed a case-control study in a group of Japanese patients with typical AMD (n = 401) or PCV (n = 510) and in 2 independent control groups--336 cataract patients without age-related maculopathy and 1,194 healthy Japanese individuals. Differences in the observed genotypic distribution between the case and control groups were tested using chi-square test for trend. Age and gender were adjusted using logistic regression analysis., Results: We targeted rs2511989 as the haplotype-tagging single nucleotide polymorphism (SNP) for the SERPING1 gene, which was reported to be associated with the risk of AMD in Caucasians. Although we compared the genotypic distributions of rs2511989 in typical AMD and PCV patients against 2 independent control groups (cataract patients and healthy Japanese individuals), SERPING1 rs2511989 was not significantly associated with typical AMD (P = 0.932 and 0.513, respectively) or PCV (P = 0.505 and 0.141, respectively). After correction for age and gender differences based on a logistic regression model, the difference in genotypic distributions remained insignificant (P>0.05). Our sample size had a statistical power of more than 90% to detect an association of a risk allele with an odds ratio reported in the original studies for rs2511989 for developing AMD., Conclusions: In the present study, we could not replicate the reported association between SERPING1 and either neovascular AMD or PCV in a Japanese population; thus, the results suggest that SERPING1 does not play a significant role in the risk of developing AMD or PCV in Japanese.

Purpose: Polymorphisms in the promoter regions of matrix metalloproteinase (MMP) genes can cause variations in the expression of the MMP genes in the sclera that can lead to a greater susceptibility to axial elongation of the eye. The purpose of this study was to determine whether functional single-nucleotide polymorphisms (SNPs) in the MMP1, -2, and -3 promoter regions are associated with high myopia in the Japanese., Methods: Seven hundred twenty-five unrelated Japanese patients with high myopia (axial length of >or=26.0 mm in both eyes, or refractive error>or=-6.0 D in phakic cases) and >or=40 years of age were studied. Five hundred forty-six healthy, unrelated Japanese who were >or=40 years of age served as population-based control subjects. All the subjects were genotyped for the four functional SNPs MMP1 -1607 1G/2G, MMP2 C-1306T, MMP2 C-735T, and MMP3 -1612 5A/6A with an SNP assay. The distribution of the genotypes in the cases and control subjects was compared by the chi2 test for trend., Results: No significant difference was detected in the distribution of the four SNPs MMP1 -1607 1G/2G (P=0.92), MMP2 C-1306T (P=0.83), MMP2 C-735T (P=0.10), and MMP3 -1612 5A/6A (P=0.62), between the high myopia cases and the general-population controls., Conclusions: The four functional SNPs in the MMP1, -2, and -3 promoter regions do not play critical roles in the development of high myopia in the Japanese population.

Purpose: To determine the characteristics of the polymorphisms in the ARMS2 gene in Japanese patients with age-related macular degeneration (AMD) and those with polypoidal choroidal vasculopathy (PCV) and in healthy controls, and also to show possible associations of the polymorphisms with the disease., Design: Case-control association study., Methods: Fifty-six unrelated Japanese individuals with AMD, 55 with PCV, and 77 controls were studied. The most common polymorphism in the ARMS2 gene on chromosome 10 was resequenced. Association tests were performed for inferred haplotypes., Results: A total of 22 polymorphisms were identified, and 13 were shared with those in White persons with AMD. The sequence of the deletion-and-insertion polymorphism, de1443ins54, a functional polymorphism causing an instability of the messenger ribonucleic acid of ARMS2 in the Japanese, did not differ from that in White persons. Among the polymorphisms seen in the White population, rs10490923 (R3H) as well as 7 other polymorphisms were not observed in the Japanese. One haplotype, which contained the T allele of the rs10490924 (A69S) and the variant of de1443ins54 polymorphism, had an odds ratio of 3.14 (P = 7.8 x 10(-6)) for AMD and 2.00 (P = .0058) for PCV. Among the 9 polymorphisms that were unique to the Japanese population, 2 had a minor allelic frequency of more than 0.05, and these 2 polymorphism were included as nonrisk haplotypes., Conclusions: The de1443ins54 polymorphism is a common variant between White and Japanese populations. It is strongly associated not only with AMD but also with PCV.

Purpose: The collagen type I alpha 1 (COL1A1) gene was recently reported to be associated with high myopia in the Japanese population. To validate this positive association, the tag single-nucleotide polymorphism (tSNP) approach was used., Methods: Eight tSNPs, including rs2075555 and rs2269336 (previously reported to be high myopia-susceptible SNPs in the Japanese), were selected to tag the linkage disequilibrium blocks harboring the COL1A1. These tSNPs were genotyped by using an SNP assay. A total of 427 unrelated Japanese cases with high myopia (axial length, >or=26.50 mm in both eyes; the refraction of the 644 phakic eyes ranged from -5.0 to -36.0 D, with a mean +/- SD of -13.61+/-4.20 D) and 420 Japanese control subjects were recruited. Genotype and allele distributions were compared between the cases and controls by using the chi(2) test, with multiple testing corrections performed by the permutation test., Results: There was no association noted between high myopia and rs2075555 (P=0.47, P(c)>0.99) and rs2269336 (P=0.40, P(c)>0.99). Meta-analysis of a previous Japanese study and new data obtained in a fixed-effect model indicated a mild significant association of high myopia with rs2075555 (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.03-1.38, P=0.022) and rs2269336 (OR, 1.18; 95% CI, 1.02-1.36, P=0.026). No significant associations were seen with further tSNPs tests., Conclusions: This study did not replicate the previously reported positive association between COL1A1 and high myopia in the Japanese population, and thus the genetic risk associated with this gene, if any, is weaker than originally reported.

Background: Typical exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are two of the major macular diseases found in Asians. Although genomic studies have shown a contribution by CFH and LOC387715/HTRA1 polymorphisms to the development of these two diseases, the correlation of the clinical phenotypes to these genotypes has not been determined in Asian patients., Methods: The prevalence of the CFH Y402H and HTRA1 rs11200638 genotypes was determined in 116 patients with typical exudative AMD and in 204 patients with PCV. Potential correlations of these polymorphisms were tested retrospectively and cross-sectionally for bilaterality of the disease, final visual acuity and the greatest linear dimension of the choroidal neovascular (CNV) lesion., Results: There was no significant difference in the incidence of CFH Y402H (P = 0.598) and HTRA1 rs11200638 (P = 0.290) between eyes with typical exudative AMD and with PCV. There was a significant association between the lesion size and HTRA1 rs11200638. For eyes with typical AMD, the size of the lesion (6363 +/- 2837 microm) was significantly larger in the high-risk homozygous group (AA), than in the low-risk homozygous group (GG) (3866 +/- 1947 microm; P = 0.0003). The same tendency was observed for the size of the lesion in PCV cases (homozygous group: 6347 +/- 2673 microm, non-risk homozygous group: 4405 +/- 2066 microm, P = 1.3 x 10(-5)., Conclusions: A common genetic background may exist between typical exudative AMD and PCV patients. Among the patients with these two clinical entities, those with a homozygous HTRA1 rs11200638 risk allele had larger CNV lesions.

Several multiple, large-scale, genetic studies on autoimmune-disease-associated SNPs have been reported recently: peptidylarginine deiminase type 4 (PADI4) in rheumatoid arthritis (RA); solute carrier family 22 members 4 and 5 (SLC22A4 and 5) in RA and Crohn's disease (CD); programmed cell death 1 (PDCD1) in systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), and RA; and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in T1D, RA, and SLE. Because these reports on association were not always evaluated in multiple ethnic groups and because ethnic difference in allele frequency of the variants has been also reported, we investigated allele frequencies of nine SNPs in four autoimmune-disease-associated loci in Caucasian, African-descent, and Japanese populations. Although SNPs in PADI4 had similar allele frequency among three groups [maximal difference 11%; (P >0.05)], the other three loci revealed statistically significant allele frequency differences (maximal difference 39% (P <0.00001), 13% (P <0.00001), and 8% (P <0.00001) in SLC22A4, PDCD1, and PTPN22, respectively). Of note, three SNPs in the three loci that had allele frequency more than 8% in the Caucasian population were either not polymorphic at all or extremely rare in the Japanese population. Our data suggest that ethnic variations of polymorphisms should be evaluated in detail, and differences should be incorporated into investigations of susceptibility variants for common diseases.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.