Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people.

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

Identification of risk factors for elevated serum IgG4 levels in subjects in a large-scale health checkup cohort study.

Introduction: To allow the identification of IgG4-related disease (IgG4-RD) from a subclinical phase as it is important to understand the risk of elevated serum IgG4 levels. We planned to evaluate serum IgG4 levels in the participants of the Nagasaki Islands Study (NaIS), a large-scale health checkup cohort study. Methods: This study included 3,240 individuals who participated in the NaIS between 2016 and 2018 and consented to participate in the study. Serum IgG4, IgG, and IgE levels and human leukocyte antigen (HLA) genotyping results of the NaIS subjects as well as lifestyle habits and peripheral blood test results were analyzed. The magnetic bead panel assay (MBA) and the standard nephelometry immunoassay (NIA) were used to measure serum IgG4 levels. The data were evaluated using multivariate analysis to identify lifestyle and genetic factors associated with elevated serum IgG4 levels. Results: Serum IgG4 levels measured with the NIA and MBA showed a tight positive correlation between the two groups (correlation coefficient 0.942). The median age of the participants in the NaIS was 69 years [63-77]. The median serum IgG4 level was 30.2 mg/dL [IQR 12.5-59.8]. Overall, 1019 (32.1%) patients had a history of smoking. When the subjects were stratified into three groups based on the smoking intensity (pack-year), the serum IgG4 level was significantly higher among those with a higher smoking intensity. Accordingly, the multivariate analysis identified a significant relationship between smoking status and serum IgG4 elevation. Conclusion: In this study, smoking was identified as a lifestyle factor correlating positively with elevated serum IgG4 levels.

Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study.

The genetic background of intracranial artery stenosis (ICAS), a major cause of ischemic stroke, remains elusive. We performed the world's first genome-wide association study (GWAS) of ICAS using DNA samples from Japanese subjects, to identify the genetic factors associated with ICAS and their correlation with clinical features. We also conducted a phenome-wide association study (PheWAS) of the top variant identified via GWAS to determine its association with systemic disease. The GWAS involved 408 patients with ICAS and 349 healthy controls and utilized an Asian Screening Array of venous blood samples. The PheWAS was performed using genotypic and phenotypic data of the Biobank Japan Project, which contained information on 46 diseases and 60 quantitative trait data from > 150,000 Japanese individuals. The GWAS revealed that the East Asian-specific functional variant of RNF213, rs112735431 (c.14429G > A, p.Arg4810Lys), was associated with ICAS (odds ratio, 12.3; 95% CI 5.5 to 27.5; P = 7.8 × 10-10). Stratified analysis within ICAS cases demonstrated that clinical features of those with and without the risk allele were different. PheWAS indicated that high blood pressure and angina were significantly associated with RNF213 rs112735431. The first GWAS of ICAS, which stratifies subpopulations within the ICAS cases with distinct clinical features, revealed that RNF213 rs112735431 was the most significant variant associated with ICAS. Thus, RNF213 rs112735431 shows potential as an important clinical biomarker that characterizes pleiotropic risk in various vascular diseases, such as blood pressure and angina, thereby facilitating personalized medicine for systemic vascular diseases in East Asian populations.

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors.

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10-9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

The association between the Moyamoya disease susceptible gene RNF213 variant and incident cardiovascular disease in a general population: the Nagahama study.

OBJECTIVE: An association between the Moyamoya disease susceptible gene ring finger protein 213 (RNF213) variant and ischemic stroke and coronary artery disease has been suggested in case-control studies. We aimed to investigate the possible association between the RNF213 variant and the incidence of cardiovascular disease in a general population. METHODS: The study participants consisted of 9153 Japanese community residents without history of cardiovascular disease. The clinical parameters employed in this analysis were observed at baseline between 2008 and 2010. The RNF213 p.R4859K variant was determined by TaqMan probe assay and then confirmed by Sanger sequencing. RESULTS: During 8.52 years follow-up period, we observed 214 incident cases of cardiovascular diseases (99 total stroke cases, 119 major adverse cardiac event cases, including 4 cases of both). The incidence rate was higher for the variant allele carriers (120 cases; incidence rate, 71.0 per 10 000 person-years) than for the homozygotes of the wild-type allele (26.9), and the group differences achieved statistical significance (P = 0.009). Although the RNF213 variant was also associated with systolic blood pressure (dominant model: coefficient of 8.19 mmHg; P < 0.001), the Cox regression analysis adjusted for major covariates including systolic blood pressure identified the RNF213 variant as an independent determinant for cardiovascular disease (hazard ratio of 3.41, P = 0.002) and major adverse cardiac event (hazard ratio of 3.80, P = 0.010) but not with total stroke (P = 0.102). CONCLUSION: The Moyamoya disease susceptible RNF213 variant was associated with blood pressure and the incidence of cardiovascular disease in a Japanese general population.

Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population.

HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10-9) and class II (P = 1.21 × 10-8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10-5), HLA-B*07:02 (P = 4.97 × 10-10), HLA-DRB1*01:01 (P = 1.15 × 10-9) and HLA-DQB1*05:01 (P = 2.30 × 10-9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10-5), HLA-DRB1*15:01 (P = 1.06 × 10-5) and HLA-DQB1*06:02 (P = 1.78 × 10-6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10-10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Prediction model for pancreatic cancer risk in the general Japanese population.

Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60-0.66) or 0.61 (0.58-0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42-0.91) and 1.98 (1.42-2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development.

Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67-2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25-1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23-1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84-4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63-0.67)]. CONCLUSIONS: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

Genotype Analyses in the Japanese and Belarusian Populations Reveal Independent Effects of rs965513 and rs1867277 but Do Not Support the Role of FOXE1 Polyalanine Tract Length in Conferring Risk for Papillary Thyroid Carcinoma.

BACKGROUND: Several functional single-nucleotide polymorphisms (SNPs) at the FOXE1 locus on chromosome 9q22.33 have been associated with the risk for papillary thyroid carcinoma (PTC). This study set out to elucidate whether their effects are independent, using genotyping results in populations of Asian and European descent. METHODS: SNPs rs965513 and rs1867277 and a polymorphic region determining the length of the FOXE1 polyalanine (poly-Ala) tract were genotyped in 501 patients with PTC and 748 healthy individuals from Japan, and in 660 patients and 820 population controls from Belarus. Functional analysis of transactivation activities of FOXE1 isoforms with varying number of alanine repeats was performed by a Dual-Luciferase® Assay. RESULTS: All three polymorphisms were significantly associated with PTC in both populations on univariate analysis. However, conditional analysis revealed independent effects of rs965513 and rs1867277 SNPs but not of the FOXE1 poly-Ala polymorphism. The independent effect of the lead rs965513 SNP was observed in both populations, while that of rs1867277 was only identified in the Japanese population, in which linkage disequilibrium between the three polymorphisms is markedly weaker. Despite the strong decrease in transcriptional activity with increasing FOXE1 poly-Ala tract length, no difference in transactivation potential of the FOXE1 poly-Ala isoforms could be seen after adjustment for the minimal promoter activity in the reporter vectors. Plasmids encoding FOXE1 isoforms of increasing poly-Ala tract length were also found to produce less FOXE1 protein after cell transfection. CONCLUSIONS: The functional variants rs965513 and rs1867277 independently contribute to genetic predisposition to PTC, while a contributing role of the FOXE1 poly-Ala polymorphism could not be confirmed.

Relationship Among Chlamydia and Mycoplasma Pneumoniae Seropositivity, IKZF1 Genotype and Chronic Obstructive Pulmonary Disease in A General Japanese Population: The Nagahama Study.

Chronic obstructive pulmonary disease (COPD) is a possible risk factor for cardiovascular disease. The association of COPD with the pathogenicity of infection with Chlamydia pneumoniae and Mycoplasma pneumoniae is controversial. We conducted a cross-sectional study to clarify the association between atypical pneumoniae seropositivity and COPD in a general population. We also investigated genetic polymorphisms conferring susceptibility to a pneumonia titer. The study included 9040 Japanese subjects (54 ±â€Š13 years). COPD was defined as a ratio of forced expiratory volume in 1 second to forced vital capacity of less than 70%. Serum levels of IgA and IgG antibodies to C pneumoniae were determined using an enzyme-linked immunoassay, and M pneumoniae seropositivity was assessed by a particle agglutination test. Subjects seropositive for C pneumoniae (26.1%) had a higher prevalence of COPD (seropositive, 5.8%; seronegative, 3.1%; P < 0.001) after adjustment for age, sex, height, weight, and smoking status. The association between M pneumoniae seropositivity (20.4%) and COPD was also significant in covariate-adjusted analysis (P < 0.001). A genome-wide association analysis of the C pneumoniae IgA index identified a susceptible genotype (rs17634369) near the IKZF1 gene, and the seropositive rate of C pneumoniae significantly differed among genotypes (AA, 22.5; AG, 25.3; GG, 29.7%, P < 0.001). On multiple regression analysis, seropositivity for both C pneumoniae (odds ratio = 1.41, P = 0.004) and M pneumoniae (odds ratio = 1.60, P = 0.002) was an independent determinant for COPD, while no direct association was found with the rs17634369 genotype. Seropositivity for both C pneumoniae and M pneumoniae is an independent risk factor for COPD in the general population.

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

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.

Significant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population - The Nagahama study.

Anti-citrullinated peptide antibody (ACPA) is a highly specific autoantibody to rheumatoid arthritis (RA). Recent studies have revealed that periodontal disease (PD) is closely associated with RA and production of ACPA in RA. Analyses of associations between PD and ACPA production in a healthy population may deepen our understandings. Here, we analyzed a total of 9554 adult healthy subjects. ACPA and IgM-rheumatoid factor (RF) was quantified and PD status was evaluated using the number of missing teeth (MT), the Community Periodontal Index (CPI) and Loss of Attachment (LA) for these subjects. PD status was analyzed for its association with the positivity and categorical levels of ACPA and RF conditioned for covariates which were shown to be associated with PD, ACPA or RF. As a result, all of MT, CPI and LA showed suggestive or significant associations with positivity (p = 0.024, 0.0042 and 0.037, respectively) and levels of ACPA (p ≤ 0.00031), but none of the PD parameters were associated with those of RF. These association patterns were also observed when we analyzed 6206 non-smokers of the participants. The significant associations between PD parameters and positivity and levels of ACPA in healthy population support the fundamental involvement of PD with ACPA production.

The common genetic variant rs944289 on chromosome 14q13.3 associates with risk of both malignant and benign thyroid tumors in the Japanese population.

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 rs2439302 (p=0.003; OR 1.266 [CI 1.087-1.493]) and rs1867277 (p=1.17E-04; OR 1.492 [CI 1.235-1.818]), and was not replicated for rs6983267 (p=0.082; OR 1.136 [CI 0.980-1.316]) in this series. A significant correlation between rs2439302 genotype and relative expression of NRG1 was detected in normal and tumor counterparts of PTC (about 10% decrease per each risk allele). NRG1 expression also significantly correlated with that of PTCSC3. CONCLUSIONS: Association of rs944289, which was previously known to confer risk for thyroid cancer, with FA, and the correlation between PTCSC3 and NRG1 expression demonstrates that predisposing genetic factors are partly common for benign and malignant thyroid tumors, and imply broader roles of the pathways they underlie in thyroid tumorigenesis, not limited to carcinogenesis.

Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations.

INTRODUCTION: The BIM deletion polymorphism in intron 2 was found in a significant percent of the Asian population. Patients with epidermal growth factor receptor (EGFR) mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to EGFR tyrosine kinase inhibitors. However, the association between the BIM deletion polymorphism and lung cancer risk is unknown. METHODS: The BIM deletion polymorphism was screened by polymerase chain reaction in 765 lung cancer cases and 942 healthy individuals. RESULTS: Carriers possessing one allele of the BIM polymorphism were observed in 13.0% of control cases and 12.8% of lung cancer cases, similar to incidence rates reported earlier in healthy individuals. Homozygote for the BIM polymorphism was observed in four of 942 healthy controls and three of 765 lung cancer cases. The frequency of the BIM deletion polymorphism in lung cancer patients was not related to age, sex, smoking history, or family history of lung cancer. The BIM deletion polymorphism was found in 30 of 212 patients with EGFR wild type lung cancers and 16 of 120 patients with EGFR mutant lung cancers. The frequency of the BIM polymorphism is similar between cancers with wild type EGFR and mutated EGFR (p = 0.78). CONCLUSION: The BIM deletion polymorphism was not associated with lung cancer susceptibility. Furthermore, the BIM polymorphism is not associated with EGFR mutant lung cancer.

A genome-wide association study of serum levels of prostate-specific antigen in the Japanese population.

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.

Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population.

OBJECTIVE: Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) are markers to rheumatoid arthritis (RA). Smoking and shared epitope (SE) in HLA-DRB1 are associated with the production of these autoantibodies in RA. Detailed distribution and characterization of ACPA and RF in the general population have remained unclear. We aimed to evaluate positivity of ACPA and RF in a general Japanese population and to detect correlates, including genetic components. METHODS: ACPA and RF were quantified in 9,804 Japanese volunteers ages 30-75 years. Logistic regression analyses were performed to evaluate the effects of candidates of correlates on the autoantibody positivity. A genome-wide association study (GWAS) was performed using 394,239 single nucleotide polymorphisms for 3,170 participants, and HLA-DRB1 alleles were imputed based on the GWAS data. RESULTS: A total of 1.7% and 6.4% of subjects were positive for ACPA and RF, respectively, and the 2 markers showed a significant correlation (P = 2.0 × 10(-23) ). Old age was associated with ACPA positivity (P = 0.00062). Sex, smoking, SE, and other candidates of correlates did not have significant effects. Interaction between smoking and SE positivity was not apparent, but smoking showed a significant association with high levels of ACPA (P = 0.0019). CONCLUSION: ACPA and RF could be detected in 1.7% and 6.4% of the Japanese adult population without RA, respectively. ACPA and RF were suggested to share mechanisms even in healthy populations. Old age was associated with increasing ACPA positivity. While positivity of ACPA and RF was not associated with SE and smoking, an association between high ACPA and smoking was observed.

Genome-wide association study of genetic factors related to confectionery intake: potential roles of the ADIPOQ gene.

OBJECTIVE: The excessive consumption of confectionery might have adverse effects on human health. To screen genetic factors associated with confectionery-intake frequency, a genome-wide association study (GWAS) in Japan was conducted. DESIGN AND METHODS: For the discovery phase (stage 1), we conducted a GWAS of 939 noncancer patients in a cancer hospital. Additive models were used to test associations between genotypes of approximately 500,000 single-nucleotide polymorphisms (SNPs) and the confectionery-intake score (based on intake frequency). We followed-up association signals with P < 1 × 10(-5) and minor allele frequency >0.01 in stage 1 by genotyping the SNPs of 4,491 participants in a cross-sectional study within a cohort (replication phase [stage 2]). RESULTS: We identified 12 SNPs in stage 1 that were potentially related to confectionery intake. In stage 2, this association was replicated for one SNP (rs822396; P = 0.049 for stage 2 and 4.2 × 10(-5) for stage 1+2) in intron 1 of the ADIPOQ gene, which encodes the adipokine adiponectin. CONCLUSIONS: Given the biological plausibility and previous relevant findings, the association of an SNP in the ADIPOQ gene with a preference for confectionery is worthy of follow-up and provides a good working hypothesis for experimental testing.