Single nucleotide polymorphisms of the resistin (RSTN) gene

Type 2 diabetes mellitus is a complex phenotype that is frequently associated with central obesity and insulin resistance. Recently, a protein named resistin, encoded by RSTN (OMIM #605565), was identified in adipose tissue. Serum resistin was elevated in obese and diabetic mice, and administration of resistin to normal mice was found to interfere with glucose tolerance and insulin action. Because of these functions, resistin is a candidate gene for diabetes and obesity. Through the use of DNA sequencing, we thus developed amplification primers for rapid screening of the RSTN gene that encodes resistin. No putative mutations were found, but two noncoding single-nucleotide polymorphisms (SNPs) were identified, and these were found to vary in frequency across various ethnic groups. The identification of amplification primers and SNPs provides tools to investigate resistin for association with other phenotypes. Received: April 11, 2001 / Accepted: June 11, 2001     

Single nucleotide polymorphisms of the fukutin gene

Mutations in the LMNA gene, which encodes nuclear lamins A and C, underlie both Emery-Dreifuss muscular dystrophy (EMD2) and Dunnigan-type familial partial lipodystrophy (FPLD). This indicates that one gene can cause different phenotypes characterized by tissue degeneration. The gene for one form of Berardinelli-Seip-type congenital total lipodystrophy (BSCL) has been mapped to chromosome 9q34. Based on the observation that one gene caused both FPLD and EMD2, we considered that a known gene for muscular dystrophy at or near the BSCL locus on chromosome 9q would be an appropriate candidate for BSCL. The gene encoding fukutin, which is mutated in Fukuyama congenital muscular dystrophy has been mapped to 9q31. We thus developed amplification primers for the coding regions of the fukutin gene. We found no putative disease mutations, but through screening of diseased and normal subjects, we identified three novel single nucleotide polymorphisms (SNPs). We conclude that mutations in fukutin are not present in subjects with BSCL. However, the identification of SNPs provides tools to investigate this protein for association with other phenotypes. Received: April 9, 2001 / Accepted: May 1, 2001     

Single nucleotide polymorphisms of the very low density lipoprotein receptor (VLDLR) gene

The very low density lipoprotein receptor (VLDLR) has a potentially important role in lipoprotein metabolism and Alzheimer's disease. We developed amplification primers for most of the coding region and 3′-untranslated region of VLDLR and used sequencing of genomic DNA to examine these regions of VLDLR in subjects with familial combined hyperlipidemia and in normal controls. We identified ten novel single nucleotide polymorphisms (SNPs) for VLDLR. We also found one rare coding sequence variant, S>R153, in a subject with familial combined hyperlipidemia, which was absent from 2360 normal alleles. The identification of intron–exon boundaries, amplification primers, and SNPs provides tools to investigate VLDLR for genetic association and linkage studies. Received: April 30, 2001 / Accepted: May 1, 2001     

单核苷酸多态性及其数据库

随着人类基因组研究计划（human genome project,HGP)DNA序列测定工作的快速发展,研究人类基因组变异的重要性日益突出。将人类DNA变异的数据收集整理和建立起数据库。不仅可以用于研究人类的起源、进化以及现代人群遗传变异的发展机理。而且为检测与疾病,尤其是肿瘤和复杂性疾病如糖尿病,肥胖症,高血压和老年痴呆症等相关的基因提供了基础。基因组变异最常见的一种形式是单核苷酸多态性（single nucleotide polymorphism,SNP)。近两年来,美国、欧洲、日本和中国相继建立了SNP数据库,现就对SNP的研究近况和SNP数据库的建立与发展进行综述。对SNP数据库的应用价值和目前存在的问题加以讨论,并且在此基础上分析了研究中国人群基因组变异和发展具有中国特色的SNP数据库的必要性,中国是世界上人口最多的国家,建立中国人群特有的SNP资料库,不仅可以为研究中国人群基因组变异及其与复杂性疾病的相关性提供迅速可靠的情报,同时还将为发展新的医药产品提供科学的依据。并为全人类基因组变异的研究提供近1/5的资料。     

Inclusion-bearing cells in industrial workers exposed to lead

Histochemical and microscopic studies have shown that a characteristic renal response to lead exposure is the formation of discrete, dense, staining intranuclear inclusion bodies in renal tubular epithelial cells. Cytologic examination of urinary sediment showed that four of 19 (21%) lead workers had exfoliated inclusion-bearing cells of proximal renal tubular origin. These lead-induced inclusion-bearing cells appeared distinctly different from viral-induced inclusions, degenerative or nonspecific intranuclear inclusions seen with tubular necrosis, or macronucleoli seen in reparative renal tubular epithelium. While their presence indicates cytologic evidence of tubular injury, the clinical significance of these cells and their application to medical monitoring is not clearly understood.     

原发性开角型青光眼患者Myocilin基因的单核苷酸多态性

目的　探讨 Myocilin(MYOC)基因的单核苷酸多态性 (single nucleotide polymorphisms,SNPs)及其与原发性开角型青光眼 (primary open- angle glaucoma,POAG)发病的关系。方法　应用高通量构象敏感性凝胶电泳和荧光标记自动测序法筛选和鉴定香港 15 7例 POAG散发患者和 15 5名对照 MYOC基因的 SNPs。结果　在 MYOC基因所有 3个外显子及邻近的非编码区共检出 17种 SNPs:1- 83G→ A、G12 R、P16 L、A17S、R4 6 X、R76 K、R91X、T12 3T、D2 0 8E、L 2 15 P、730 35 A→ G、A2 6 0 A、I2 88I、E30 0 K、T35 3I、Y4 71C和 15 15 73G→ C。其中 ,R91X、E30 0 K和 Y4 71C仅在 POAG患者中检测到。此外 ,15 15 73G→ C各基因型在 POAG患者与对照人群中的分布差异具有显著意义 ,POAG患者中 CG型频率为 0 .6 % ,低于对照组的 4 .5 % (P=0 .0 36 )。其余 16种 SNPs各基因型在两组人群中的分布差异均无显著意义。结论　 MYOC基因多态性可能与中国人 POAG发病有关 ,提示 MYOC基因是 POAG的相关基因。     

Single nucleotide polymorphisms of the ALDH2 gene in six Indian populations

BACKGROUND: Aldehyde dehydrogenase-2 (ALDH2) degrades acetaldehyde metabolized from ethanol. Its encoding gene ALDH2 has a functional polymorphism, ALDH2 Glu487Lys associated with low enzyme activity. AIM: Since Glu487Lys of this locus is fixed for the functional subunit in all non-East Asian populations, this polymorphism was examined along with G-357A promoter (SacI) and four other intronic loci to identify informative markers to study the role of this gene in Indian populations. SUBJECTS AND METHODS: A total of 397 males belonging to six ethnic populations, from four linguistic groups of India were included in the present study. No test was performed to detect the phenotype of alcoholism. Genotype of ALDH2*E487K and G-357A promoter site along with four non-coding single nucleotide polymorphisms (SNPs) in the upstream of this polymorphism were determined by PCR and sequencing. RESULTS: All of the subjects were found to have the common homozygous genotype (ALDH2*1/ALDH2*1) for the E487K site. Allele frequencies of non-coding SNPs varied among populations but genetic variance (F(st)) indicated little variation among populations. Four major SNP-defined haplotypes accounted for almost all chromosomes in all populations. The ancestral haplotype was found in high frequency in all populations and linkage disequilibrium was strong and highly significant between all sites (p < 0.05). CONCLUSION: The small number of haplotypes in this region is suggesting the strong linkage disequilibrium across the region and confirms the global long-range linkage disequilibrium around the ALDH2 locus. This study provides a baseline for future research into the role of the ALDH2 locus in alcoholism in Indian populations.     

Single nucleotide polymorphisms in MHC2TA, the gene encoding the MHC class II transactivator (CIITA)

The MHC class II transactivator (CIITA) is the master regulator for HLA-D (DP, DQ, DR) gene expression. In this report the coding and promoter regions of the CIITA gene, MHC2TA, were evaluated for polymorphisms in 50 normal Caucasian individuals. Allele frequencies were obtained for four separate single nucleotide (nt) polymorphisms (SNPs) identified in the MHC2TA coding region: nt 1614 (C-->G), nt 2509 (G-->A), nt 2536 (T-->G), and nt 2791 (G-->A). MHC2TA sequence analysis of 100 chromosomes from these 50 individuals revealed a SNP in MHC2TA promoter (p) III at nt (-)155 (A-->G), but none in CIITA pI or pIV. In addition, we demonstrate the presence of splice variant at a previously undiscovered intron, accounting for a three nt (TAG) insertion at position 474 that was originally described in association with one of the disease-causing CIITA cDNA mutations in bare lymphocyte syndrome.     

Single nucleotide polymorphisms in the leptin receptor gene: studies in anorexia nervosa

Anorexia nervosa is an eating disorder of unknown aetiology. There is significant evidence for a genetic component in the pathogenesis of this disorder. A region on chromosome 1 has been identified as a susceptibility locus. The leptin receptor has been mapped to a similar region, further upstream of this susceptibility locus. Leptin and its receptor are known to be important factors in the control and regulation of body weight. Single nucleotide polymorphisms (SNPs) in the leptin receptor are associated with measures of body weight. In the present study, SNPs in the coding region of the leptin receptor were analysed and their possible association with anorexia nervosa was investigated. Two cohorts of young women, 176 Caucasian anorexia nervosa patients and 152 normal Caucasian females, were genotyped for three SNPs in the leptin receptor. There was no significant difference in allele or genotype frequency, for any SNP, between the normal controls and the cohort of anorexia subjects. There were no significant associations with any genotype and body mass index in either the control or anorexic cohorts. When the anorexic cohort was subdivided into restricting and bingeing/purging behaviours, we found no significant association with any genotype. Analysis of haplotypes showed no significant evidence of association with anorexia. In summary, leptin receptor SNPs do not appear to be important factors in the regulation of body weight in young, pre-menopausal women or have any significant association with anorexia nervosa.     

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher''s exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.     

Single nucleotide polymorphisms of the gonadotrophin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment

BACKGROUND: Gonadotropin-regulated testicular RNA helicase (GRTH) is a testis-specific RNA helicase that is essential for completion of spermatogenesis and is involved in pathogenesis of impaired spermatogenesis in mouse. It is therefore reasonable to postulate that human GRTH gene may also play a role in impaired spermatogenesis in humans. To test this hypothesis, we investigated the possible association between the variations of the GRTH gene and human spermatogenesis impairment. METHODS: Mutation screening of exons and intron/exon boundaries of GRTH gene was carried out by denaturing high-performance liquid chromatography (DHPLC) in 347 infertile patients with idiopathic azoospermia and severe oligozoospermia as well as 201 fertile men. RESULTS: Four single nucleotide polymorphisms (SNP), namely IVS6+55G-->T, ISV8+10A-->C, c.852C-->T and c.927G-->A, were identified. Among them, significant differences in polymorphism frequencies were observed at the polymorphic IVS6+55G-->T and c.852C-->T loci between the patients and controls, and a significant association between haplotypes of these two loci and male infertility with impaired spermatogenesis was detected. CONCLUSIONS: Results of the present study indicate that SNP IVS6+55G-->T and c.852C-->T of GRTH gene may be associated with male infertility with azoospermia or severe oligozoospermia, suggesting that variations in GRTH gene may contribute to susceptibility to spermatogenic impairment in humans.     

Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation

Human physical pigmentation is determined by the type and amount of melanin and the process of pigmentation production probably involves more than 100 genes. A failure to synthesize melanin results in oculocutaneous albinism (OCA). A recently identified form of OCA results from mutations in the Membrane Associated Transporter Protein (MATP) gene. The role of MATP in human pigmentation is not clear. We investigated the role of two nonpathogenic nonsynonymous single nucleotide polymorphisms (SNPs) in the MATP gene to determine if they are associated with normal human skin, hair, and eye color variation. A total of 608 individuals from four different population groups (456 Caucasians, 31 Asians, 70 African-Americans, and 51 Australian Aborigines) were genotyped for c.814G>A (p.Glu272Lys) and c.1122C>G (p.Phe374Leu). Results indicate that the allele frequencies of both polymorphisms are significantly different between population groups. The two alleles, 374Leu and 272Lys, are significantly associated with dark hair, skin, and eye color in Caucasians. The odds ratios (ORs) of the LeuLeu genotype for black hair and olive skin are 25.63 and 28.65, respectively, and for the LysLys genotype are 43.23 and 8.27, respectively. The OR for eye color is lower at 3.48 for the LeuLeu and 6.57 for LysLys genotypes. This is the first report of this highly significant association of MATP polymorphisms with normal human pigmentation variation.     

Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema

BACKGROUND: Human IL-18 is an inflammatory cytokine that plays a role in atopic diseases, such as atopic eczema (AE), by enhancing IL-4 and IL-13 production and stimulating the synthesis of IgE. OBJECTIVE: To evaluate associations of polymorphisms in the IL18 gene on chromosome 11q22 with AE, we performed genotyping for single nucleotide polymorphisms (SNPs) in the IL18 gene in 225 patients with AE and 175 healthy control volunteers. METHODS: Genotyping was performed by means of restriction fragment length polymorphism analysis. RESULTS: Analyses revealed significant associations of SNPs +113[t/g] and +127[c/t] in exon 1, -137[g/c] in promoter region 1, and -133[c/g] in promoter region 2 with AE. These associations were not directly dependent on a specific subtype of AE or the concomitant manifestation of allergic rhinitis or asthma. On the functional level, the amount of IL-18 in the supernatants of PBMCs of patients with AE stimulated with Staphylococcus aureus enterotoxin B was significantly higher than that in healthy control subjects. In parallel, the amount of active IL-18 in the sera of patients with AE was enhanced at the exacerbation of their disease. CONCLUSION: In conclusion, our data suggest that SNPs in the IL18 gene might be involved in the development of AE by contributing to a functional dysregulation of the IL-18 production in vivo .     

韩国人calpain-10基因单核苷酸多态性及其组合型的分析

目的分析发现于墨西哥裔美国人群中的2型糖尿病易感基因calpain-10单核苷酸多态性（single nucletide polymorphism。SNP）及其组合型在韩国人群中的分布。方法采用聚合酶链式反应．限制性片段长度多态性技术，分析312名健康韩国人calpain-10基因UCSNP-43、-19、-63位点的基因型及其组合型，计算基因型、等位基因和组合型频率。结果UCSNP-43位点基因型频率为1／1型的是86．2％、1／2型的是13．5％、2／2型的是0．3％，等位基因频率为G的是0．930、A0．070。UCSNP-19位点基因型频率为1／1型的是9．9％、1／2型的是44．6％、2／2型的是45．5％，等位基因频率为D的是0．322、I的是0．678。UCSNP-63位点基因型频率为1／1型的是57．4％、1／2型的是35．9％、2／2型的是6．7％，等位基因频率为C的是0．754、T的是0．246。各基因型分布匀符合Hardy-Weinberg平衡定律。韩国人中上述3个单核苷酸多态性基因型组合类型共见12种，75．6％由3种基因型组合构成。按UCSNP-43，-19，-63排列，分别为GG-DI-CC（单倍型组合111／121）、GG-DI-CT（112／121）、GC-II-CC（121／121），其频率分别为10．6％、28．8％、36．2％。结论韩国人calpain-10基因SNP分布与白人、美籍墨西哥人及美籍Pima印第安人等种族间存在较大差异，与中国和日本人群较为相近，其112／121单倍型组合频率显著高于美籍墨西哥人。     

Single nucleotide polymorphisms and haplotypes of TLR6 gene in Chinese Cantonese population

Sequence polymorphisms in the coding region of Toll-like receptor 6 gene were investigated in Chinese Cantonese population. By amplifying and sequencing a 2787 bp segment containing the entire coding region of TLR6 gene of 191 individuals in Chinese Cantonese population, a total of seven single nucleotide polymorphisms (SNP) along with their frequencies were detected. Comparing these data with SNP published in dbSNP database of National Center for Biotechnology Information (NCBI), two SNP (+176T/C and +1408G/T) were firstly reported, and five SNP caused amino-acid substitution. Sixteen haplotypes and their distributions were reconstructed. Linkage disequilibrium analysis and neutrality test were also performed. Comparing with other ethnic populations, Chinese Cantonese displayed obvious differences in TLR6 polymorphism. It may in part reflect the ethnic diversity of pathogen susceptibility and facilitate to develop the disease-association studies as well as population genetics and evolutionary research.     

GATA5基因启动子序列单核苷酸多态性可增加急性心肌梗死的易感性

目的:通过病例-对照研究,探讨GATA结合蛋白5(GATA binding protein 5,GATA5)基因启动子序列单核苷酸多态性(single nucleotide polymorphism,SNP)与急性心肌梗死(acute myocardial infarction,AMI)的相关性。方法:通过χ²检验、logistic回归、单倍型分析、细胞转染及电泳迁移率变动分析(electrophoretic mobility shift assay,EMSA)对SNPs进行遗传及功能分析。结果:校正混杂因素后,rs80197101位点GA和GA+AA基因型与AMI显著相关(OR=2.280,95%CI:1.027～5.061,P=0.043;OR=2.312,95%CI:1.045～5.116,P=0.039)。rs77067995位点CT和CT+TT基因型也与AMI显著相关(OR=2.280,95%CI:1.027～5.061,P=0.043;OR=2.312,95%CI:1.045～5.116,P=0.039)。rs80197101和rs77067995呈完...     

Prevalence and characterization of hearing loss in workers exposed to industrial noise of the turbogenerated electric plant of a petrochemical industry

The purpose of the present study was to assess the impact of occupational exposure to noise and its relationship with other factors that can induce hearing loss in the electric plant workers of a petrochemical industry of the west of Venezuela. A cross-sectional study was conducted that included sonometry tests, carried out according to the established methodology by COVENIN rules, and the occupational medical evaluation and liminal tonal audiometrics test in 75 workers. The equivalent noise levels (Leq) was quantified in different workplaces. It was found out that most of the workers are exposed to high noise levels [>85 dB(A)] and during more time than the recommended. All workers use hearing protectors appropriately. The hearing loss prevalence in workers was 16.0%, there were not noise-induced hearing losses. The hearing threshold registered in the audiometrics test was diminished, but inside the normal threshold values. We diagnosed 12 cases of conductive hearing loss, all grade I; there were not sensorial or mixed hearing losses. There was not a relationship between the equivalent noise level and hearing loss. It is suggested the design and implantation of a program of auditory conservation to protect the health and security of the workers and to conduct a longitudinal study considering the findings of the present study as it basis.     

中国维吾尔族人群MBL基因启动子及第一外显子区SNP及其单倍型与基因型研究

收集新疆维吾尔族自治区维吾尔族一般人群血标本,提取白细胞基因组DNA,以序列特异性引物-多聚酶链反应技术检测其甘露聚糖结合凝集素(MBL)基因启动子区单核苷酸多态性位点-550G/C(称H/L等位基因)、-221C/G(X/Y)、+4C/T(P/Q)和结构基因第一外显子点突变CGT52TGT、GGC54GAC和GGA57GAA(分别称为D、B、C等位基因,野生型即A等位基因),并分析其单倍型与基因型。发现MBL基因启动子区等位基因主要为L、Y、P,第一外显子等位基因只发现B,未检出C和D;检出5种单倍型,其频率分别是HYPA 0.282、LYPA 0.268、LXPA 0.260、LYPB 0.120、LYQA 0.070。检出12种基因型,其频率分别为HYPA/HYPA 0.183、LXPA/LXPA 0.141、LYPA/LYQA 0.113、LYPA/LYPA 0.112、LYPA/LXPA 0.085、HYPA/LYPA 0.085、LXPA/LYPB 0.085、HYPA/LXPA 0.070、HYPA/LYPB 0.042、LYPA/LYPB 0.028、LYPB/LYQA 0.028、YPB/LYPB 0.028。     

Analysis of interleukin-23 receptor (IL23R) gene polymorphisms in systemic lupus erythematosus

The aim of this study was to evaluate the association between systemic lupus erythematosus (SLE) and polymorphisms in the interleukin-23 receptor (IL23R) gene, which have been previously found to be associated with two autoimmune diseases: inflammatory bowel disease and psoriasis. Our study includes 224 SLE patients and 342 healthy controls. The genotyping of IL23R variants was carried out using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assays. No statistically significant differences were observed between SLE patients and healthy controls with any of the IL23R genetic variants. In addition, we did not find any significant differences when we stratified SLE patients according to their clinical and demographic features. These results suggest that IL23R polymorphisms do not appear to play an important role in the susceptibility or severity of SLE in the Spanish population.