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Background: CYP2A6 is an enzyme involved in oxidation of a number of environmental chemicals, including nicotine, pro-carcinogenic nitrosamines and polycyclic aromatic hydrocarbons (PAHs). The whole gene deletion of CYP2A6 (CYP2A6*4) is prevalent in East Asian population. Whether or not CYP2A6*4 associates with cancer is still controversial.Methods: We undertook an association study to determine whether deletion of CYP2A6 gene associates with total cancer and major cancer types employing data of consecutive autopsy cases registered in the Japanese single-nucleotide polymorphisms for geriatric research (JG-SNP) database. The presence of cancer were inspected at the time of autopsy and pathologically confirmed. Genotyping for CYP2A6 wild type (W) and deletion (D) was done by allele specific RT-PCR method.Results: Among 1373 subjects, 826 subjects (60.2%) were cancer positive and 547 subjects (39.8%) were cancer negative. The genotype frequency in the whole study group for WW, WD and DD were 65.0, 30.6 and 4.4%, respectively, which obeyed the Hardy-Weinberg equilibrium (p = 0.20). Total cancer presence, as well as major cancers including gastric, lung, colorectal, and blood cancers did not show any positive association with CYP2A6 deletion. When male and female were separately analyzed, CYP2A6 deletion associated with decreased gastric cancer risk in female (OR = 0.49, 95%CI: 0.25-0.95, p = 0.021, after adjustment for age, smoking and drinking). When smoker and non-smoker were separately analyzed, CYP2A6 deletion associated with decreased total cancer in female nonsmokers (OR = 0.67, 95%CI: 0.45-0.99, p = 0.041 after adjustment). On the other hand, CYP2A6 deletion associated increase blood cancers in smokers (OR = 2.05, 95%CI: 1.19-3.53, p = 0.01 after adjustment).Conclusion: The CYP2A6 deletion may not grossly affect total cancer. It may associate with individual cancers in sex and smoking dependent manner. Further studies with larger sample size are warranted to confirm our results. [ABSTRACT FROM AUTHOR]

A genetic risk score (GRS) was developed for predicting fracture risk based on lifetime prevalence of femoral fractures in 924 consecutive autopsies of Japanese males. A total of 922 non-synonymous single nucleotide polymorphisms (SNPs) located in 62 osteoporosis susceptibility genes were genotyped and evaluated for their association with the prevalence of femoral fracture in autopsy cases. GRS values were calculated as the sum of risk allele counts (unweighted GRS) or the sum of weighted scores estimated from logistic regression coefficients (weighted GRS). Five SNPs (α-ʟ-iduronidase rs3755955, C7orf58 rs190543052, homeobox C4 rs75256744, G patch domain-containing gene 1 rs2287679, and Werner syndrome rs2230009) showed a significant association (P < 0.05) with the prevalence of femoral fracture in 924 male subjects. Both the unweighted and weighted GRS adequately predicted fracture prevalence; areas under receiver-operating characteristic curves were 0.750 [95 % confidence interval (CI) 0.660-0.840] and 0.770 (95 % CI 0.681-0.859), respectively. Multiple logistic regression analysis revealed that the odds ratio (OR) for the association between fracture prevalence and unweighted GRS ≥3 (n = 124) was 8.39 (95 % CI 4.22-16.69, P < 0.001) relative to a score <3 (n = 797). Likewise, the OR for a weighted GRS of 6-15 (n = 135) was 7.73 (95 % CI 3.89-15.36, P < 0.001) relative to scores of 0-5 (n = 786). The GRS based on risk allele profiles of the five SNPs could help identify at-risk individuals and enable implementation of preventive measures for femoral fracture. [ABSTRACT FROM AUTHOR]

The intermediate filament nestin is upregulated in stem/progenitor cells and cancers, and regulates cell proliferation, migration, invasion and stemness. The present study comparatively analyzed serial autopsies of Japanese patients (n=2,206; males, 1,225; females, 981; median, 80.7 years old; range, 33–104 years old) with malignant tumors of whole organs, with respect to the clinical information, and 5 single nucleotide polymorphisms of the nestin gene. p.A1199P associated with pancreatic cancer (odds ratio, 4.4; 95% confidence interval, 1.9–10.0, P=0.001) while it did not associate with malignant neoplasms in other organs. p.A1199P did not associate with precancerous lesions of the pancreas. Single nucleotide polymorphisms of nestin were not associated with sex, drinking, smoking, or body weight. In conclusion, the amino acid 1,199 of nestin is localized in the tail structure of the filament and polymerizes with other intermediate filament proteins. The present results suggest that missense variations of nestin affect pancreatic carcinogenesis in Japanese patients. [ABSTRACT FROM AUTHOR]

Werner syndrome is a rare autosomal recessive disorder caused by mutations in the human WRN gene and characterized by the early onset of normal aging symptoms. Given that patients with this disease exhibit osteoporosis, the present study aimed to determine whether the WRN gene contributes to the etiology of osteoporosis. A genetic association study of eight non-synonymous polymorphisms in the WRN gene and the incidence of femoral fracture was undertaken in 1,632 consecutive Japanese autopsies in which 140 patients had experienced the fracture during their lifetime. The results were validated in 251 unrelated postmenopausal Japanese women with osteoporosis and 269 non-institutionalized, community-dwelling Japanese adults. A statistically significant association was observed between rs2230009 (c.340G > A)--which results in a Val to Ile substitution--and fracture risk; the incidence of femoral fracture increased dose-dependently with the number of A alleles (p = 0.0120). Femoral neck bone and whole bone densities were lower among postmenopausal women with osteoporosis and community-dwelling adults, respectively, if they were of the AG instead of the GG genotype. The results suggest that Japanese subjects bearing at least one A allele of rs2230009 of the WRN gene are at a significantly higher risk of femoral fracture, possibly due to decreased bone density. [ABSTRACT FROM AUTHOR]

The transporter associated with antigen processing 2 (TAP2) gene is involved in the immunological response to tuberculosis (TB) infection. Variations in the TAP2 gene have been associated with TB infection in small population studies in India, Columbia, and Korea. We investigated the association of TAP2 polymorphisms with TB susceptibility in an elderly Japanese population. We analyzed samples from consecutive autopsy cases (n = 1850) registered in the Japanese Geriatric SNP Research database. TB was diagnosed pathologically by TB granuloma on autopsy samples. There were 289 cases and 1529 controls. Twenty-four single nucleotide variations (SNVs), including four missense variations in the TAP2 region, were genotyped using the Illumina Infinium Human Exome BeadChip array. Of the 24 SNVs in the TAP2 gene, rs4148871, rs4148876 (R651C), and rs2857103 showed statistically significant associations with TB susceptibility, and rs4148871 and rs2857103 also showed significant genotypic associations in a dominant allele model adjusted for age, sex, and smoking. Haplotype analysis showed that TAP2 allele *0103 conferred an increased TB risk (OR = 1.48, p = 0.0008), while the TAP2 *0201 allele was protective against TB (OR = 0.73, p = 0.0007). Our results suggest that TAP2 polymorphisms influence TB susceptibility in a Japanese population. [ABSTRACT FROM AUTHOR]

Background The Ryanodine receptor 3 gene (RYR3) encodes an intracellular calcium channel that mediates the efflux of Ca2+ from intracellular stores. Two single-nucleotide polymorphisms (SNPs) in the RYR3 gene have been shown to associate with stroke (rs877087) and carotid intima-media thickness (rs2229116) in two independent genome-wide association studies (GWAS) in Caucasian. We investigated the effect of these two SNPs as well as the 31.1 kilobases spanning region on atherosclerosis in Japanese population. Methods Atherosclerotic severity was assessed by carotid artery (n = 1374) and pathological atherosclerosis index (PAI) (n = 1262), which is a macroscopic examination of the luminal surfaces of 8 systemic arteries in consecutive autopsy samples. 4 tag SNPs in the 31.1 Kb region, rs877087, rs2132207, rs658750 and rs2229116, were genotyped and haplotypes were inferred to study the association with atherosclerotic indices. Results rs877087 and rs2229116 were associated with PAI (OR = 2.07[1.04-4.12] (95%CI), p = 0.038; and OR = 1.38[1.02-1.86], p = 0.035, respectively). rs2229116 was also associated with common carotid atherosclerosis (OR = 1.45 [1.13-1.86], p = 0.003). The risk allele of rs2229116 was opposite from the original report. The haplotype block of this 31.1 Kb region was different between Caucasian and Japanese. Haplotype analysis revealed that only TAGG haplotype was associated with PAI (OR = 0.67[0.48-0.94], p = 0.020) and atherosclerosis of common carotid artery (OR = 0.75[0.58-0.98], p = 0.034). Conclusion rs877087 and rs2229116 of RYR3 gene are associated with atherosclerosis severity in Japanese. The functional difference caused by rs2229116 needs to be investigated. [ABSTRACT FROM AUTHOR]

We previously reported 2 osteoporosis-susceptibility genes-formiminotransferase N-terminal sub-domain containing gene (FONG) and thrombospondin, type 1, domain-containing 7A (THSD7A)-in which we identified two common single-nucleotide polymorphisms, rs7605378 (FONG) and rs12673692 (THSD7A). The former was associated with a predisposition to osteoporosis and the latter with bone mineral density. To further elucidate the importance of these polymorphisms in the pathogenesis of osteoporosis, we examined their association with the incidence of vertebral fracture. DNA extracted from the renal cortex of 2427 consecutive Japanese autopsies (1331 men, mean age: 79 years; 1096 women, mean age: 82 years) were examined in this study. The presence or absence of vertebral fracture during each subject's lifetime was determined by a thorough examination of the clinical records, as well as autopsy reports. After adjustments for sex and age at autopsy, logistic regression analysis revealed that homozygotes for the risk alleles of rs7605378 (A-allele) or rs12673629 (A-allele) possess an increased risk of vertebral fracture. The subjects simultaneously homozygous for both the risk alleles of rs7605378 (AA genotype) and rs12673629 (AA genotype) showed significantly higher risk of vertebral fracture (odds ratio 2.401, 95% confidence interval 1.305-4.416, P=0.0048) than those who had at least one non-risk allele of either rs7605378 (AC/CC genotypes) or rs12673629 (AG/GG genotypes). The results suggest that Japanese subjects homozygous for the risk alleles of rs7605378 and rs12673629 have a higher risk of vertebral fracture. [ABSTRACT FROM AUTHOR]

Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema.Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed.A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P=1.1 × 10−5) and overall LAA% (P=1.0 × 10−4), and negatively correlated with the serum concentration of SFTPD (P=7 × 10−11) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations.Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema. [ABSTRACT FROM AUTHOR]

The fucosyltransferase 8 gene (FUT8) encodes an enzyme that transfers fucose to the innermost N-acetylglucosamine unit of N-glycan chains. Recent study showed that fut8-deficient mice develop pathological and physiological phenotypes resembling pulmonary emphysema (PE). The role of FUT8 in human PE is not known. A non-synonymous single-nucleotide polymorphism at the amino-acid position of 267 in FUT8 (rs35949016; C/A, C allele=Thr, A allele=Lys) was genotyped in a total of 1149 consecutive autopsies of elderly Japanese. A following study included 182 outpatients with chronic obstructive pulmonary disease, whose emphysematous changes were assessed quantitatively as the percentage of low attenuation area (%LAA) by high-resolution computed tomography. PE was detected in 163 of 1149 autopsy subjects (14.2%). Comparison of patient with vs without PE indicated that the FUT8 A allele was associated with PE (AA+AC vs CC; odds ratio=1.74, 95% confidence intervals=1.19-2.56, P=0.005). In the clinical study, presence of the FUT8 A allele significantly correlated with %LAA after adjustment (AA+AC vs CC=37.5±14.7 vs 32.7±13.9, P=0.02). The FUT8 gene Thr267Lys polymorphism is associated with human PE, and the Lys allele is the risk. The core fucosylation might be involved in the molecular pathogenesis of human PE. [ABSTRACT FROM AUTHOR]

• HOTAIR is a lncRNA involved in carcinogenesis. • Rs920778 has been implicated in susceptibility for cancers but with controversy. • We assessed the association of HOTAIR SNP rs920778 in consecutive autopsy samples. • Rs920778 does not contribute to cancer susceptibility in a Japanese population. The HOTAIR gene encodes a long noncoding RNA (lncRNA), which functions in development and tumorigenesis. A single nucleotide polymorphism (SNP) rs920778 in the HOTAIR gene, has been recurrently studied for susceptibility to many cancers including oesophageal cancer, gastric cancer, lung cancer, and hepatocellular carcinoma. Most of these studies were conducted in Chinese populations, and a few in Turkish, Iranian, and Portuguese populations. They mostly give rise to controversial results. It still remains largely unknown whether the cancer risk is conferred in a Japanese population. Here, we established an association study on the representative SNP rs920778, to examine its contribution to the presence of cancer in consecutive autopsy cases in the JG-SNP database. A total of 1373 subjects (mean age 80) including 827 cancer positive and 546 cancer negative subjects were analyzed. As a result, the occurrence of overall cancer was not associated with the rs920778 polymorphism (p > 0.05). For each cancer type, we did not find association except for lung cancer (p = 0.04) which was more likely a by-chance association after multiple testing. Our findings imply that rs920778 polymorphism does not affect total cancer presence and the effect on specific cancer types is also weak in the Japanese population. [ABSTRACT FROM AUTHOR]