Association of habitual smoking and drinking with single nucleotide polymorphism (SNP) in 40 candidate genes: data from random population-based Japanese samples

Basic information on the association between lifestyle factors and candidate genes is valuable for genetic–environmental study. We screened the association of habitual smoking or drinking with polymorphism in 40 candidate genes for a total of 153 single nucleotide polymorphisms (SNPs) using a sample of 339 middle-aged, randomly selected Japanese men. Smoking and drinking statuses were elicited during questionnaire-based interviews. Genes were selected based on their possible involvement in genetic–environmental, life-style interactions and constitute the genes expressing xenobiotic metabolism enzymes, DNA repair enzymes, and other stress-related proteins. The P values of odds ratios to habitual smoking for CYP17A1, ESR1, EPHX1, GSTT2, ALDH2, NOS2A, OGG1, and SLC6A4 and those of odds ratios to habitual drinking for CYP1B1, ESR1, HSD17B3, GSTM3, COMT, ADH1C, ALDH2, NOS3, and NUDT1 were under 0.05. These variables were included in a stepwise logistic analysis in order to develop a predictive model for smoking or drinking behavior. In the final model, the only significant variables selected for smoking were OGG1, SLC6A4, EPHX1, ESR1, and CYP17A1, and for drinking, ALDH2 and NUDT1. The findings of the present study suggest that polymorphism in associated candidate genes plays a role in the habitual use of tobacco and alcohol among Japanese men.     

Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria

Acetyl salicylic acid (ASA) is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6), cytochrome P4502C9 (CYP2C9), and N-acetyl transferase 2 (NAT2). Variations in the activities of these enzymes may modulate adverse ASA-related symptoms such as urticaria. We examined whether polymorphisms in the UGT1A6, CYP2C9, and NAT2 genes are related to ASA-intolerant urticaria (AIU). The genotypes of 148 subjects with AIU (AIU group) and 260 normal healthy control subjects (NC group) were analyzed with respect to the following single nucleotide polymorphisms: CYP2C9 -1188T>C and CYP2C9(*)3A1075C; UGT1A6 T181A A>G and UGT1A6 R184S A>C; and NAT2 9796A>T, NAT2 197G>A, NAT2 286G>A, NAT2 9601A>G, and NAT2 9306A>G. There were significant differences in the allele frequencies for the CYP2C9 polymorphisms between the two groups. The frequency of the minor allele CYP2C9 -1188T>C was significantly higher in the AIU group than in the NC group (P=0.005). The frequency of the variant genotype CC was higher in the AIU group compared with the controls in both the co-dominant (P=0.007) and recessive models (P=0.012). The frequency of haplotype 2 [CA] was also significantly higher in the AIU group in both the co-dominant (P=0.006) and dominant models (P=0.012). There was no significant difference in genotype frequencies for any of the UGT1A6 or NAT2 polymorphisms between the two groups. Clinical parameters did not differ according to genotype. These results suggest that the C allele of CYP2C9 -1188T>C may be associated with AIU.     

Genetic polymorphism of N-acetyltransferase-2, glutathione S-transferase-M1, and cytochromes P450IIE1 and P450IID6 in the susceptibility to head and neck cancer.

AIMS: To analyse the allele frequencies of DNA polymorphisms at the genes for cytochromes P450IIE1 and P450IID6, N-acetyltransferase-2, and glutathione S-transferase-M1 in patients with head and neck squamous cell carcinoma, in an attempt to define genetic factors involved in the susceptibility to this cancer, which is strongly associated with tobacco consumption. METHODS: Determination of restriction fragment length polymorphism (RFLP) at cytochromes P450IIE1/P450IID6 and NAT2 genes, and the presence of homozygous deletion of the GSTM1 gene, in 200 controls and 75 head and neck cancer patients. Allelic frequencies between the two groups were compared using a chi 2 test, and odds ratio with 95% confidence intervals were calculated. RESULTS: There was no evidence of an association between alleles of CYP2D6 and CYP2E1 and head and neck cancer in our population. Similarly, frequencies of individuals lacking the GSTM1 gene did not differ between controls and patients. However, individuals with the NAT2-SA phenotype were at higher risk of developing head and neck cancer. The frequencies of the most common SA genotype (homozygous for the NAT2*5 allele) were higher in patients than in controls (27% v 15%, respectively). Slow acetylators homozygous for the NAT2*6 allele, the second most common SA allele, were also more common in patients than in controls (11% v 5%, respectively). CONCLUSIONS: Slow NAT2 activity is a risk factor possibly leading to the development of head and neck cancer in response to tobacco carcinogens.     

Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency

Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.     

Association study of CYP17 and HSD11B1 in polycystic ovary syndrome utilizing comprehensive gene coverage

Cytochrome P450-C17 enzyme (CYP17) is an important component of the androgen synthesis pathway, a pathway that is dysfunctional in polycystic ovary syndrome (PCOS). Variation in 11-beta hydroxysteroid dehydrogenase (HSD11B1) is associated with cortisone reductase deficiency, a condition with a phenotype similar to PCOS. Both CYP17 and HSD11B1 genes have been previously studied for their possible relationship with PCOS, yielding inconsistent results. In this study, we evaluated the association between variation in these genes and PCOS. Two-hundred and eighty-seven Caucasian PCOS women and 187 Caucasian controls were genotyped for single nucleotide polymorphisms (SNPs) that were specifically chosen to allow full coverage of CYP17 and HSD11B1, including four SNPs in CYP17 and eight SNPs in HSD11B1. SNP and haplotype association analyses were conducted. Our results indicate that variants in the two genes are not associated with PCOS, or with the quantitative traits characteristic of PCOS, suggesting that these genes are not major risk factors for the syndrome.     

韩国人CYP450 1A1、CYP450 2E1和GSTM1、GSTT1、GSTP1基因座遗传多态性分析

目的 调查代谢相关的CYP4501A1、CYP4502E1和GSTM1、GSIT1、GSTP1基因座在韩国人群中的遗传多态性分布状况。方法 采用多重聚合酶链式反应、聚合酶链式反应-限制性片段长度多态性技术，分析300名韩国健康大学生的CYP1A1基因3′端限制性内切酶Msp Ⅰ位点、CYP2E1基因5′端转录调节区Pst Ⅰ位点和GSTM1、GSTT1缺失与存在、GSTP1基因第5外显子BsmA Ⅰ位点的基因型，计算基因型和基因频率。结果 CYP1A1基因型频率为ml／ml型39．7％、ml／m2型49．7％、m2／m2型10．7％，基因频率为ml 0．645、m2 0．355。CYP2E1基因型频率为cl／cl型66．7％、cl／c2型30％、c2／c2型3．3％，基因频率为C1 0．818、C2 0．182。GSTM1基因缺失型频率为53．3％。GSTT1基因缺失型频率为54．7％。GSTP1基因型频率为Ile／Ile型62％、Ile／Val型34．3％、VaL／Val型3．7％，基因频率为Ile 0．792、Val 0．208。基因分布符合Hardy-Weirtberg平衡定律。结论 韩国人CYP1A1、CYP2E1、GSTM1、GSTT1基因分布与我国人群较为相近，半数以上人缺乏GSTM1和GSTT1基因，纯合缺失型频率超过印度人的3倍。     

The high prevalence of the poor and ultrarapid metabolite alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 in Taiwanese population

Genetic polymorphisms of drug metabolizing enzymes, such as cytochromes P450 (CYPs), play major roles in the variations of drug responsiveness in human. The aim of this study is to identify the high prevalence (minor allele frequencies >1%) of the abnormal metabolite alleles of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Taiwanese population. The genotyping of the functional single nucleotide polymorphisms (SNPs) of CYPs were conducted by direct exon sequencing in 180 Taiwanese volunteers. Twenty-one unique SNPs including three newly identified SNPs were detected in the Taiwanese population. Six of the 21 SNPs in five genes showed frequencies more than 1%. The results indicated that it could be very useful and important in developing an inexpensive, convenient, and precise genotyping method for the high prevalence of CYPs metabolizing abnormal alleles in the Taiwanese population.     

Single nucleotide polymorphisms and haplotype frequencies of CYP3A5 in a Japanese population

In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A5 in a Japanese population, we sequenced the proximal promoter region, all exons, and the surrounding intronic regions using genomic DNA from 187 Japanese subjects. Thirteen SNPs, including seven novel ones: 13108T>C, 16025A>G, 16903A>G, 16993C>G, 27448C>A, 29782A>G, and 31551T>C (A of the translational start codon of GenBank Accession # NG_000004.2 is numbered 1 according to the CYP Allele Nomenclature), were identified. The most common SNP was 6986A>G (key SNP for CYP3A5*3), with a 0.759 frequency. Two novel SNPs, 29782A>G (I456V) and 31551T>C (I488T), as well as 12952T>C (*5 marker) were found, but these alterations were always associated with the *3A marker SNPs, 6986A>G and 31611C>T. Using these 13 SNPs, haplotype analysis was performed and five novel *1 haplotypes (subtypes) (*1e to *1i) and six novel *3 haplotypes (subtypes) (*3d to *3i) were identified. Our findings suggest that CYP3A5*3 is the major defective allele and that other functional exonic SNPs are rare in the Japanese.     

The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men

To identify the association between the polymorphisms of genes encoding alcohol metabolizing enzymes and alcoholism, the alcohol dehydrogenase 2 (ADH2), alcohol dehydrogenase 3 (ADH3), aldehyde dehydrogenase 2 (ALDH2), and cytochrome P450 2E1 (CYP2E1) genes were studied in 101 male Mexican American alcoholics. One hundred and four Mexican American nonalcoholic males served as controls. The allele frequency of ADH2*2 (4.3%) and ALDH2*2 (0%), which are considered as protective alleles against alcohol drinking, is very low in Mexican Americans and no association is found between these alleles and alcohol dependence. A strong association was found between ADH3 genotype and alcoholism; the percentage of subjects who carry the ADH3*2 allele was significantly higher in alcoholics (64.4%) than controls (50%). Association was also found between the CYP2E1 RsaI c2 allele and alcohol dependence; the percentage of subjects who carry the RsaI c2 allele was significantly higher in alcoholics (34.7%) than in nonalcoholics (22.1%). The subjects whose alcohol drinking onset age is younger than 25 have much higher CYP2E1 c2 allele frequency than those whose alcohol drinking onset age is older than 25 (22.1% vs 15.7%). Among 101 alcoholics, only 18 subjects carry neither ADH3*2 nor CYP2E1 c2 alleles. For those subjects who have an ADH*1/*1 background, a strong association is found between CYP2E1 RsaI/DraI genotype and alcoholism; the CYP2E1 RsaI c2 and DraI C allele frequencies are much higher in alcoholics than in nonalcoholics (26.4% vs 9.6% for c2 and 27.8% vs 13.5% for C allele). Taken together, ADH3*2 and CYP2E1 c2/C alleles might independently contribute to the development of alcoholism in Mexican American men.     

Association of CYP1A1 gene polymorphism with recurrent pregnancy loss in the South Indian population

BACKGROUND: We investigated the relationship between idiopathic recurrent pregnancy loss (RPL) and genetic polymorphisms in phase I and phase II detoxification genes which include CYP1A1, CYP2D6, GSTM1, GSTP1 and GSTT1. METHOD: A case-control study comprised 160 females with RPL and 63 healthy controls with a successful reproductive history. RESULTS: The CYP1A1 variant allele was present at frequencies of 0.61 and 0.44 in cases and controls, respectively (odds ratio=1.93; P=0.023, 95% confidence interval 1.10-3.38). The CYP2D6 variant allele was present at a frequency of 0.17 in females with RPL, while in the control population the frequency was 0.16. The GSTM1 and GSTT1 null genotypes were present at frequencies of 0.39 and 0.26 in RPL cases, whereas in controls the frequencies were 0.37 and 0.17, respectively. The mutant GSTP1 frequencies in case and control women were 0.38 and 0.40, respectively. We report a significant association of the CYP1A1*2A allele with RPL which is confirmed by logistic regression analysis. No association was observed for the other polymorphisms or in their combinations studied. CONCLUSIONS: The present study suggests the occurrence of the CYP1A1*2A allele as a probable risk factor in idiopathic recurrent miscarriages.     

Association between endometriosis and genetic polymorphisms of the estradiol-synthesizing enzyme genes HSD17B1 and CYP19

BACKGROUND: Endometriosis, an estrogen-dependent disease, is believed to be influenced by multiple genetic and environmental factors. Here, we evaluated whether the risk and severity of endometriosis are associated with polymorphisms in estradiol-synthesizing enzyme genes: the Ser312Gly polymorphism in 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) and the Arg264Cys polymorphism in cytochrome P450, subfamily XIX (CYP19). METHODS: All participants underwent diagnostic laparoscopy, and the stage of endometriosis was determined according to the Revised American Fertility Society classification. Of the 138 women enrolled, 59 had no endometriosis, 21 had stage I, 10 had stage II, 23 had stage III and 25 had stage IV. SNPs were discriminated by allele-specific oligonucleotide hybridization. RESULTS: Individuals having at least one A-allele (A/G or A/A genotype) of HSD17B1 showed a significantly increased risk of endometriosis (A/G genotype: adjusted OR, 3.06; 95%CI 1.21-7.74; A/A genotype: adjusted OR, 3.02; 95%CI 1.08-8.43). There was a significant trend associating A/G + A/A genotypes with severity of endometriosis (P for trend < 0.01). No statistically significant association was found for the CYP19 polymorphism. CONCLUSIONS: Evidence for association between the Ser312Gly polymorphism in HSD17B1 and endometriosis was found in a Japanese population. The A-allele of HSD17B1 appears to confer higher risk for endometriosis.     

A polymorphism in the CYP17 gene and intrauterine fetal growth restriction

Intrauterine fetal growth restriction is a multifactorial disorder, and its aetiology includes both environmental and genetic components. We aimed to investigate whether maternal genetic polymorphisms of metabolic enzymes affects fetal growth and pregnancy duration. Genomic DNA was obtained from 134 women who experienced singleton deliveries beyond 24 weeks of gestation. Maternal age, birth weight, gestational age at birth and frequencies of fetal growth restriction, prematurity and pregnancy-induced hypertension were compared among genotypic subgroups of cytochrome p450 (CYP) and glutathione S-transferase (GST) genes. The polymorphisms of CYP1A1 (MspI), CYP17 (MspAI) and GSTP1 (BsmAI) genotypes, and the presence or absence of GSTM1 and GSTT1 genes were analysed by PCR-based methods. The frequency of fetal growth restriction (<10th percentile/<-1.5 SD; 22.7%/11.4%) in 44 women who were homozygous for the A1 allele (A1A1) of CYP17 was significantly higher than that (7.8%/2.2%) in 90 women who carried the A2 allele (A1A2/A2A2) of CYP17 (P < 0.05), with an odds ratio =3.41 (95% confidence interval = 1.18-9.84). The gestational age at birth (mean +/- SD, 37.5 +/- 3.1 weeks) in 67 women with GSTM1 null genotype was significantly lower than that (38.5 +/- 2.4 weeks) in 67 women who carried GSTM1 (P < 0.05). The polymorphism of CYP17 that encodes the cytochrome p450c17alpha enzyme might be associated with the pathophysiology underlying fetal growth restriction.     

Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1, and L1CAM in the Japanese population

By direct sequencing of regions of the human genome containing five genes belonging to the acetyltransferase family, arylamine N-acetyltransferase (NAT1), arylamine N-acetyltransferase (NAT2), arylalkylamine N-acetyltransferase (AANAT), L1 cell adhesion molecule (L1CAM), and the human homolog of Saccharomyces cerevisiae N-acetyltransferase ARD1, we identified 53 single-nucleotide polymorphisms (SNPs) and two insertion/deletion polymorphisms in 48 healthy Japanese volunteers. NAT1 and NAT2 are so-called drug-metabolizing enzymes. In the NAT1 gene we found two SNPs and a 3-bp insertion/deletion polymorphism that corresponded to the NAT1^*3, ^*10, and ^*18A/^*18B alleles reported in other populations. The frequencies of NAT1^* alleles in our Japanese subjects were 52.6% for NAT1^*4, 1.0% for NAT1^*3, 40.6% for NAT1^*10, 2.6% for NAT1^*18A and 3.1% for NAT1^*18B. In the NAT2 gene we found 32 SNPs and a 1-bp insertion/deletion polymorphism; 6 SNPs within the coding region were reported previously and belonged to the slow acetylator group (NAT2^*5, NAT2^*6 and NAT2^*7), and 2 of the 8 SNPs in the 5′ flanking region were reported in the dbSNP of GenBank, but the remaining 24 SNPs and the insertion/deletion polymorphism were novel. The frequencies of NAT2^* alleles in Japanese (51.3% for NAT2^*4, 1.6% for ^*5B, 26.1% for ^*6A, 2.2% for ^*6B, 1.2% for ^*7A, 10.1% for ^*7B, 7.4% for ^*12A, and 1.1% for ^*13) were significantly different from those reported in Caucasian populations. In the AANAT gene we found 4 novel SNPs: 2 in the 5′ flanking region, 1 in exon 4, and 1 in intron 3. In the two genes belonging to the N-terminal N-acetyltransferase family, we identified 9 SNPs, 7 of them novel, for ARD1, and six novel SNPs for L1CAM. Variations at these loci may contribute to an understanding of the way in which different genotypes may affect the activities of human N-acetyltransferases, especially as regards the therapeutic efficacy of certain drugs and antibiotics. Received: February 9, 2001 / Accepted: February 19, 2001     

Determination of ancestral allele for possible human cancer-associated polymorphisms

To determine ancestral allele in possible cancer-associated polymorphisms, DNA samples from 10 chimpanzees (Pan troglodytes) were sequenced for alleles corresponding to 17 polymorphisms: 8 short tandem repeats [IL1RN (alias IL-1RA) variable number tandem repeat (VNTR); TYMS (previously TS) VNTR; AR CAG repeat; dinucleotide repeats of UGT1A1, IGF1, IFNG (alias IFN-gamma), ESR1 (alias ER-alpha), and EGFR] and 9 single nucleotide polymorphisms (MMP1-1607 1G/2G, MMP3-1171 5A/6A, OGG1 Ser326Cys, ALDH2 Gly487Lys, TP53 Arg72Pro, ABCG2 Gln141Lys, MGMT Leu84Phe, SOD2 Ala-9Val, and MTHFR Ala222Val). No chimpanzee polymorphism corresponded to human IL1RN VNTR; the ancestral allele was a repeat lost in humans. Dinucleotide repeat polymorphisms of IGF1, IFNG, ESR1, and EGFR were shared by chimpanzees, but the length of repeats tended to be longer in humans than in chimpanzees. This tendency was particularly evident for IGF1. All of the SNPs tested are human-specific nucleotide changes. The ancestral allele 7A was shown to be lost in MMP3-1171 5A/6A. Thus, all of the possible cancer-associated polymorphisms tested have human-specific alleles, and the ancestral allele is lost in three polymorphisms (IL1RN VNTR, UGT1A1 CA repeat, and MMP3-1171 5A/6A), suggesting a possible involvement of human-specific alleles in cancer susceptibility.     

广州地区汉族人群多巴胺受体基因多态性

目的 探讨广州地区汉族人群多巴胺Ｄ２（ＤＲＤ２）、Ｄ５（ＤＲＤ５）受体基因的多态性分布规律。方法 用聚合酶链反应－限制性片段长度多态性和聚合酶链反应－等位基因特异性扩增技术对１４１名广州地区汉族人的ＤＲＤ２、ＤＲＤ３、ＤＲＤ５基因多态性进行了检测,并与其他人群做了比较。结果 ＤＲＤ２基因３’端非翻译区的Ｔａｑ１Ａ突变点Ａ１（ＴａｑＩ－）、Ａ２（ＴａｑＩ＋）等位基因频率分别为４８％和５２％;Ａ１Ａ１     

中国南方汉族人群三种代谢酶基因多态性的分布特征

目的 了解中国南方某汉族人群3种肿瘤易感代谢酶基因多态性的分布特征。方法 以社区为基础的病例－对照研究中对照人群为分析对象，包括有血缘关系内对照290人和无血缘关系外对照404人。结果 3种代谢酶基因多态性在性别、居信地区、胃癌家族史、吸烟史等混杂因素中的频率差异均无显著性，个别组在年龄、饮酒史中的分布有差异，在相关性分析时需调整。CYP1A1 Ile/Val基因型频率为33.43%，Val/Val为5.62%，与中国人、日本人频率接近，但明显高于美洲、欧洲白人及美国黑人；GSTM1缺失基因频率为53.48%，在中国人群中也有一定差异；GSTT1缺失基因频率为45.78%，显著高于白种人和美国黑人。结论 中国南方汉族人CYP1A1突变基因频率和GSTT1缺失基因频率高于其它种族，而GSTM1缺失基因频率与其它种族的差异较小。     

Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake

Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.     

Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women

Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.     

中国北方汉族人细胞色素P4501 A1基因MspⅠ多态性的研究

目的　探讨中国北方汉族人细胞色素P(cytochromeP ,CYP) 4 5 0 1A1基因MspⅠ多态性。方法　用聚合酶链反应 限制性片段长度多态性 (PCR RFLP)技术 ,分析了 172名北方汉族正常健康成人CYP1A1基因 3′端限制性内切酶MspⅠ位点的3种基因型 (A、B、C)的分布频率。结果　MspⅠ等位基因m1、m2分别占 6 0 8%、39 2 %。MspⅠ基因型A占 34 9% ,基因型B占 5 1 7% ,基因型C占 13 4 %。结论　本研究结果提示中国北方汉族人解毒酶CYP1A1基因存在MspⅠ多态性。     

IL10 polymorphisms are associated with airflow obstruction in severe alpha1-antitrypsin deficiency

Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1) 相似文献