RAD51 135G>C polymorphism and risk of familial breast cancer in a South American population

Several studies have reported that mutations in genes involved in maintenance of genome integrity may be responsible for increased cancer risk. Human RAD51, known to function in DNA repair, interacts with a number of proteins implicated in breast cancer (BC), including BRCA1 and BRCA2. Few studies have investigated the role of RAD51 gene variations in familial BC. To detect potential novel gene defects that may contribute to hereditary BC susceptibility, 143 patients belonging to 143 Chilean families tested for BRCA1 and BRCA2 mutations were screened for mutations in RAD51, using conformational sensitive gel electrophoresis (CSGE) and DNA sequencing. No mutations were detected in the exon or splice-boundary regions of the RAD51 gene in these families. The RAD51 135G>C polymorphism (c.-98G>C, rs1801320) was studied in a case-control design, to evaluate its possible association with BC susceptibility. The frequency of the RAD51 135C allele was established in 143 cases and 247 controls, using restriction fragment length polymorphism-polymerase chain reaction. RAD51 135C genotypes (G/C and C/C) were associated with an increased BC risk only among women with (a) a family history of BC, (b) BRCA1/2 negative (n = 131), and (c) age at onset <50 years (P = 0.020; OR = 2.17, 95% CI = 1.11-4.24). Thus, we propose that RAD51 135G>C polymorphism presents an increased risk of familial BC in women with age < 50 years at diagnosis, and this polymorphism may be a BC risk variant. This finding should be confirmed in other populations.     

RAD51基因G135C单核苷酸多态性及p53突变在肺癌中的意义

目的探讨RAD51基因G135C多态性与肺癌发病风险、病理特点及p53基因突变的相关性。方法选择80例肺癌患者为病例组,40例非肿瘤肺疾病患者为对照组。以PCR-RFLP技术检测病例组和对照组的RAD51基因型,比较不同基因型与肺癌危险性以及肺癌病理特点的关系;并采用免疫组化法对病例组进行p53突变的检测。结果 (1)RAD51基因型G/G、G/C和C/C在病例组的分布频率分别为77.5%、15.0%和1.3%,在对照组的分布频率分别为92.5%、7.5%和0。与携带G/G的个体相比,携带RAD51变异基因型(G/C和C/C)的个体具有更高的患癌风险(P<0.05);(2)RAD51基因型与肺癌的病理学类型及组织学分级无相关性;(3)RAD51 G135C基因型在不同p53基因突变状态肺癌中的分布频率差异无显著性(P>0.05)。结论 RAD51基因多态性与肺癌发病风险有关,携带RAD51变异基因型(G/C和C/C)的个体易患肺癌。     

RAD51基因135G/C多态与人群发生肺癌的易感性研究

目的 探讨DNA双链断裂修复基因RAD51的5'-UTR区135G/C多态与我国人群肺癌发病的关联.方法 采用PCR-RFLP技术,检测300对肺癌病例与正常对照RAD51基因135FG/C多态位点的基因型.用SAD9.13软件进行非条件Logistic回归,校正混杂因素的影响,分析该位点变异与肺癌发病的关联.结果 病例及对照组中,皆未检测出135CC基因型.病例组135GC基因型频率显著低于对照组(26.7%比34.7%,P=0.0336).以携带GG野生基因型个体为参照,携带GC基因型能显著减少个体发生肺癌的危险性(调整优势比=0.72;95%置信区间=0.49～0.98;P=0.042).结论 RAD51的5'-UTR区135G/C多态与我国人群肺癌发病存在显著性关联,135C可能是我国人群肺癌发生的一个遗传保护因素.     

Polymorphism of the homologous recombination repair genes RAD51 and XRCC3 in breast cancer

The RAD51 protein and its paralog, XRCC3, play an important role in the repair of DNA double-strand breaks (DSBs) by homologous recombination. Since DSBs may contribute to the pathogenesis of breast cancer and variability in DNA repair genes may be linked with some cancers, we performed a case-control study (135 cases and 175 controls) to check the association between the genotypes of the Thr241Met polymorphism of the XRCC3 gene and the 135G>C polymorphism of the RAD51 gene and breast cancer occurrence and progression. Genotypes were determined in peripheral blood lymphocytes by RFLP-PCR. We did not find any association between either polymorphism singly and breast cancer occurrence. Both polymorphisms were not related to tumor size, estrogen and progesterone receptors status, cancer type and grade. However, the Thr241Met genotype of the XRCC3 polymorphism slightly increased the risk of local metastasis in breast cancer patients (OR 2.56, 95% CI 1.27-5.17). The combined Thr241Met/135G>C genotype decreased the risk of breast cancer occurrence (OR 0.22, 95% CI 0.08-0.59). Our results suggest that the variability of the DNA homologous recombination repair genes RAD51 and XRCC3 may play a role in breast cancer occurrence and progression, but this role may be underlined by a mutual interaction between these genes.     

Association between survivin -31G > C promoter polymorphism and cancer risk: a meta-analysis

Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin -31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin -31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin -31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations.     

Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer

The tumor suppressor TP53 pathway plays a crucial role in preventing carcinogenesis through its ability to impose cell cycle arrest and apoptosis following DNA damage and oncogene activation. MDM2 is a key negative regulator of the TP53 pathway and is overexpressed in many cancers as oncoprotein. We investigated the association between genetic variation in the promoter region of MDM2 (c.-5+309G>T, rs2279744:g.G>T) and the coding region of TP53 (c.215G>C, rs1042522:g.G>C, designated Arg72Pro) and the risk of developing lung cancer. The genotypes of 1,106 patients and 1,420 controls were determined by tetra-primer amplification refractory mutation system (ARMS)-PCR or PCR-based restriction fragment length polymorphism (RFLP). Associations with risk of lung cancer were estimated by logistic regression. We observed an increased lung cancer risk associated with the MDM2 GG (odds ratio [OR] = 1.83, 95% confidence interval [CI] = 1.45-2.32) and TG (OR = 1.33, 95% CI = 1.09-1.63) genotypes. An increased risk was also associated with the TP53 Pro/Pro genotype (OR = 1.47, 95% CI = 1.17-1.85, P = 0.003) compared to the Arg/Arg genotype. The gene-gene interaction of MDM2 and TP53 polymorphisms increased lung cancer risk in a supermultiplicative manner (OR for the presence of both MDM2 GG and TP53 Pro/Pro genotypes = 4.56, 95% CI = 2.76-7.54). Significant interactions were observed between these polymorphisms (respectively and jointly) and smoking (OR = 10.41, 95% CI = 5.26-20.58) for smokers with both the MDM2 GG and TP53 Pro/Pro genotypes. In conclusion, genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 contribute to the risk of developing lung cancer.     

Polymorphisms of the XRCC3 C722T and the RAD51 G135C genes and the risk of head and neck cancer in a Polish population

Genetic variations in DNA repair genes may affect an individual's susceptibility to head and neck cancer. We performed a case–control study to test the association between head and neck cancer risk and two polymorphisms: the C722 T of the XRCC3 and the G135C of the RAD51 —genes of DNA double strand break (DSB) repair by homologous recombination (HRR). Genotypes were determined by PCR-restriction fragment lenght polymorphism (PCR-RFLP). DNA was isolated from peripheral blood lymphocytes of a group of 288 patients consisting of 97 subjects with precancerous hyperplastic laryngeal lesions (PHLL) and 191 subjects with head and neck squamous cell carcinoma (HNSCC) as well as 353 healthy control donors. We found an association between PHLL and the 722CT (OR 6.67; 95% CI 3.02–14.74) as well as 722 TT (OR 4.65; 95% CI 2.30–9.43) variants of the XRCC3 gene. Similar relation was observed between these genotypes and HNSCC (OR 2.59; 95% CI 1.61–4.16 and OR 5.54; 95% CI 3.22–9.52, respectively). Moreover, we also observed an association between PHLL (OR 6.04; 95% CI 3.69–9.90) and HNSCC (OR 6.04; 95% CI 3.69–9.90) and the135GC variant of the RAD51 gene. The gene–gene interaction between XRCC3 and RAD51 polymorphic variants may contribute to higher prevalence of PHLL. The increased risk of this disease was observed in case of the combination of the 722CT/135GC (OR 3.81; 95% CI 1.55–9.75) as well as the 722 TT/135GC genotypes (OR 5.33; 95% CI 1.96–14.47). The presence of the same genes combinations plays a part in higher probability of HNSCC occurrence (OR 2.42; 95% CI 1.22–4.79 for 722CT/135GC and OR 3.63; 95% CI 1.69–7.76 for 722 TT/135GC). We also found an association between these XRCC3 or RAD51 polymorphic variants and smoking status in PHLL (ORs 2.85–10.28 and 1.82–7.35, respectively) and HNSCC patients (ORs 2.94–13.93 and 1.36–3.94, respectively) as well as alcohol intake among PHLL (ORs 3.44–6.12 and 3.52–8.43, respectively) and HNSCC subjects (ORs 2.71–7.01 and 2.33–4.62, respectively). In conclusion our data showed that the C722 T and the G135C polymorphisms of the XRCC3 and the RAD51 genes might be associated with HNSCC. Finally we suggested that these polymorphisms might be used as predictive factor of precancerous lesion for head and neck cancer in a Polish population.     

Association of TIM4 promoter polymorphism −1419G>A with childhood asthma in a Chinese Han population

TIM4, which is expressed on dendritic cells and macrophages, plays an important role in the proliferation of T helper type 2 (Th2) cells. Asthma, as a complex genetic disease, is thought to arise from the development of a Th2-lymphocyte-predominant immune response. To evaluate the effects of the promoter polymorphisms (-1419G>A and -1609G>A) in TIM4 on asthma susceptibility, case-control and family-based association studies were conducted by polymerase chain reaction and restriction fragment length polymorphism. Our results showed that TIM4 -1419G>A polymorphism was associated with asthma susceptibility in our study population (χ²= 9.88, P < 0.001, OR = 1.91, 95% CI 1.37–2.64). The -1419A/A and -1419A/G genotypes were observed more common in asthmatic group (6.3%, 41.8%) than in control group (1.7%, 29.3%). No significant difference was found in genotype and allele frequencies of TIM4 -1619G>A polymorphism between asthmatic and control groups. No association between the two SNPs and total serum IgE levels, lung function was observed. In conclusion, the present findings suggest that TIM4 -1419G>A polymorphism might be the genetic factor for the risk of childhood asthma in Chinese Han population.     

Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women

Maternal impairments in folate metabolism and elevated homocysteinemia are known risk factors for having a child with Down syndrome (DS) at a young age. The 80G>A polymorphism of the reduced folate carrier gene (RFC-1) has been recently demonstrated to affect plasma folate and homocysteine levels, alone or in combination with the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. We performed the present study on 80 Italian mothers of DS individuals, aged less than 35 at conception, and 111 Italian control mothers, to study the role of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C genotypes to the risk of a DS offspring at a young maternal age. When polymorphisms were considered alone, both allele and genotype frequencies did not significantly differ between DS mothers and control mothers. However, the combined MTHFR677TT/RFC-1 80GG genotype was borderline associated with an increased risk (OR 6 (CI 95%: 1.0-35.9), P = 0.05), and to be MTHF1298AA/RFC-1 80(GA or AA) was inversely associated with the risk (OR 0.36 (CI 95%: 0.14-0.96), P = 0.04). Present results seem to indicate that none of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C polymorphisms is an independent risk factor for a DS offspring at a young maternal age; however, a role for the combined MTHFR/RFC-1 genotypes in the risk of DS pregnancies among young Italian women cannot be excluded.     

Independent effects of the -219 G>T and epsilon 2/ epsilon 3/ epsilon 4 polymorphisms in the apolipoprotein E gene on coronary artery disease: the Southampton Atherosclerosis Study

A number of studies have shown that coronary artery disease severity is associated with the epsilon 2/ epsilon 3/ epsilon 4 polymorphism in the coding region of the apolipoprotein E gene. In this study, we investigated whether the severity of the disease was also influenced by a functional polymorphism (-219 G>T) in the promoter of the gene, and if so, whether the effects of the two polymorphisms were independent. A cohort of 1170 patients with angiographically documented coronary artery disease were genotyped for the two polymorphisms. The frequency of the epsilon 4 allele of the epsilon 2/ epsilon 3/ epsilon 4 polymorphism increased linearly with increasing number of diseased vessels, so did the -219T allele of the -219 G>T polymorphism. In the sample as a whole, logistic regression analyses indicated that compared with the G/G genotype, the T/T genotype conferred an odds ratio of 1.598 (95% CI=1.161-2.201, P=0.004) in favor of increased disease severity, and the relationship remained significant after adjustment for epsilon 2/ epsilon 3/ epsilon 4 polymorphism genotypes, plasma cholesterol and triglyceride levels, and other risk factors. The effect of the T/T genotype on disease severity was more significant in patients who did not carry the epsilon 4 allele (OR=1.510, 95% CI=1.028-2.221) than in epsilon 4 allele carriers (OR=1.303, 95% CI=0.619-2.742). There was considerable linkage disequilibrium between the two polymorphisms (rho=0.9, P<0.001). Logistic regression analysis showed that the -219T- epsilon 4 haplotype conferred an odds ratio of 1.488 (95% CI=1.133-1.954). These findings suggest that the -219 G>T and epsilon 2/ epsilon 3/ epsilon 4 polymorphisms, which may affect respectively the quantity and quality of apoE, have independent and possibly additive effects on coronary artery disease severity.     

Polymorphisms of the Homologous Recombination Gene RAD51 in Keratoconus and Fuchs Endothelial Corneal Dystrophy

Purpose. We investigated the association between genotypes and haplotypes of the c.-61G>T (rs 1801320) and c.-98G>C (rs 1801321) polymorphisms of the RAD51 gene and the occurrence of keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD) in dependence on some environmental factors. Methods. The polymorphisms were genotyped in peripheral blood lymphocytes of 100 KC and 100 FECD patients as well as 150 controls with PCR-RFLP. Results. The G/T genotype of the c.-61G>T polymorphism was associated with significantly increased frequency occurrence of KC (crude OR 2.99, 95% CI 1.75–5.13). On the other hand, the G/G genotype of this polymorphism was positively correlated with a decreased occurrence of this disease (crude OR 0.52, 95% CI 0.31–0.88). We did not find any correlation between genotypes/alleles of the c.-98G>C polymorphism and the occurrence of KC. We also found that the G/G genotype and G allele of the c.-98G>C polymorphism had a protective effect against FECD (crude OR 0.51, 95% CI 0.28–0.92; crude OR 0.53, 95% CI 0.30–0.92, resp.), while the G/C genotype and the C allele increased FECD occurrence (crude OR 1.85, 95% CI 1.01–3.36; crude OR 1.90, 95% CI 1.09–3.29, resp.). Conclusions. The c.-61T/T and c.-98G>C polymorphisms of the RAD51 gene may have a role in the KC and FECD pathogenesis and can be considered as markers in these diseases.     

The interleukin-6 gene -572G>C promoter polymorphism is related to intracranial aneurysms in Chinese Han nationality

There is evidence suggesting that inflammation plays an important role in the pathogenesis of intracranial aneurysms (IAs). Interleukin-6 (IL-6) is an important pro-inflammatory cytokine, and some authors have demonstrated that IL-6 promoter polymorphism -572G>C is associated with IAs in Caucasian population. We performed a case-control study to investigate whether this single nucleotide polymorphism (SNP) might affect the development of IAs in Chinese Han population. The study groups comprised 240 Chinese Han nationality aneurysmal patients and 240 controls. Differences in genotype and allele frequencies between patients and controls were tested by the chi-square method. The results showed that among the Chinese Han subjects, there were significant differences in genotypic distribution and allele frequencies between aneurysmal patients and controls. The GG genotype was significantly more common in patients than in controls (24.5% vs. 3.7%, p<0.001, odds ratio 8.366, 95% CI: 4.040-17.324), and the G allele was much more frequent in patients than in controls (51.7% vs. 20.8%, p<0.001, odds ratio 4.062, 95% CI: 3.058-5.395).     

Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk

The ataxia telangiectasia mutated (ATM) gene is known to be activated by DNA damage and involved in cell cycle arrest, apoptosis and DNA repair. Therefore, ATM gene polymorphisms may act as important factors predicting individual susceptibility to lung cancer. To evaluate the role of ATM gene polymorphisms in lung cancer development, genotypes of the ATM polymorphisms, -4518A>G, IVS21-77C>T, IVS61-55T>C, and IVS62+60G>A, were determined in 616 lung cancer patients and 616 cancer-free controls. When the effects of selected ATM genotypes were evaluated separately, only one ATM genotype (IVS62+60G>A) showed an association with lung cancer risk. Subjects with the A allele at the site (IVS62+60G>A) have significantly higher risk of lung cancer than those with the G allele [odds ratio (OR)=1.6, 95% confidence interval (CI) 1.1-2.1]. When the haplotypes of four ATM single nucleotide polymorphism sites (-4518A>G, IVS21-77C>T, IVS61-55T>C and IVS62+60G>A) were studied, the ATTA haplotype showed significantly increased risk of lung cancer compared with the GCCA haplotype, the most common haplotype (OR=7.6, 95% CI 1.7-33.5). Furthermore, subjects with the (NN)TA haplotype showed highly significant and increased risk of lung cancer when compared with those without the (NN)TA haplotype (OR=13.2, 95% CI 3.1-56.1). Therefore, our results suggest that polymorphisms or haplotypes of the ATM gene play an important role in the development of lung cancer.     

Association of total plasma homocysteine with methylenetetrahydrofolate reductase genotypes 677C>T, 1298A>C, and 1793G>A and the corresponding haplotypes in Swedish children and adolescents

We studied 692 Swedish children and adolescents (aged 9-10 or 15-16 years, respectively), in order to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C>T, 1298A>C, and 1793G>A polymorphisms on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing technology. The MTHFR 677C>T polymorphism was associated with increased tHcy concentrations in both the children and the adolescents (P<0.001 for both age groups) in both genders. The effect of MTHFR 1298A>C was studied separately in subjects with the 677CC and 677CT genotypes, and the 1298C allele was found to be associated with higher tHcy levels both when children were stratified according to 677C>T genotypes, and when using haplotype analyses and diplotype reconstructions. The 1793A allele was in complete linkage disequilibrium with the 1298C allele. It was still possible to show that the 1793A allele was associated with lower tHcy levels, statistically significant in the adolescents. In conclusion, a haplotype-based approach was slightly superior in explaining the genetic interaction on tHcy plasma levels in children and adolescents than a simple genotype based approach (R2 adj 0.44 vs. 0.40). The major genetic impact on tHcy concentrations is attributable to the MTHFR 677C>T polymorphism. The common 1298A>C polymorphism had a minor elevating effect on tHcy, whereas the 1793G>A polymorphism had a lowering effect on tHcy.     

基质金属蛋白酶1基因多态性与肺癌易感性的关联研究

目的研究我国西北汉族人群基质金属蛋白酶（matrix metalloproteinase 1，MMP1）基因-1607（1G→2G）多态与肺癌发生风险的关系。方法应用聚合酶链反应-限制性片段长度多态性分析的方法，检测了150例肺癌患者和200名正常对照者删1G→2G多态的基因型，比较不同基因型与肺癌发生风险的关系。结果肺癌组2G／2G基因型频率要高于对照组（X^2=5．896，P〈0．05），2G／2G基因型者患肺癌的风险是1G／2G和1G／1G基因型的1．77倍（OR=1．77；95％CI：1．12—2．91）。吸烟者中2G／2G基因型发生肺癌的风险是1G／2G和1G／1G基因型的3．20倍（OR=3．20；95％CI：1．50～6．82）。结论我国西北汉族人群MMP1基因-1607（1G→2G）多态性与肺癌易感性有关，2G／2G基因型可以增加肺癌发生风险。     

CD40 -1C>T polymorphism and the risk of lung cancer in a Chinese population

Background: The co-stimulatory molecule CD40 plays an important role in anti-tumor responses by promoting cytotoxic T lymphocyte (CTL) activity and differentiation of helper T cells. Growing evidence suggests that single nucleotide polymorphisms (SNPs) in CD40 are associated with the susceptibility to cancer. This study investigated the association between the CD40 -1C/T SNP (rs1883832) and lung cancer in a Chinese population. Methods: We conducted a hospital-based case-control study including 105 lung cancer patients and 109 healthy control subjects. The -1C/T SNP in CD40 was genotyped by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and its association with lung cancer susceptibility was evaluated. Results: The distribution of the genotypes of CD40-1C/T was significantly different between lung cancer patients and controls. The frequency of the TT genotype (adjusted P = 0.017; overall risk [OR] = 2.94; 95% confidence interval [CI] = 1.21-7.13) and TT/CT genotype (adjusted P = 0.020; OR = 1.95; 95% CI = 1.11-3.43) were significantly higher in lung cancer patients than that in controls. When the cases were categorized by tumor histology, the TT genotype was associated with a significantly increased risk of squamous cell carcinoma (adjusted OR = 6.53; 95% CI = 1.97-21.61; P = 0.002). Conclusion: Our findings suggest that the CD40 -1C/T SNP (rs1883832) is correlated with the susceptibility to lung cancer in Chinese, and the TT genotype may further increase the risk of lung cancer.     

The MLH1 -93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer

The MLH1 -93 G>A promoter polymorphism has been reported to be associated with an increased risk of microsatellite unstable colorectal cancer. Other than microsatellite instability, however, the genetic and most epigenetic changes of tumors associated with this polymorphism have not been studied. We evaluated associations between the -93 G>A polymorphism and CpG island methylator phenotype (CIMP), BRAF V600E mutations, and MLH1 methylation in tumors from a sample of 1,211 individuals with colon cancer and 1,968 controls from Utah, Northern California, and Minnesota. The -93 G>A polymorphism was determined by the five prime nuclease assay. CIMP was determined previously by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A (p16). The BRAF V600E mutation was determined by sequencing exon 15. The MLH1 -93 G>A promoter polymorphism was associated with CIMP (odds ratio (OR) 3.44, 95% confidence interval (CI) 1.85, 6.42), MLH1 methylation (OR 4.16, 95%CI 2.20, 7.86), BRAF mutations (OR 4.26, 95%CI 1.83, 9.91), and older age at diagnosis (OR 3.65, 95%CI 2.08, 6.39) in microsatellite unstable tumors. These associations were not observed in stable tumors. Increased age at diagnosis and tumor characteristics of microsatellite unstable tumors associated with MLH1 -93 G>A suggests the polymorphism is acting at a relatively late stage of colorectal carcinogenesis to drive CIMP+ tumors down the microsatellite instability pathway.     

Parkin基因多态性与四川地区散发性帕金森病的相关性研究

目的了解四川地区散发性帕金森病parkin基因多态性与帕金森病(Parkinson’s disease,PD)的相关性。方法采用病例-对照研究,应用聚合酶链反应、限制性片段长度多态性、变性高效液相色谱及DNA测序等技术,对四川地区汉族人群198例帕金森病患者和187名正常对照parkin基因-258T/G及IVS3-20T/C多态性位点进行研究,并通过比较各多态性在PD患者和正常对照人群中的频率分布,探讨基因多态性与PD的可能关系。结果parkin基因-258T/G多态性PD组G等位基因频率明显高于对照组(52.5%vs43.3%),两组差异有统计学意义(χ2=6.17,P<0.025,OR=1.45,95%CI:1.04~1.86);进一步将PD组按发病年龄分层发现,只有50岁以上发病患者与对照组相比G等位基因频率差异具有统计学意义(χ2=9.048,P<0.01,OR=1.57,95%CI:1.08~2.06);同样,与对照组(69.51%)相比,PD组TG GG基因型频率(78.79%)亦增加,两者间差异具有统计学意义(χ2=3.854,P<0.05,OR=1.63,95%CI0.88~2.38);PD组不同基因型组间发病年龄差异具有统计学意义(P<0.05),GG基因型组的平均发病年龄比TT或TG基因型的发病晚近5年左右。parkin基因IVS3-20T/C多态性以CC基因型多见,TC型杂合子的频率较低,该实验未发现TT基因型。结论核心启动子区-258T/G多态G等位基因可能增加了四川地区汉族人群散发性PD发生的风险,尤其是50岁以后的发病风险;四川地区汉族人群IVS3-20T/C位点,以CC基因型多见,TC型杂合子的频率较低,无TT基因型。     

RAD51C is a susceptibility gene for ovarian cancer

A homozygous mutation in the RAD51C gene was recently found to cause Fanconi anemia-like disorder. Furthermore, six heterozygous deleterious RAD51C mutations were detected in German breast and ovarian cancer families. We screened 277 Finnish familial breast or ovarian cancer patients for RAD51C and identified two recurrent deleterious mutations (c.93delG and c.837+1G>A). These mutations were further genotyped in 491 familial breast cancer patients, 409 unselected ovarian cancer patients and two series of unselected breast cancer cases (884 from Helsinki and 686 from Tampere) and population controls (1279 and 807, respectively). The mutation frequency among all breast cancer cases was not different from the controls (4 out of 2239, 0.2% versus population controls 2 out of 2086, 0.1%, P= 0.7). In the Helsinki series, each mutation was found in four cases with personal or family history of ovarian cancer. No mutations were found among cases with familial breast cancer only, four out of the eight carriers did not have family history of breast cancer. The mutations associated with an increased risk of familial breast and ovarian cancer (OR: 13.59, 95% CI 1.89-97.6, P= 0.026 compared with controls), but especially with familial ovarian cancer in the absence of breast cancer (OR: 213, 95% CI 25.6-1769, P= 0.0002) and also with unselected ovarian cancer (OR: 6.31, 95% CI 1.15-34.6, P= 0.033), with a significantly higher mutation rate among the familial cases (two out of eight, 25%) than the unselected ovarian cancer cases (4 out of 409, 1%) (OR: 33.8, 95% CI 5.15-221, P= 0.005). These results suggest RAD51C as the first moderate-to-high risk susceptibility gene for ovarian cancer.