hTERT promoter polymorphism, -1327C\u3eT, is associated with the risk of epithelial cancer

Telomeres are repetitive nucleotide sequences that cap the end of eukaryotic chromosomes. Attrition of these structures has been associated with carcinogenesis in many tissues, and therefore, they are essential for chromosome stabilization. Telomeres are maintained by telomerase complexes, of which human telomerase reverse transcriptase (hTERT) is an essential component. A functional polymorphism, -1327C\u3eT (rs2735940), located in the promoter of the hTERT gene is associated with telomere length in peripheral blood leukocytes. We hypothesized that this polymorphism might affect susceptibility to various epithelial malignancies. The -1327C\u3eT polymorphism was examined in 1,551 consecutive autopsy cases (mean age, 80.3 years), and we focused on its effect on the risks of overall and each primary malignancies. The polymorphism was further studied in 391 clinical prostate cancer patients who were diagnosed via prostate biopsy, using autopsy cases as controls. In the autopsy cases, the risk of epithelial malignancy, after adjusting for age, sex, smoking, and drinking habits, was significantly lower for the TT genotype than the CC (reference) genotype (adjusted odds ratio = 0.61, 95% CI = 0.42-0.90). Among primary malignancies, latent prostate cancer, colorectal cancer, and lung cancer were the most strongly associated with the polymorphism. In the study using clinical prostate cancer patients, susceptibility to clinical prostate cancer was lower for -1327 T carriers than for -1327 T non-carriers, but this finding was not significant. The data suggest that the hTERT promoter polymorphism, -1327C\u3eT, is an independent factor influencing the risk of various epithelial malignancies in elderly Japanese

Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study

DNA methylation is an important epigenetic modification that has been implicated in the pathogenesis of atherosclerosis. Although previous studies have identified various CpG sites and genes whose methylation is associated with atherosclerosis in populations with European or Mexican ancestry, the genome‑wide pattern of DNA methylation in the atherosclerotic human aorta is yet to be elucidated in Japanese individuals. In the present study, a genome‑wide analysis of DNA methylation at ~853,000 CpG sites was performed using 128 postmortem aortic intima specimens obtained from 64 Japanese patients. To avoid the effects of interindividual variation, intraindividual paired comparisons were performed between atheromatous plaque lesions and corresponding plaque‑free tissue for each patient. Bisulfite‑modified genomic DNA was analyzed using a specific microarray for DNA methylation. DNA methylation at each CpG site was calculated as the β value, where β = (intensity of the methylated allele)/(intensity of the methylated allele + intensity of the unmethylated allele + 100). Bonferroni\u27s correction for statistical significance of association was applied to compensate for multiple comparisons. The methylation of 2,679 CpG sites differed significantly (P0.15 (plaque lesion‑plaque‑free intima) and 11 had a β ratio of >1.50 (plaque/plaque‑free intima). A further 15 and 17 hypomethylated CpG sites in atheromatous plaques were observed to have a difference in β value of <‑0.15 or a β ratio of <0.67, respectively. According to these limits, a total of 16 novel genes that were significantly hyper‑ or hypomethylated in atheromatous plaque lesions compared with the plaque‑free intima were identified in the present study. The results of the present study suggest that the methylation of these genes may contribute to the pathogenesis of atherosclerosis in the Japanese population

Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study

DNA methylation is an important epigenetic modification that has been implicated in the pathogenesis of atherosclerosis. Although previous studies have identified various CpG sites and genes whose methylation is associated with atherosclerosis in populations with European or Mexican ancestry, the genome‑wide pattern of DNA methylation in the atherosclerotic human aorta is yet to be elucidated in Japanese individuals. In the present study, a genome‑wide analysis of DNA methylation at ~853,000 CpG sites was performed using 128 postmortem aortic intima specimens obtained from 64 Japanese patients. To avoid the effects of interindividual variation, intraindividual paired comparisons were performed between atheromatous plaque lesions and corresponding plaque‑free tissue for each patient. Bisulfite‑modified genomic DNA was analyzed using a specific microarray for DNA methylation. DNA methylation at each CpG site was calculated as the β value, where β = (intensity of the methylated allele)/(intensity of the methylated allele + intensity of the unmethylated allele + 100). Bonferroni\u27s correction for statistical significance of association was applied to compensate for multiple comparisons. The methylation of 2,679 CpG sites differed significantly (P0.15 (plaque lesion‑plaque‑free intima) and 11 had a β ratio of >1.50 (plaque/plaque‑free intima). A further 15 and 17 hypomethylated CpG sites in atheromatous plaques were observed to have a difference in β value of <‑0.15 or a β ratio of <0.67, respectively. According to these limits, a total of 16 novel genes that were significantly hyper‑ or hypomethylated in atheromatous plaque lesions compared with the plaque‑free intima were identified in the present study. The results of the present study suggest that the methylation of these genes may contribute to the pathogenesis of atherosclerosis in the Japanese population

Significance of common variants on human chromosome 8q24 in relation to the risk of prostate cancer in native Japanese men

<p>Abstract</p> <p>Background</p> <p>Common variants on human chromosome 8q24, rs1447295 (C/A) and rs6983267 (T/G), have been recently linked to the prevalence of prostate cancer in European and American populations. Here, we evaluated whether the single-nucleotide polymorphisms rs1447295 and rs6983267 were associated with the risk of sporadic prostate cancer as well as latent prostate cancer in a native Japanese population.</p> <p>Results</p> <p>We analyzed genomic DNA samples from 391 sporadic prostate cancer patients, 323 controls who had died from causes unrelated to cancer and 112 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results. The polymorphisms were determined by allelic discrimination using a fluorescent-based TaqMan assay. The A allele of rs1447295 was significantly associated with the risk of sporadic prostate cancer (<it>p </it>= 0.04; age-adjusted OR, 1.34), while the G allele of rs6983267 showed a trend towards being a high-risk allele (<it>p </it>= 0.06; age-adjusted OR, 1.27). No significant difference between these two polymorphisms and the risk of latent prostate cancer was observed in the present Japanese population.</p> <p>Conclusion</p> <p>Known variants on human chromosome 8q24 may be risk factors for sporadic prostate cancer in native Japanese men.</p

A gene variant in the Atp10d gene associates with atherosclerotic indices in Japanese elderly population

AbstractBackgroundATP10D belongs to a subfamily of P-type ATPases implicated in phospholipids translocation from the exoplasmic to the cytoplasmic leaflet of cellular biological membrane. Previous genome-wide association study (GWAS) identified that a variant in Atp10d gene (rs2351791) associates with serum lipid profile and myocardial infarction. The objective of this study is to assess the effect of this variant on atherosclerosis in Japanese elderly population.MethodConsecutive autopsy cases registered in JG-SNP study were recruited (n = 1536). The samples were pathologically assessed for atherosclerosis using macroscopic examination of the formalin-fixed arteries, and coronary stenotic index (CSI), intracranial atherosclerotic index (ICAI) and pathological atherosclerotic index (PAI), which represent systemic arteries were calculated. The variant rs2351791 (G/T) in Atp10d gene was genotyped by Taqman genotyping assay and association determined.ResultBoth CSI and ICAI were significantly higher in GG genotype than GT genotype and TT genotype (p = 0.003 and p = 0.001, respectively). Both associations remained significant in minor allele dominant model after adjusting for age, hypertension, diabetes, HDL, smoking and drinking (p = 0.001 and p = 0.001, respectively). PAI was not associated with this variant. Consistent with the previous report, plasma HDL cholesterol level was lower in GG genotype compared to GT + TT genotypes (p = 0.001).ConclusionThe rs2351791 SNP in the Atp10d gene affects the susceptibility for cardiac and intracranial vascular stenosis in the elderly Japanese population

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome‑wide association study

An exome‑wide association study (EWAS) was performed to identify genetic variants, particularly low‑frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome‑12 DNA Analysis BeadChip or Infinium Exome‑24 BeadChip arrays. The association of atrial fibrillation with allele frequencies of 41,243 single nucleotide polymorphisms (SNPs) that passed quality control was examined with Fisher\u27s exact test. Based on Bonferroni\u27s correction, a P<1.21x10‑6 was considered statistically significant. The EWAS for atrial fibrillation revealed that 122 SNPs were significantly associated with this condition. The association of the identified SNPs to atrial fibrillation was further examined by multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension. Eight SNPs were related (P<0.01) to atrial fibrillation, among which three polymorphisms, rs11552708 [G/A (G67R)]of TNF superfamily member 13 (TNFSF13; dominant model; P=9.36x10‑9; odds ratio, 0.58), rs113710653 [C/T (E231 K)] of spermatogenesis and centriole associated 1 like (SPATC1L; dominant model; P=1.09x10‑5; odds ratio, 3.27), and rs11231397 [G/C (R300T)] of solute carrier family 22 member 25 (SLC22A25; additive model; P=3.71x10‑5; odds ratio, 1.77), were significantly (P<1.02x10‑4) associated with this condition. The minor T allele of rs113710653 and the minor C allele of rs11231397 were risk factors for atrial fibrillation, whereas the minor A allele of rs11552708 was protective against this condition. In addition, rs77538589 [C/T (G117R)] of SALL4 exhibited a tendency to be associated with atrial fibrillation (dominant model; P=0.0002; odds ratio, 1.88), with the minor T allele representing a risk factor for this condition. TNFSF13, SPATC1L, SLC22A25 and SALL4 may thus be novel susceptibility loci for atrial fibrillation in the Japanese population

Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes

Background: Senescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene mutations have not yet been fully elucidated. Results: To identify mutations specific to SAMP strains, we performed whole exome sequencing of 6 SAMP and 3 SAMR strains. This analysis revealed 32,019 to 38,925 single-nucleotide variants in the coding region of each SAM strain. We detected Ogg1 p.R304W and Mbd4 p.D129N deleterious mutations in all 6 of the SAMP strains but not in the SAMR or AKR/J strains. Moreover, we extracted 31 SAMP-specific novel deleterious mutations. In all SAMP strains except SAMP8, we detected a p.R473W missense mutation in the Ldb3 gene, which has been associated with myofibrillar myopathy. In 3 SAMP strains (SAMP3, SAMP10, and SAMP11), we identified a p.R167C missense mutation in the Prx gene, in which mutations causing hereditary motor and sensory neuropathy (Dejerine-Sottas syndrome) have been identified. In SAMP6 we detected a p.S540fs frame-shift mutation in the Il4ra gene, a mutation potentially causative of ulcerative colitis and osteoporosis. Conclusions: Our data indicate that different combinations of mutations in disease-causing genes may be responsible for the various phenotypes of SAMP strains.ArticleBMC GENOMICS. 14:248 (2013)journal articl