Association results in Japanese woman of previously identified SNPs with age at menarche in Caucasian woman.

<p>Genotyping result of 15,495 Japanese subjects were anlayzed in this study. Imputed SNPs with R2 of less than 0.7 were excluded from this analysis. A1 frequency of JPT were those from release 24 Hapmap JPT. N.D.; no data. References: 1 Elks et al Nat Genet 2010, 2 He et al Nature Genet 2009, 3 Liu et al Plos Genet 2009. P-value of 0.0015 (0.05/33) was set at the significant threshold for this candidate analysis.</p>*<p>:Effect size and S.E. of allele1 on age at menarche (year per allele) and P-values were obtained by inverse-variance method.</p>**<p>Concordance of association direction between this study and the previous report.</p

Association of rs364663 with age at menarche.

*<p>Effect size and S.E. of allele1 on age at menarche (year per allele) and P-values were obtained by inverse-variance method.</p

Results from meta-analysis of four genome-wide association studies.

<p>A total of 15,495 female samples were analyzed in this study.</p

Characteristics of study population.

<p>Characteristics of study population.</p

The result of genome wide association analysis of age at menarche.

<p>Genotyping result of 15,495 Japanese subjects were anlayzed in this study. Imputed SNPs with R2 of less than 0.7 were excluded from this analysis. A1 frequency of JPT was those from release 24 Hapmap JPT.</p>*<p>Effect size and SE of allele1 on age at menarche (year per allele) and P-values were obtained by inverse-variance method.</p

Regional association plot at rs364663.

<p>Upper panel; <i>P</i> values of genotyped SNPs are plotted (as −log₁₀ values) against their physical location on chromosome 6 (NCBI Build 36). Estimated recombination rates from HapMap JPT shows the local LD structure. Inset; Colors of other SNPs indicate LD with rs2596542 according to a scale from <i>r</i>² = 0 to <i>r</i>² = 1 based on pair-wise <i>r</i>² values from HapMap JPT. Lower panel; Gene annotations from the University of California Santa Cruz genome browser.</p

Identification of a Functional Variant in the <i>MICA</i> Promoter Which Regulates <i>MICA</i> Expression and Increases HCV-Related Hepatocellular Carcinoma Risk

<div><p>Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the <i>MHC class I polypeptide-related sequence A</i> (<i>MICA</i>) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the <i>MICA</i> gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10⁻⁵ and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.</p> </div

Association of rs2596542 with the progression from CHC to LC and HCC.

<p>MAF, minor allele frequency; OR, odds ratio for minor allele. C.I., confidence interval. SNP rs2596542 was analyzed in 1,043 chronic hepatitis C (CHC), 586 liver cirrhosis without hepatocellular carcinoma (LC) and 1,394 HCV-induce hepaticellular carcinoma patients (HCC). ^*calculated by Armitage trend test.</p

Impact of <i>PSCA</i> Variation on Gastric Ulcer Susceptibility

<div><p>Peptic ulcer is one of the most common gastrointestinal disorders with complex etiology. Recently we conducted the genome wide association study for duodenal ulcer and identified disease susceptibility variations at two genetic loci corresponding to the <i>Prostate stem cell antigen</i> (<i>PSCA</i>) gene and the <i>ABO blood group</i> (<i>ABO</i>) gene. Here we investigated the association of these variations with gastric ulcer in two Japanese case-control sample sets, a total of 4,291 gastric ulcer cases and 22,665 controls. As a result, a C-allele of rs2294008 at <i>PSCA</i> increased the risk of gastric ulcer with odds ratio (OR) of 1.13 (<i>P</i> value of 5.85×10⁻⁷) in an additive model. On the other hand, SNP rs505922 on <i>ABO</i> exhibited inconsistent result between two cohorts. Our finding implies presence of the common genetic variant in the pathogenesis of gastric and duodenal ulcers.</p></div

SNP rs2596538 affects the binding affinity of nuclear proteins.

<p>(<b>A</b>) Real-time quantitative PCR (upper) and Western blotting (lower) of MICA before and after heat shock treatment in HLE cells. <i>B2M</i> and β-actin are served as internal and protein loading control. (<b>B</b>) EMSA using 31 bp labeled probes flanking each SNP located within the 4.8 kb region upstream of <i>MICA</i> transcription start site. A black arrow indicates the shifted band specific to G allele of SNP rs2596538. (<b>C</b>) EMSA using the labeled G allele of SNP rs2596538 and nuclear extract from heat treated HLE cells. Non-labeled A or G allele of SNP rs2596538 at different concentrations are used as competitors. Pointed arrow indicates shifted band. *<i>P</i><0.05 by Student's <i>t</i>-test.</p