Showing papers by "Fumihiko Matsuda published in 2015"

Integrated molecular analysis of adult T cell leukemia/lymphoma

Abstract: Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

New loci and coding variants confer risk for age-related macular degeneration in East Asians

Abstract: Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

Brief report: Takayasu arteritis and ulcerative colitis: High rate of co-occurrence and genetic overlap

Abstract: Objective Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA–B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases. Methods We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases. Results Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3–9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P = 0.0070) and showed significant enrichment of HLA–B*52:01 compared to TAK patients without UC (P = 1.0 × 10−5) (odds ratio 12.14 [95% confidence interval 2.96–107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P = 0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 × 10−10). Conclusion UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA–B*52:01 may play a central role in their co-occurrence.

A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Abstract: Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

Abstract: Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 × 10(-13)) and corneal curvature (Pmeta=2.9 × 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.

Descriptive epidemiology of spot urine sodium-to-potassium ratio clarified close relationship with blood pressure level: the Nagahama study.

Abstract: Objectives:We undertook descriptive epidemiology of spot urine sodium-to-potassium ratio (Na/K) in a population sample to clarify the close relationship between Na/K and blood pressure level independently of potential confounding factors.Methods:Study participants consisted of 9144 apparently health

Association of Postural Instability With Asymptomatic Cerebrovascular Damage and Cognitive Decline: The Japan Shimanami Health Promoting Program Study

Abstract: Background and Purpose—Asymptomatic cerebral small-vessel disease (cSVD) in elderly individuals are potent risk factors for stroke. In addition to common clinical risk factors, postural instability...

The Common Genetic Variant rs944289 on Chromosome 14q13.3 Associates with Risk of Both Malignant and Benign Thyroid Tumors in the Japanese Population

Abstract: Background: Several single nucleotide polymorphisms (SNP) have been identified to be associated with the risk for differentiated thyroid cancer in populations of distinct ethnic background. The relationship of these genetic markers to a benign tumor of the thyroid, follicular adenoma (FA), is not well established. Methods: In a multicenter retrospective case-control study, five thyroid cancer-related SNPs—rs966513 (9q22.33, FOXE1), rs944289 (14q13.3, PTCSC3), rs2439302 (8p12, NRG1), rs1867277 (9q22.23, FOXE1), and rs6983267 (8q24, POU5F1B)—were genotyped in 959 cases of histologically verified FA, 535 papillary thyroid carcinomas (PTC), and 2766 population controls. Results: A significant association was found between FA and rs944289 (p=0.002; OR 1.176 [CI 1.064–1.316]), and suggestively with rs2439302 (p=0.033; OR 1.149 [CI 1.010–1.315]). In PTC, significant associations were confirmed for rs965513 (p=4.21E-04; OR 1.587 [CI 1.235–2.000]) and rs944289 (p=0.003; OR 1.234 [CI 1.075–1.408]), newly found for ...

Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels

Abstract: Alpha-1 antitrypsin deficiency is a common genetic disorder in Europeans. Here Setoh et al. perform a genome-wide association study of AAT serum levels in a Japanese population and find three missense variants in the metabolism genes ALDH2, HNF1A and GCKR.

The KSS 2011 Reflects Symptoms, Physical Activities, and Radiographic Grades in a Japanese Population

Abstract: Background Cultural and ethnic differences are present both in subjective and objective measures of patient health, but scoring systems do not always reflect these differences, and so validation of outcomes tools in different cultural settings is important. Recently, a revised version of The Knee Society Score® (KSS 2011) was developed, but to our knowledge, the degree that this tool evaluates clinical symptoms, physical activities, and radiographic grades in the general Japanese population is not known.

Rheumatoid Factor Is Associated With the Distribution of Hand Joint Destruction in Rheumatoid Arthritis.

Abstract: Objective Rheumatoid arthritis (RA) is a chronic disease leading to joint destruction. Although many studies have addressed factors potentially correlated with the speed of joint destruction, less attention has been paid to the distribution of joint destruction in patients with RA. In this study, destruction of the hand bones in patients with RA was classified into 2 anatomic subgroups, the fingers and the non-fingers, with the aim of analyzing which factors are associated with destruction of the finger joints. Methods A total of 1,215 Japanese patients with RA were recruited from 2 different populations. The degree of joint destruction was assessed using the total modified Sharp/van der Heijde score (SHS) of radiographic joint damage. The SHS score of joint damage in the finger joints was used as the dependent variable, and the SHS score in the non-finger joints was used as a covariate. Age, sex, disease duration, smoking, C-reactive protein level, treatment for RA, and positivity for and levels of anti–citrullinated protein antibodies and rheumatoid factor (RF) were evaluated as candidate correlates. Overall effect sizes were assessed in a meta-analysis. In addition, associations observed in the Japanese patients were compared to those in a cohort of 157 Dutch RA patients in the BeSt study (a randomized, controlled trial involving 4 different strictly specified treatment strategies for early RA). Results Not surprisingly, disease duration in Japanese patients with RA was associated with the finger SHS score (P ≤ 0.00037). Both positivity for and levels of RF showed significant associations with the finger SHS score after adjustment for covariates (P = 0.0022 and P = 8.1 × 10−7, respectively). These associations were also true in relation to the time-averaged finger SHS score. An association between RF positivity and the finger SHS score was also observed in Dutch patients with RA in the BeSt study (P = 0.049). Conclusion Positivity for and levels of RF are associated with finger joint destruction independent of non-finger joint destruction and other covariates. Our findings suggest that there are different mechanisms of joint destruction operating in the finger joints of patients with RA.

Central blood pressure relates more strongly to retinal arteriolar narrowing than brachial blood pressure: The Nagahama Study

Abstract: Objectives:Although central blood pressure (BP) is considered to be more closely associated with large arterial remodeling and cardiovascular outcomes than brachial BP, few studies have investigated these associations with changes in small arteries. As morphological changes in retinal vessels might

Tooth Loss and Atherosclerosis The Nagahama Study

Abstract: Several epidemiologic studies have suggested that oral disease is a risk factor for cardiovascular disease (CVD). However, whether a clinically significant association exists between the 2 disorders remains controversial. Here, we investigated the association between tooth loss, as an indicator of oral disease, and arterial stiffness, as a marker of atherosclerosis, in Japanese adults. Cross-sectional data were collected for 8,124 persons aged 30 to 75 y with no history of tooth loss for noninflammatory reasons, such as orthodontic treatment, malposition, and trauma. Participants received a comprehensive dental examination and extensive in-person measurements of CVD risk factors, and arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI). We examined the association between CAVI and tooth loss using general linear models with adjustment for age, sex, body mass index, smoking status, hemoglobin A1c, and a history of insulin or hypoglycemic medication depending on the model. In addition, we performed an analysis that included interaction terms of the centered variables tooth loss, sex, and age. The results of the multiple regression analysis that included the interaction terms detected that the relationship between CAVI and tooth loss was dependent on sex, with only men showing a positive correlation (β for interaction = 0.04; 95% confidence interval, 0.02-0.06). The findings from this study suggest that a linear relationship exists between tooth loss and degree of arterial stiffness and that the association differed depending on sex.

Brief Report: Main Contribution of DRB1*04:05 Among the Shared Epitope Alleles and Involvement of DRB1 Amino Acid Position 57 in Association With Joint Destruction in Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis.

Abstract: Objective The shared epitope is associated with increased joint destruction in rheumatoid arthritis (RA) as well as susceptibility to RA and the production of anti–citrullinated protein antibody (ACPA). However, previous studies addressing whether the association of the shared epitope with joint destruction is independent of ACPA have shown different results in different populations. Different allele distributions in the shared epitope may explain this ethnic heterogeneity. This study was undertaken to assess the associations of the shared epitope and HLA–DRB1*04:05, the most common shared epitope allele in the Japanese population, with joint destruction in patients with ACPA-positive RA. Methods A total of 861 patients with ACPA-positive RA who had not received any biologic agents were recruited from the institute of Rheumatology, Rheumatoid Arthritis cohort (sets 1 and 2) and the Kyoto University Rheumatoid Arthritis Management Alliance cohort (set 3). Joint destruction was assessed using the modified Sharp/van der Heijde score (SHS). The associations of the shared epitope alleles, HLA–DRB1*04:05, and other shared epitope allele groups with the SHS were analyzed in a linear regression analysis. Amino acid variations associated with the SHS were also analyzed. Results The shared epitope was significantly associated with an increased SHS (P = 0.0017). Although HLA–DRB1*04:05 was significantly associated with an increased SHS (P = 2.7 × 10−5), the group of other shared epitope alleles, including HLA–DRB1*01:01, did not show an association with the SHS in spite of sufficient power (P = 0.67). HLA–DRB1*04:05 was associated with joint destruction in a dose-dependent manner. Analyses of amino acid associations of HLA–DRB1 revealed that serine at position 57, recently shown to have a susceptibility effect for ACPA-positive RA in Asian populations, showed a significant association (P = 5.0 × 10−6). Conclusion HLA–DRB1*04:05, characterized by serine at position 57, accounts for the detrimental association between the shared epitope and SHS in Japanese patients with ACPA-positive RA.

Functional Impact and Evolution of a Novel Human Polymorphic Inversion That Disrupts a Gene and Creates a Fusion Transcript.

Abstract: Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000–50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far.

Knee Pain and Low Back Pain Additively Disturb Sleep in the General Population: A Cross-Sectional Analysis of the Nagahama Study.

Abstract: Introduction Association of knee and low back pain with sleep disturbance is poorly understood. We aimed to clarify the independent and combined effects of these orthopedic symptoms on sleep in a large-scale general population. Methods Cross-sectional data about sleep and knee/low back pain were collected for 9,611 community residents (53±14 years old) by a structured questionnaire. Sleep duration less than 6 h/d was defined as short sleep. Sleep quality and the presence of knee and low back pain were evaluated by dichotomous questions. Subjects who complained about knee or low back pains were graded by tertiles of a numerical response scale (NRS) score and a Roland-Morris disability questionnaire (RDQ) score respectively. Multivariate regression analyses were performed to determine the correlates of short sleep duration and poor sleep quality. Results Frequency of participants who complained of the orthopedic symptoms was as follows; knee pain, 29.0%; low back pain, 42.0% and both knee and low back pain 17.6%. Both knee and low back pain were significantly and independently associated with short sleep duration (knee pain: odds ratio (OR) = 1.19, p<0.01; low back pain: OR = 1.13, p = 0.01) and poor sleep quality (knee pain: OR = 1.22, p<0.01; low back pain; OR = 1.57, p<0.01). The group in the highest tertile of the NRS or RDQ score had the highest risk for short sleep duration and poor sleep quality except for the relationship between the highest tertile of the RDQ score and short sleep duration.(the highest tertile of the NRS: OR for short sleep duration = 1.31, p<0.01; OR for poor sleep quality = 1.47, p<0.01; the highest tertile of the RDQ: OR for short sleep duration = 1.11, p = 0.12; OR for poor sleep quality = 1.81, p<0.01) Further, coincident knee and low back pain raised the odds ratios for short sleep duration (either of knee or low back pain: OR = 1.10, p = 0.06; both knee and low back pain: OR = 1.40, p<0.01) and poor sleep quality (either of knee or low back pain: OR = 1.61, p<0.01; both knee and low back pain: OR = 2.17, p<0.01). Conclusion Knee and low back pains were independently associated with short sleep duration and poor sleep quality. Further, they additively increased the correlation with these sleep problems in the general population.

Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population.

Abstract: 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. 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. 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. Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis.

Abstract: Objective Anti–citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA–DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA–DRB1 and ACPA levels in patients with RA. Methods We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA–DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA–DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. Results HLA–DRB1*09:01 and HLA–DR15 were confirmed to be associated with ACPA levels. HLA–DRB1*08:03 and DRB1*14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P = 1.9 × 10−51). The association was mainly conferred by alanine residue (P = 4.5 × 10−51). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA–DRB1 alleles (HLA–DRB1*08:03, DRB1*09:01, DRB1*14:06, DRB1*15:01, and DRB1*15:02). Conclusion Amino acid position 74 in HLA–DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.

Effect of PNPLA3 rs738409 variant (I148 M) on hepatic steatosis, necroinflammation, and fibrosis in Japanese patients with chronic hepatitis C

Abstract: Background Host genetic factors have been suspected to influence histological liver damage in chronic liver disease. The nonsynonymous single-nucleotide polymorphism rs738409 C > G in the patatin-like phospholipase domain-containing 3 gene (PNPLA3, also known as adiponutrin), encoding the I148 M protein variant, has been identified as a novel genetic marker for hepatic steatosis and fibrosis in nonalcoholic fatty liver disease and alcoholic liver disease. We aimed to determine whether the PNPLA3 rs738409 variant was associated with hepatic steatosis, necroinflammation, and fibrosis in Japanese patients with chronic hepatitis C.

The Contribution of Genetic Architecture to the 10-Year Incidence of Age-Related Macular Degeneration in the Fellow Eye.

Abstract: Purpose To correlate a genetic risk score based on age-related macular degeneration (AMD) susceptibility genes with the risk of AMD in the second eye. Methods This is a retrospective, open cohort study consisting of 891 unilateral AMD patients, who were followed for at least 12 months and recruited from three institutes. DNAs were genotyped using Illumina OmniExpress, HumanOmni2.5-8, and/or HumanExome. Survival analyses and Cox proportional hazard models were used to examine the association between 11 AMD susceptibility genes and the duration until second-eye involvement in 499 samples from Kyoto University, which were replicated in two other cohorts. Genetic risk score (GRS) was also evaluated. Results The ARMS2 rs10490924 recessive model (hazard ratio [HR]meta = 2.04; Pmeta = 3.4 × 10⁻³) and CFH rs800292 additive model (HRmeta = 1.77; Pmeta = 0.013) revealed significant associations with second-eye involvement. The dominant model of TNFRSF10A rs13278062, VEGFA rs943080, and CFI rs4698775 showed consistent effects across three datasets (I² = 0%; HRmeta = 1.46, 1.30, 1.51, respectively). The GRS using these five single nucleotide polymorphisms (SNPs) was also significantly associated (HRmeta [per score] = 2.42; P = 2.2 × 10⁻⁵; I² = 0%). After 10 years from the first visit, the patients within the top 10% by GRS showed a 51% hazard rate, in contrast to 2.3% among patients within the lowest 10% by GRS. Conclusions We demonstrated that the GRS using ARMS2, CFH, TNFRSF10A, VEGFA, and CFI was significantly associated with second-eye involvement. Genetic risk has high predictive ability for second-eye involvement of AMD.

Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia

Abstract: Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

Impact of metallothionein gene polymorphisms on the risk of lung cancer in a Japanese population

Abstract: Metallothioneins (MTs) are cysteine-rich proteins that act as antioxidants. A case-control study was conducted to assess the effects of gene polymorphisms in the MT region on the risk of lung cancer in Japanese subjects: 769 lung cancer cases and 939 non-cancer controls. Associations were evaluated using logistic regression models with adjustment for potential confounders (age, sex, and lifestyle factors including smoking, drinking, and green-yellow vegetable intake). We found five polymorphisms in the MT-1 gene region that showed statistically significant associations with lung cancer. Of these polymorphisms, rs7196890 showed the strongest association (odds ratio: 1.30, P = 0.004, 95% confidence interval: 1.09–1.55). The impact of the polymorphism decreased with the increase of smoking, and virtually no association with lung cancer was observed among heavy smokers whose pack-year values were 30 or more (odds ratio: 1.02, P = 0.93, 95% confidence interval: 0.67–1.55). These results suggest that polymorphisms in the MT gene are moderately associated with the risk of lung cancer and that the associations are modified by lifestyle factors. © 2014 Wiley Periodicals, Inc.

Calcium, ARMS2 Genotype, and Chlamydia Pneumoniae Infection in Early Age-Related Macular Degeneration: a Multivariate Analysis from the Nagahama Study

Abstract: Calcium, ARMS2 Genotype, and Chlamydia Pneumoniae Infection in Early Age-Related Macular Degeneration: a Multivariate Analysis from the Nagahama Study

New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan

Abstract: Objective: To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent. Methods: From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin. Results: All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff–positive macrophages and 2–7 μm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy. Conclusions: We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis.

Corrigendum: New loci and coding variants confer risk for age-related macular degeneration in East Asians

Abstract: Nature Communications 6: Article number: 6063 (2015); Published 28 January 2015; Updated 30 March 2015. The financial support for this Article was not fully acknowledged. The Acknowledgements should have included the following: This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014055007), Ministry of Education, Science and Technology (2012004585), and by the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111345).

Plasma lipid analysis by hydrophilic interaction liquid chromatography coupled with electrospray ionization tandem mass spectrometry

Abstract: A novel method for the analysis of endogenous lipids and related compounds was developed employing hydrophilic interaction liquid chromatography with electrospray ionization tandem mass spectrometry. A hydrophilic interaction liquid chromatography with carbamoyl stationary phase achieved clear separation of phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, ceramide, and mono-hexsosyl ceramide groups with good peak area repeatability (RSD% 0.99). The established method was applied to human plasma assays and a total of 117 endogenous lipids were successfully detected and reproducibly identified. In addition, we investigated the simultaneous detection of small polar metabolites such as amino and organic acids co-existing in the same biological samples processed in a single analytical run with lipids. Our results show that hydrophilic interaction liquid chromatography is a useful tool for human plasma lipidome analysis and offers more comprehensive metabolome coverage.

AB0636 Ustekinumab as a Therapeutic Option for Takayasu Arteritis –from Genetic Findings to Clinical Application-

Abstract: Background Takayasu arteritis (TAK) is a systemic vasculitis affecting aorta and its large branches. While patients with TAK respond to glucocorticoids and immunosuppressants, they often flare up. A novel therapeutic option based on pathophysiological findings of TAK is desired. We recently identified IL12B as a susceptibility gene through genome-wide association study. Since ustekinumab, monoclonal antibody to IL-12/23p40 encoded by IL12B, is an effective treatment for Crohn9s disease and psoriasis both of which share IL12B as a susceptibility gene, we hypothesized that ustekinumab would be effective to patients with TAK. Objectives To perform a pilot clinical trial where we used ustekinumab to assess its safety and efficacy for patients with TAK. Methods We administered 40mg of ustekinumab at day 0 and 28 to a total of three patients with refractory TAK. All patients were evaluated for disease activity by MRI at baseline and on day 84. Results All of the three patients showed enhancement in vascular walls at baseline.Two patients showed acute inflammatory responses at registry and the other suffered from severe head and neck pain and general fatigue. Both patients with acute inflammatory responses showed decreased levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (p Conclusions Ustekinumab would be a safe and effective treatment option for TAK warranted by the genetic association. A large-scale clinical study is necessary to accumulate evidence of its usefulness. References Terao C, Yoshifuji H, Mimori T. Recent advances in Takayasu arteritis. Int. J. Rheum. Dis. 2014;17:238-47. Terao C, Yoshifuji H, Kimura A, et al. Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population. Am. J. Hum. Genet. 2013;93:289-97. Saruhan-Direskeneli G, Hughes T, Aksu K, et al. Identification of Multiple Genetic Susceptibility Loci in Takayasu Arteritis. Am. J. Hum. Genet. 2013. Yeilding N, Szapary P, Brodmerkel C, et al. Development of the IL-12/23 antagonist ustekinumab in psoriasis: past, present, and future perspectives–an update. Ann. N. Y. Acad. Sci. 2012;1263:1-12. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn9s disease. N. Engl. J. Med. 2012;367:1519-28. Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 2007;80:273-90. Acknowledgements We would like to thank members of the Department of Rheumatology and Clinical Immunology in Kyoto University for their support. We also thank Dr. Hirofumi Makino in Okayama University as well as members of the working group of vasculitis for helping us to obtain a grant for this project. This work was supported by research grants from the Japan Intractable Diseases Research Foundation. Disclosure of Interest None declared