Single Nucleotide Polymorphisms in the Human Gene for Osteoprotegerin are Not Related to Bone Mineral Density or Fracture in Elderly Women

Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50–0.64, C1217T P = 0.51–1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61–0.66, C1217T P = 0.14–0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.     

粘病毒抵抗基因-1启动子88位点G/T多态性影响乙型肝炎病毒感染的自然转归

目的探讨乙型肝炎病毒（HBV）自限感染和慢性感染与粘病毒抵抗基因-1（MxA）启动子的-88位点G／T单核苷酸多态性的关系。方法收集100例抗-HBs和抗-HBc阳性的HBV自限感染者和340例慢性感染者的外周全血，提出基因组DNA；采用竞争分化聚合酶链反应技术为基础的方法进行MxA-88G／T基因分型；采用单因素Odds ratio和x^2检验等方法进行统计学分析。结果MxA-88G／G基因型（低表达型）检出率为50．2％（221／440），T／T基因型（高表达型）检出率为5．5％（24／440），G／T杂合型检出率为44．3％（195／440）。与慢性感染患者相比，自限感染患者携带较低的G／G基因型（41．0％与52．9%，P〈0．05）、G等位基因（62．5％与75．3％，P〈0．01）和较高的T／T基因型（16．0％与2．4%，P〈0．01）、T等位基因（37．5％与24．7％，P〈0．01），而两者之间的G／T杂合型差异无统计学意义。结论MxA-88G／T基因型能在一定程度上影响HBV感染的自然转归，有望成为临床上HBV感染转归的预测指标。     

神经调节素1基因SNPrs2954041多态性与精神分裂症及其认知功能的关联研究

目的探讨昆明地区汉族人群神经调节素1(NRG-1)基因SNPrs2954041多态性与精神分裂症及认知功能的关系。方法采用聚合酶链反应限制性片段长度多态性(PCR-RFLP)的方法检测141例精神分裂症患者和84名正常对照的NRG-1基因SNPrs2954041多态性;采用韦氏记忆量表(WMS)和威斯康辛卡片分类测验(WCST)评估两组人群的记忆功能和执行功能,并用PANSS量表评定患者的临床症状。结果两组NRG-1基因SNPrs2954041多态性的基因型和等位基因频率差异有统计学意义(2=34.01,P<0.05;2=30.201,P<0.05)。按性别分组后比较,结果仍同前。患者组中各基因型组间认知功能比较结果示:①各基因型组间韦氏记忆量表的理解记忆得分差异有统计学意义(P<0.05),两两比较显示G/G与T/T基因型患者间差异有统计学意义(P<0.05)。②G/G与T/T基因型患者比较,威斯康辛卡片分类测验中的错误数、持续错误数和分类个数差异有统计学意义(P<0.05)。结论NRG1基因SNPrs2954041多态性与精神分裂症存在关联,他也与精神分裂症患者的认知功能相关。     

肿瘤坏死因子α基因多态性与多发性硬化的相关性研究

目的:研究肿瘤坏死因子α(TNFα)基因多态性与多发性硬化(MS)的相关性。方法:①采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术对58例MS患者和79名健康人进行TNFα基因多态性分析。②对MS组患者分别进行扩展病残状态评分(expanded disability status scale,EDSS)、首次发病年龄、病程、发病次数临床资料收集。结果:①MS组TNFα基因型分布及等位基因频率与正常对照组比较均无明显差异(χ2=0.466,P=0.495;χ2=0.229,P=0.632)。②基因型为TNFα1/1、TNFα1/2、TNFα2/2的EDSS评分、首次发病年龄、病程及发病次数各组间比较差异均无统计学意义(F=0.53,P=0.5914;F=1.34,P=0.2699;F=0.37,P=0.6914;F=0.49,P=0.6182)。结论:TNFα等位基因多态性与MS的易患性、EDSS评分、首次发病年龄、病程及发病次数均无显著相关性。     

Polymorphism p53 codon-72 and invasive cervical cancer: a meta-analysis.

OBJECTIVES: Although some studies have reported that the arginine isoform on codon 72 of p53 increases the susceptibility to invasive cervical cancer, such data remain controversial. The objective of this study was to quantitatively summarize the evidence for such a relationship. METHODS: Our data sources consisted of a MEDLINE search of the literature published before December 2002, bibliography review, and expert consultation. Thirty-seven studies met the inclusion criteria. Information on sample size, study design, Hardy-Weinberg equilibrium, and method of genotype determination was abstracted by two reviewers using a standardized protocol. The overall odds ratio (OR) of the p53 gene on invasive cervical cancer was estimated using the Mantel-Haenzel method. RESULTS: The overall OR (95% confidence interval) for cervical cancer among those with the homozygous mutant (Arg/Arg) was 1.2 (1.1-1.3, P=0.001) compared with those with the heterozygous mutant (Arg/Pro). By a cellular type of cervical cancer, the overall OR among those with Arg/Arg was statistically significant in adenocarcinomas (1.7, 1.1-2.6, P=0.024), but not in squamous cell carcinomas (1.1, 0.9-1.2, P=0.960), compared with Pro/Pro. Compared with Arg/Pro, the OR among those with Arg/Arg was statistically significant in HPV types 16 (1,5, 1.2-2.0, P=0.002). CONCLUSIONS: Overall, the p53 gene was associated with increased risk for invasive cervical cancer. However, the risk varied by country, cellular, and HPV type.     

IL-6–174G/C genotype is associated with the bone mineral density response to oestrogen replacement therapy in post-menopausal women

A reduction in interleukin-6 (IL-6) activity may contribute to the beneficial effects of hormone replacement therapy (HRT) on the menopausal decline in bone mineral density (BMD). We have examined this hypothesis using a genetic strategy. The –174C (rather than G) IL-6 gene variant is associated with lower IL-6 expression. As such, we might anticipate the C allele to be associated with a greater response to HRT. We have tested this hypothesis. Mean three-site [spine (L1-L4), neck of femur, and Wards triangle] BMD was measured in 65 women in a 1-year randomised controlled trial of HRT with 0.625 mg oestrogen/day and 0.15 mg norgestrel (n=30). Baseline BMD was genotype-independent for both the control and HRT group. In the control group, the percentage change in BMD after 1 year was similar between genotypes (P=0.45). In contrast, in the HRT group, the rise was genotype-dependent. Those homozygous for the G allele showed a 3.62 (2.14)% increase in BMD compared with 10.44 (4.68)% for the C-homozygous group. Heterozygotes had an intermediate BMD increase of 5.6 (2.82)% [P=0.006 (P value for interaction between HRT and genotype was 0.04)] Although the study was limited by its small sample size, these are the first data to demonstrate the importance of IL-6 genotype in determining response to oestrogen therapy, rather than its physiological withdrawal.     

A promoter variant of the ATP-binding cassette transporter A1 gene alters the HDL cholesterol level in the general Japanese population

To investigate the effects of polymorphisms in the ATP-binding cassette transporter A1 (ABCA1) gene on the high-density lipoprotein cholesterol (HDL-C) level and the incidence of myocardial infarction (MI), we performed association studies. Sequence analysis identified 14 polymorphisms in the promoter region of ABCA1. After considering linkage disequilibrium, three polymorphisms in the promoter region and 11 polymorphisms from the JSNP database were determined in 1,880 subjects recruited from the Suita Study, representing the general population in Japan. We evaluated the association between the ABCA1 genotype and HDL-C level adjusted not only for standard factors, but also for genetic factors including ApoA1 and ApoE genotypes. Of the 14 polymorphisms tested, the G(–273)C (P=0.0074), C(–297)T (P=0.0195), and IMS-JST071749 (P=0.0093) polymorphisms were significantly associated with the HDL-C level in the Suita population. We could reconfirm that the G(–273)C genotype was influential in another set of subjects (P=0.0310, n=743). However, the distribution of the ABCA1 G(–273)C genotype in subjects with MI (n=598) was not different from that in the control population (n=801). These results indicate that ABCA1 G(–273)C has a significant effect on the HDL-C level in the general Japanese population, but not on the incidence of MI.     

Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human matrix Gla protein (MGP) locus

Matrix Gla protein (MGP) is an 84-residue, vitamin K-dependent protein expressed by chondrocytes and vascular smooth muscle cells, and is a potent regulator of calcium deposition in cartilage and arterial wall. We isolated a polymorphic dinucleotide CA repeat marker from a genomic clone containing the human MGP gene. This polymorphism will be useful in genetic studies of arteriosclerosis and osteoporosis. Received: November 5, 1997 / Accepted November 27, 1997     

Eleven single nucleotide polymorphisms and one triple nucleotide insertion of the human TGF-β III receptor gene

We found 11 single nucleotide polymorphisms and one triple nucleotide insertion in the cDNA of the human transforming growth factor β (TGF-β) III receptor gene (TGFBR3) located on 1p33–p32, encoding betaglycan, a component of the TGF-β receptor system. Inside the 5′ untranslated region (UTR), a G→A polymorphism was identified at position 311. In the open reading frame (ORF), a non-conservative T→C polymorphism was identified at position 392, and three conservative polymorphisms were found at positions 563 (G→A), 1548 (G→A), and 2370 (C→T). A triple nucleotide insertion (GCA) was identified at position 1419. Inside the 3′ UTR, six polymorphisms were identified: four G→A, at positions 2918, 3055, 3098, and 3355; one T→A, at position 3183; and one G→C, at position 3966. In addition to these changes, some divergences from the published sequence were observed in all 12 chromosomes tested. These included, in the ORF, an additional C after position 555, two additional G after position 563, and an additional T after position 1388. No T was found at position 1394. The alterations translate to a changed amino acid sequence. Inside the 3′ UTR, additional discrepancies were identified. The discovered changes and polymorphisms may be useful for further genetic studies of TGFBR3 receptor deficiencies. Received: December 22, 1999 / Accepted: February 25, 2000