Allele frequencies of single nucleotide polymorphisms (SNPs) in 40 candidate genes for gene-environment studies on cancer: data from population-based Japanese random samples

Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures. The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms (SNPs) of select genes, which may be included in future gene-environment studies on cancer in Japan. SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan. We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes: CYP1A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP17A1, CYP19A1, AHR, ESR1, ESR2, ERRRG, PGR, EPHX1, EPHX2, HSD17B2, HSD17B3, GSTM2, GSTM3, GSTT2, GSTP1, NAT1, NAT2, COMT, ADH1A, ADH1B, ADH1C, ALDH2, NOS2A, NOS3, IL1A, IL1B, OGG1, NUDT1 [MTH1], DRD2, DRD3, DRD4, SLC6A4, NR3C1 [GCCR], MTHFR, and NQO1. In the present study, the Japanese allele frequencies were verified by using nationwide population samples.     

AQP7和AQP9基因多态性与中国汉族人群2型糖尿病的相关性研究

目的探讨水通道蛋白7(aquaporin 7, AQP7)以及水通道蛋白9(aquaporin 9, AQP9)基因单核苷酸多态性(single nucleotide polymorphism, SNP)与中国汉族人群患2型糖尿病(type 2 diabetes mellitus, T2DM)的相关性。方法随机纳入1194例T2DM个体和1274例非糖尿病个体(non-diabetic, NDM)进行对照研究, 采用MassArray质谱基因分型方法对3个SNP位点(AQP7基因rs3758269、AQP9基因rs16939881和rs57139208)进行基因分型。评估以上3个SNP位点与T2DM的相关性;探讨NDM组SNP位点处不同基因型与糖脂代谢指标的关联。结果 AQP7基因rs3758269、AQP9基因rs16939881和rs57139208的等位基因频率及基因型频率在T2DM组和NDM组中的分布无统计学差异(P > 0.05);且分析结果显示不同遗传模式与T2DM无相关性(P > 0.05)。在NDM组中, AQP7基因rs3758269、AQP9基因rs16939881和rs57139208的不同基因型与糖脂代谢指标无相关性(P > 0.05)。结论 AQP7基因rs3758269和AQP9基因rs16939881和rs57139208与中国汉族人群T2DM遗传易感性无关。     

AQP7和AQP9基因多态性与中国汉族人群2型糖尿病的相关性研究CSCD

目的探讨水通道蛋白7(aquaporin 7, AQP7)以及水通道蛋白9(aquaporin 9, AQP9)基因单核苷酸多态性(single nucleotide polymorphism, SNP)与中国汉族人群患2型糖尿病(type 2 diabetes mellitus, T2DM)的相关性。方法随机纳入1194例T2DM个体和1274例非糖尿病个体(non-diabetic, NDM)进行对照研究, 采用MassArray质谱基因分型方法对3个SNP位点(AQP7基因rs3758269、AQP9基因rs16939881和rs57139208)进行基因分型。评估以上3个SNP位点与T2DM的相关性;探讨NDM组SNP位点处不同基因型与糖脂代谢指标的关联。结果 AQP7基因rs3758269、AQP9基因rs16939881和rs57139208的等位基因频率及基因型频率在T2DM组和NDM组中的分布无统计学差异(P > 0.05);且分析结果显示不同遗传模式与T2DM无相关性(P > 0.05)。在NDM组中, AQP7基因rs3758269、AQP9基因rs16939881和rs57139208的不同基因型与糖脂代谢指标无相关性(P > 0.05)。结论 AQP7基因rs3758269和AQP9基因rs16939881和rs57139208与中国汉族人群T2DM遗传易感性无关。     

Association of single nucleotide polymorphisms in the promoter region of the pro-opiomelanocortin gene (POMC) with low bone mineral density in adult women

Among multiple factors influencing osteoporosis, genetic variations involved in bone-mineral metabolism can affect risks predisposing to the disease onset. Here, we studied single-nucleotide polymorphisms (SNPs) in the pro-opiomelanocortin (POMC) gene for possible association with bone mineral density (BMD) among 384 adult Japanese women and observed significant correlation between adjusted BMD and three SNPs in the promoter region (r>0.14, p<0.01). The most significant correlation was observed for –2353G/A (r=–0.16, p=0.002); homozygous carriers of the major (G) allele had the highest BMD (0.405±0.054 g/cm²) while heterozygous carriers were intermediate (0.390±0.053 g/cm²) and homozygous A-allele carriers had the lowest BMDs (0.369±0.048 g/cm²). Although no association was detected between these SNPs and body weight or body mass index (BMI), significant association was detected between the –2313A/C genotype and plasma total cholesterol level (r=–0.12, p=0.019). We propose that POMC is among the likely susceptibility genes for osteoporosis and may also be involved in dyslipidemia.     

TBX20基因启动子区的单核苷酸多态性与扩张型心肌病的相关性分析

目的:探讨TBX20基因启动子区的单核苷酸多态性(SNP)与扩张型心肌病(DCM)的相关性。方法:采用病例-对照研究方法,收集136例DCM患者和210例健康对照。采用PCR和Sanger测序的方法获得TBX20基因启动子区的SNPs。通过细胞转染和电泳迁移率变动分析(EMSA)对TBX20基因启动子区的SNPs进行遗传功能分析。采用卡方检验和两独立样本t检验对数据进行统计学分析。使用SNPStats在线软件进行相关性分析。结果:校正混杂因素后,rs73099190在共显性遗传模型和超显性遗传模型中的TC基因型和显性遗传模型中的TC+CC基因型均与DCM显著相关(OR=1.96,95%CI:1.20~3.20,P=0.019;OR=1.98,95%CI:1.22~3.24,P=0.006;OR=1.86,95%CI:1.15~3.03,P=0.012)。转染结果显示,TBX20基因启动子区的SNPs显著改变了TBX20基因启动子的转录活性(P<0.01)。进一步EMSA实验表明,rs1191745927和rs73099190影响了TBX20基因启动子与转录因子的结合。结论:DCM患者TBX20基因启动子的变异可能影响转录因子的结合,进而改变了TBX20基因的转录活性,可能作为罕见的低频危险因素促进DCM的发生发展。     

TBX20基因启动子区的单核苷酸多态性与扩张型心肌病的相关性分析

目的:探讨TBX20基因启动子区的单核苷酸多态性(SNP)与扩张型心肌病(DCM)的相关性。方法:采用病例-对照研究方法,收集136例DCM患者和210例健康对照。采用PCR和Sanger测序的方法获得TBX20基因启动子区的SNPs。通过细胞转染和电泳迁移率变动分析(EMSA)对TBX20基因启动子区的SNPs进行遗传功能分析。采用卡方检验和两独立样本t检验对数据进行统计学分析。使用SNPStats在线软件进行相关性分析。结果:校正混杂因素后,rs73099190在共显性遗传模型和超显性遗传模型中的TC基因型和显性遗传模型中的TC+CC基因型均与DCM显著相关(OR=1.96,95%CI:1.20~3.20,P=0.019;OR=1.98,95%CI:1.22~3.24,P=0.006;OR=1.86,95%CI:1.15~3.03,P=0.012)。转染结果显示,TBX20基因启动子区的SNPs显著改变了TBX20基因启动子的转录活性(P<0.01)。进一步EMSA实验表明,rs1191745927和rs73099190影响了TBX20基因启动子与转录因子的结合。结论:DCM患者TBX20基因启动子的变异可能影响转录因子的结合,进而改变了TBX20基因的转录活性,可能作为罕见的低频危险因素促进DCM的发生发展。     

CSPG2和HSPG2基因单核苷酸多态性与中国汉族人颅内动脉瘤的相关性研究

目的 分析CSPG2和HSPG2基因单核苷酸多态性(single nucleotide polymorphism,SNP)与中国汉族散发颅内动脉瘤的相关性.方法 采用病例-对照关联研究方法,收集颅内动脉瘤患者537例以及年龄和性别匹配的正常对照1071名的外周血样各5 mL并提取基因DNA.通过聚合酶链式反应扩增目的DNA,用单碱基延伸(SNaPshot)法进行SNP分型.选取文献报道的CSPG2和HSPG2基因的两个标签SNPs位点rs251124和rs3767137,分析其与汉族散发颅内动脉瘤发病的关联性.结果 CSPG2和HSPG2基因的两个标签SNPs位点rs251124和rs3767137的基因型均满足Hardy-Weinberg平衡.CSPG2rs251124的等位基因频率在患者组与对照组之间差异无统计学意义(P=0.22);HSPG2 rs3767137的等位基因频率在两组之间亦差异无统计学意义(P=0.26),但其相应的OR值大于1(OR=1.12;95％CI=0.92～1.37).患者组与对照组rs251124、rs3767137的基因型频率均差异无统计学意义(P=0.46,0.53).结论 未发现CSPG2和HSPG2基因rs251124、rs3767137 SNPs与中国人颅内动脉瘤发病的相关性.     

Twenty single nucleotide polymorphisms (SNPs) and their allelic frequencies in four genes that are responsible for familial long QT syndrome in the Japanese population

We report here 20 single nucleotide polymorphisms (SNPs), including 10 novel ones, and their allelic frequencies detected in four genes that are known to be responsible for familial long QT syndrome in the Japanese population; 7 polymorphisms are in the KCNQ1 gene, 6 in the KCNH2 gene, 5 in the SCN5A gene, and 2 in the KCNE1 gene. These data will be of use for genetic association studies of acquired cardiac arrhythmias. Received: December 25, 1999 / Accepted: December 27, 1999     

RANTES基因-28C／G单核苷酸多态性与子宫内膜异位症遗传易感性的研究

目的探讨调节正常T细胞表达和分泌活性因子（regulated on activation, normal T cell expressed and secreted,RANTES）基因启动子区-28C／G单核苷酸的多态性与广东籍汉族患者子宫内膜异位症的关系。方法应用聚合酶链反应-限制性酶切片段长度多态性技术（PCR—RFLP）并进行基因测序的方法检测广东籍汉族子宫内膜异位症患者59例（内异症组）,非子宫内膜异位症患者49例（对照组）,比较分析各组间基因型频率和等位基因频率。结果RANTES基因启动子区-28C／C基因型在子宫内膜异症组及对照组分布频率分别为81．36％、81．63％,C／G基因型分布频率分别为18．64％、18．37％;两组间的基因型分布频率比较差异无显著性（P〉0．05）。RANTES基因启动子区-28位点C等位基因型在内异症组及对照组中的分布频率分别为90．68％、90．82％,G等位基因型分布频率分别为9．32％、9．18％,两组间等位基因型频率比较差异无统计学意义（P〉0．05）。结论在广东籍汉族妇女中,RANTES基因启动子区-28C／G单核苷酸多态性与子宫内膜异位症遗传易感性可能无关联。     

Association of single nucleotide polymorphisms of CDH13 gene with metabolic syndrome among ethnic Han ChineseCSCD

Objective: To assessthe association of single nucleotide polymorphisms (SNPs) of the T-cadherin (CDH13) gene with metabolic syndrome (MS) among ethnic Han Chinese. Methods: Genotypes of 6 SNPs(rsll646213, rsl2596316, rs3865188, rsl2444338, rsl2051272, and rs7195409) of the CDH13 gene among 453 patients with MS and 526 controls were determined with a TaqMan method, and their association with MS was assessed. Results: For 5 SNPs (rsll646213, rs3865188, rsl2444338, rsl2051272, and rs7195409), no difference was found in allelic and genotypic frequencies of the CDH13 gene between the two groups. Comparing with rsl2596316 (AA+GG) genotype, rsl2596316 AG genotype has significantly increased the risk of MS(P = 0.01, OR=1.38, 95%CI: 1.07-1.78), though no association was found between particular alleles of the rsl2596316 with MS. There was no difference in the frequencies of rsll646213-rsl2596316-rs3865188-rsl2444338-rsl2051272 haplotype between the two groups(P>0.05). Conclusion: No association was found between the five SNPs (rsll646213, rs3865188, rsl2444338, rsl2051272 and rs7195409) of the CDH13 gene with the MS, while the rsl2596316AG genotype of the CDH13 gene is associated with the susceptibility to MS among ethnic Han Chinese. © 2018 West China University of Medical Sciences. All rights reserved.     

Association of single nucleotide polymorphisms of LEPR gene with essential hypertension among ethnic Mongolian and Han Chinese from Inner Mongolia regionCSCD

Objective: To assess the association of single nucleotide polymorphisms (SNPs) of leptin receptor (LEPR) gene with essential hypertension (EH) and body mass index (BMI) among ethnic Mongolian and Han Chinese from Inner Mongolia region. Methods: In total 411 Han Chinese patients with EH and 480 healthy controls, together with 658 Mongolian patients with EH and 403 healthy controls, were collected. The SNPs of the LEPR gene were determined with ligase detection reaction (LDR). Logistic regression was used to analyze the association of the polymorphisms of each locus with EH and BMI. MDR software was used to analyze the interaction between above loci and environmental factors. Results: Genotypic frequencies of LEPR gene rs7555955, rsll37100 and rsll37101 loci had differed significantly among ethnic Hans with EH and the control group (All P <0. 05). While those of rs7555955, rsl805094, rsll37100, rsll579567, rsl805134 and rs6669354 loci had differed significantly among ethnic Mongolians with EH and the control group (All P<0. 05). After adjustment for confounders, logistic regression analysis indicated that age(Oi=2. 97, 95%CJ: 1. 94-3. 99), BMI (Ofl = 3. 93, 95%CI:2. 91-5. 96), and rsll37101 (AA) (Oi=3. 96, 95%CI-.l. 32-11. 90) were independent risk factors for EH among ethnic Hans, while age (Oi=2. 99, 95%C7:2. 98-4. 57), BMI (Oi = 3. 03, 95%CI-. 1. 05-1. 27), rs7555955 (AG, AA) (OR = 12.12, 95%CI:2.80-52.43) OP = 6.35, 95%CI: 1. 44-27. 94), and rs7555955 (GG) were independent risk factors for EH among ethnic Mongolians (P <0. 05). Conclusion: Age and BMI are independent risk factors for EH in both ethnic Han and Mongolian Chinese. rsll37101 locus is associated with EH among ethnic Hans, while rs7555955 locus is associated with EH among ethnic Mongolians. © 2018 MeDitorial Ltd. All rights reserved.     

TBX21基因rs16947078位点的多态性与哮喘易感性的研究

目的研究TBX21基因的rs16947078位点的多态性与哮喘易感性的关系。方法应用基质辅助激光解吸附电离飞行时间质谱(MALDI-TOF-MS)平台及MassARRAY-IPLEX技术,分别对重庆地区汉族人群中199名正常对照组和223名哮喘患者组的TBX21基因rs16947078位点进行检测并分析其基因型及等位基因分布情况,研究TBX21基因rs16947078位点的多态性与哮喘易感性间的关系。结果 TBX21基因rs16947078位点基因型和等位基因在病例组与对照组间均存在显著差异,P值分别为0.010和0.011;对年龄和性别进行校正后,相对于AA基因型,AG基因型的人群患哮喘的风险增加(OR=9.433,95%CI:1.170~76.022);等位基因G的携带者患哮喘的风险也有所增加(OR=9.232,95%CI:1.152~74.006)。结论研究结果提示TBX21基因中rs16947078位点与哮喘的易感性相关。     

Identification of a novel single nucleotide polymorphism (SNP) in the human organic cation transporter-like 2-antisense (ORCTL2S) gene

We found a single nucleotide polymorphism (SNP) in exon 3 of the human organic cation transporter-like 2-antisense (ORCTL2S) gene: a base substitution A266G which was confirmed by direct sequencing. Heterozygosity of the polymorphic alleles was 0.45 in a Japanese population. This polymorphism will be useful in the allelic expression analysis of the ORCTL2S gene. Received: September 13, 1999 / Accepted: September 27, 1999     

Association of genetic variations of genes encoding thrombospondin, type 1, domain-containing 4 and 7A with low bone mineral density in Japanese women with osteoporosis

Twins and family studies have shown that genetic factors are important determinants of bone mass. Important aspects of bone mineral density (BMD) regulation are endocrine systems, notably hormonal regulation of adrenal corticoids, as indicated by clinical knowledge of glucocorticoid-induced osteoporosis. Glucocorticoid is known to negatively regulate bone mass in vivo, and glucocorticoid increases thrombospondin messenger ribonucleic acid (mRNA) levels. We studied single nucleotide polymorphisms (SNPs) in genes encoding thrombospondin, type 1, domain-containing 4 and 7A (THSD4 and THSD7A) for possible association with lumbar and femoral BMD among 337 Japanese women with osteoporosis who participated in the BioBank Japan project. Genetic variations of THSD4 and THSD7A loci displayed significant association with lumbar and femoral BMD. Most significant correlation was observed for THSD7A SNP rs12673692 with lumbar BMD (P = 0.00017). Homozygous carriers of the major (G) allele had the highest BMD [0.886 +/- 0.011 g/cm2, mean +/- standard deviation (SD)], whereas heterozygous carriers were intermediate (0.872 +/- 0.013 g/cm2) and homozygous A-allele carriers had the lowest (0.753 +/- 0.023 g/cm2). THSD4 SNP rs10851839 also displayed strong association with lumbar BMD (P = 0.0092). In addition, both THSD7A and THSD4 displayed significant association with femoral BMD in a recessive model (P = 0.036 and P = 0.0046, respectively). Results suggest that variations of THSD7A and THSD4 loci may be important determinants of osteoporosis in Japanese women.     

Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP)

To facilitate geriatric research on the roles of genetic polymorphisms of candidate genes, two databases were developed based on data obtained from autopsy examinations of elderly subjects: the geriatric autopsy database (GEAD) and the Japanese single nucleotide polymorphisms (SNP) database for geriatric research (JG-SNP) which is accessible on the Internet (http://www.tmgh.metro.tokyo.jp/jg-snp/english/E_top.html). The data for the GEAD were derived from 1074 consecutive autopsy cases (565 male and 509 female cases) with an average age of 80 years. The GEAD was installed on a stand-alone Windows 2000 server using Oracle 8i as the database application. The GEAD contains clinical diagnoses of 26 geriatric diseases, histories of smoking and alcohol consumption, pathological findings (720 items), severity of atherosclerosis, genetic polymorphism data, etc. On the JG-SNP website, case distribution corresponding to a specified SNP or disease can be searched or downloaded. Although there are several Internet-based SNP databases such as dbSNP, no databases are available at present on the web that contain both SNP data and phenotypic data. As autopsy studies can provide large amounts of accurate medical information, including the presence of undiagnosed diseases such as latent cancers, the GEAD is a unique and excellent database for research on genetic polymorphisms.     

Association analysis of the functional Ala111Glu polymorphism of the glyoxalase I gene in panic disorder

The zinc metalloenzyme glyoxalase I (GLO1) is thought to play a role in anxiety disorders because a reduced brain expression of GLO1 has been associated with increased anxiety-behaviours in mice. Recently, a functional Ala111Glu polymorphism in GLO1 has been shown to result in a reduced enzyme activity. The present study tested the hypothesis that this common genetic variant could confer susceptibility to panic disorder using an Italian population sample of 162 panic disorder patients and 288 matched controls. Statistical analysis failed to show association with the overall diagnosis of the disease. However, a weak but significant association was demonstrated between this polymorphism and panic disorder without agoraphobia. While our data suggest that this polymorphism is unlikely to have a major function in the pathogenesis of panic disorder, it could play a role in the subgroup of patients without agoraphobic avoidance.     

OX40基因rs2298212位点与汉族人群冠状动脉粥样硬化疾病的关联研究

目的 探讨OX40基因(TNFRSF4)rs2298212G/A位点与山东汉族人群冠状动脉粥样硬化疾病的相关性.方法 在山东大学齐鲁医院心内科和健康体检中心分别收集到冠状动脉粥样硬化疾病患者536例和正常对照544名,采用聚合酶链反应-限制性片段长度多态性方法 对OX40基因rs2298212G/A多态性位点进行基因分型,并对数据进行统计分析.结果 基因型与等位基因频率分布在病例组与对照组之间差异均无统计学意义(P＞0.05).在回归校正了年龄、性别、体重指数、收缩压、舒张压、血糖、总胆固醇及甘油三酯等因素的影响后,基因型频率分布差异仍无统计学意义(P＞0.05).在对冠状动脉受累支数进行的分层分析发现,受累1支与受累3支之间,基因型与等位基因频率分布差异均有统计学意义(P＜0.05).结论 OX40基因rs2298212G/A多态位点同山东汉族人群冠状动脉粥样硬化疾病之间无关联性存在,但该位点可能与冠状动脉粥样硬化的严重程度相关.     

骨保护素基因单核苷酸多态性与类风湿关节炎发病的相关性研究

 目的：探讨骨保护素（OPG）基因163A/G及245T/G单核苷酸多态性（SNPs）与我国汉族人群类风湿关节炎（RA）发病的相关性。方法：采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术检测我国南方汉族正常人群及RA患者的OPG 163A/G 和245T/G 2个SNP位点;进行Hardy-Weinberg平衡检验;计算基因型和等位基因频率,及这2个位点的连锁关系,并分析这2个SNP位点与RA的关系。结果：所研究基因分布符合Hardy-Weinberg平衡,163A/G 位点基因型AA、AG、GG分布频率在2组比较有显著差异（P<0.05）;等位基因A、G分布比较在2组有显著差异（P<0.05）,携带163GG基因型者发生RA的危险性是非携带者的1.219倍（OR=1219, 95％CI：1066~2.339, P<0.05)。但245T/G位点各基因型及等位基因频率在2组中均未见差异（P>005）。结论：OPG 基因 163A/G SNP可能与我国汉族人群RA发病相关,携带G等位基因可能是发病的危险因素。     

CASP3基因单核苷酸多态性与中国儿童川崎病的相关性研究

目的 分析半胱氨酸蛋白酶3基因(caspase-3,CASP3)多态性与中国儿童川崎病(Kawasakidisease,KD)临床表型的潜在相关性,以寻找中国儿童KD发生发展的高风险分子标记.方法 采用病例对照研究,实验组包括238例KD患儿,对照组包含年龄与性别组成匹配的364名非KD儿童.同时应用聚合酶链式反应-限制性片段长度多态性与DNA测序技术,对研究对象的CASP3基因包括功能性单核苷酸多态位点(single nucleotide polymorphism,SNP)rs113420705在内的3个多态位点进行基因分型,分别比较KD组与对照组、继发与不继发冠状动脉损伤(coronary artery lesions,CALs)以及静脉注射免疫球蛋白(intravenous immunoglobulin,IVIG)治疗敏感与抗性情况下这些SNP位点等位基因与基因型频率.结果 KD组中rs113420705的T等位基因频率与该等位基因携带者频率均显著高于对照组.在3种常见的单倍型中,2种包含SNP rs113420705风险等位基因的单倍型更常见于KD患者组.3个SNP位点的等位基因、基因型与次等位基因携带者频率在继发与不继发CALs患者组,以及IVIG治疗敏感与不敏感患者组之间差异均无统计学意义.结论 CASP3基因rs113420705与中国人群川崎病的发生存在显著的相关性,提示该SNP的风险等位基因有希望成为判断中国儿童川崎病易患性的分子遗传标记.CASP3基因风险单倍型的证实为该基因在KD发生中的作用提供了新的证据.