Estrogen receptor codon 594 and HER2 codon 655 polymorphisms and breast cancer risk

The estrogen receptor (ER) and the human epithelial growth factor receptor 2 (HER2) genes have been implicated in the development and prognosis of breast cancer. Several genetic polymorphic sites in these genes have been identified and associated with the risk of breast cancer. We have investigated the association between the estrogen receptor codon 594 (ACA to ACG) and HER2 codon 655 (ATC to GTC) polymorphisms and breast cancer risk. Genomic DNA from breast cancer patients and control subjects was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). When allelic frequencies of the ER codon 594 and HER2 codon 655 gene were compared, no significant differences were observed between the patient and control groups. (P = 0.063, OR = 1.55, 95% CI = 0.25-9.41 and P = 0.949, OR = 1.01, 95% CI = 0.55-1.88, respectively). In conclusion, our results support the view that both the ER codon 594 and HER2 codon 655 polymorphisms are not associated with increased risk of breast cancer.     

(CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population

Alleles of the CAG and the GGC repeat in the first exon of the human androgen receptor (AR) gene have been shown to be associated with the risk of (advanced) prostate cancer. These studies had been carried out in the United States. We have analysed these polymorphisms in a French-German collection of 105 controls, 132 sporadic cases, and a sample of prostate cancer families comprising 85 affected and 46 not affected family members. The allele distributions were very similar in all four groups and chi square statistics on contingency tables did not detect any significant differences. The relative risk (odds ratio, OR) were calculated using logistic regression and did not reach significance despite sufficient numbers of patients and controls. Typical results were OR = 1.007; 95% Confidence Interval (CI) 0.97-1.1, P = 0.87 for CAG as continuous variable and OR = 1.2 (95% CI 0.7-2.0), P = 0.47 for CAG classes < 22 and > = 22 repeats. Similar results were obtained for subgroups defined by age or Gleason score. We conclude that these polymorphisms can not be used as predictive parameters for prostate cancer in the French or German population.     

Linkage of angiotensin I-converting enzyme gene insertion/deletion polymorphism to the progression of human prostate cancer

Angiotensin-converting enzyme (ACE) degrades vasodilator kinins and generates angiotensin II (Ang II). It has been reported that ACE is synthesized by the prostate and that the AT-1 receptor subtype is the predominant prostatic Ang II receptor. A polymorphism in the human ACE gene has been described and the highest levels of circulating and tissue ACE activity are found in carriers of the DD genotype. In the present study, ACE genotypes were determined in 170 patients with prostate cancer and their association with disease progression was analysed. It was found that the DD genotype was present in 31 of 78 (39.8%) patients with advanced disease and in 19 of 82 (23.2%) with localized disease: this difference was statistically significant (OR = 2.18, 95% CI = 1.11-4.03; p = 0.024). Step-wise logistic regression analysis was used to identify predictive parameters of advanced disease and it was observed that the DD genotype (p = 0.002, OR = 5.4, 95% CI = 1.84-16.06), high-grade tumour (p < 0.001, OR = 8.04, 95% CI = 3.03-21.33), and high serum PSA (p < 0.001, OR = 10.87, 95% CI = 4.06-29.13) were significantly associated with advanced disease. The results of this study support the hypothesis that genetic factors related to ACE may influence the behaviour of human prostate cancer.     

Meta-analysis of three polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and risk of prostate cancer

The steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2) gene plays a crucial role in androgen metabolism pathway in human prostate. It encodes SRD5A2 enzyme, which catalyses testosterone to dihydrotestosterone (DHT). DHT is the main active structure binding with androgen receptor (AR). After the activation of AR, it further regulates a series of target genes in androgen metabolism pathway. However, no clear consensus has been reached on the association between the SRD5A2 V89L, A49T and TA repeat polymorphisms and prostate cancer (PCa) risk. Thus, we performed a meta-analysis of 31 association studies with 14,726 PCa cases and 15,802 controls. We found no association between PCa and 89L compared with 89V allele [odds ratio (OR) = 1.02, 95% confidence interval (CI) 0.98-1.06, P(heterogeneity) = 0.44]. The 49T allele showed a significantly elevated effect on the high stage (Stages III-IV) of PCa risk both under the dominant genetic model (OR = 2.13, 95% CI 1.44-3.15, P(heterogeneity) = 0.65) and in the contrast T versus A allele (OR = 2.06, 95% CI 1.41-3.02, P(heterogeneity) = 0.69). There was a significantly decreased association between PCa and long TA repeat as compared versus short TA repeat (OR = 0.86, 95% CI 0.74-1.00, P(heterogeneity) = 0.79). No significant between-study heterogeneity was found in all subjects under four genetic models (dominant model, recessive model, allele comparison and homozygosity comparison) for these three polymorphisms, respectively, so the fixed effects model was used to pool the result. Our result indicated that carriers of 49T might improve the risk of PCa in higher stages (Stages III-IV), carriers of long TA repeat might decrease the risk of PCa and 89L may not be an important risk factor for PCa. However, due to the limited sample sizes, this meta-analysis did not achieve sufficiently conclusive results. Still more well-designed studies should be performed to clarify the role of these three polymorphisms in the development of PCa.     

Pooled analysis of genetic variation at chromosome 8q24 and colorectal neoplasia risk

Several different genetic variants at chromosome 8q24 have been related to prostate, breast and colorectal cancer risk with evidence of region-specific risk differentials for various tumor types. We investigated the association between 15 polymorphisms located in 8q24 regions associated with cancer risk in a pooled analysis of 2587 colorectal adenoma cases, 547 colorectal cancer cases and 2798 controls of European descent from four studies. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations. Three polymorphisms (rs10808555, rs6983267 and rs7837328) located between 128.47 and 128.54 Mb were found to be associated with colorectal tumor risk. The association was strongest for the previously reported rs6983267 variant and was similar for both adenoma (OR(per allele) = 1.16, 95% CI: 1.07-1.25, P = 0.0002) and cancer (OR (per allele) = 1.17, 95% CI: 1.01-1.35, P = 0.03). The strength of the association of the regional haplotype containing variant alleles at rs10808555, rs6983267 and rs7837328 but not rs10505476 was greater than that of any single variant of both adenoma (OR = 1.27, P = 0.0001) and cancer (OR = 1.26, P = 0.03). The risk associated with rs6983267 was stronger for multiple adenomas (OR(per allele) = 1.29, P = 5.6 x 10(-6)) than for single adenoma (OR(per allele) = 1.10, P = 0.03) with P(heterogeneity) = 0.008. This study confirms the association between colorectal neoplasia and the 8q24 polymorphisms located between 128.47 and 128.54 Mb and suggests a role for these variants in the formation of multiple adenomas.     

Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.     

Association of prostate cancer with rapid N-acetyltransferase 1 (NAT1*10) in combination with slow N-acetyltransferase 2 acetylator genotypes in a pilot case-control study

N-acetyltransferase-1 (NAT1) and N-acetyltransferase-2 (NAT2) are important in the metabolism of aromatic and heterocyclic amine carcinogens that induce prostate tumors in the rat. We investigated the association of genetic polymorphisms in NAT1 and NAT2, alone and in combination, with human prostate cancer. Incident prostate cancer cases and controls in a hospital-based case-control study were frequency-matched for age, race, and referral pattern. The frequency of slow acetylator NAT1 genotypes (NAT1*14, *15, *17) was 5.8% in controls but absent in cases. In contrast, in comparison with all other NAT1 genotypes the putative rapid acetylator NAT1 genotype (NAT1*10) was significantly higher in prostate cancer cases than controls (OR, 2.17; 95% CI, 1.08-4.33; P = 0.03). Combinations of NAT1*10 with NAT2 slow acetylator genotypes (OR, 5.08; 95% CI, 1.56-16.5; P = 0.008) or with NAT2 very slow (homozygous NAT2*5) acetylator genotypes (OR, 7.50; 95% CI, 1.55-15.4; P = 0.016) further increased prostate cancer risk. The results of this small pilot study suggest increased susceptibility to prostate cancer for subjects with combinations of NAT1*10 and slow (particularly very slow) NAT2 acetylator genotypes. This finding should be investigated further in larger cohorts and in other ethnic populations.     

Telomere length,telomere‐related genes,and breast cancer risk: The breast cancer health disparities study

Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere‐related genes with cancer. We evaluated associations between telomere‐related genes, TL, and breast cancer risk in an admixed population of US non‐Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL‐related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL‐related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (OR_adj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER?/PR+) tumors and TERT rs2735940 (OR_adj 0.73, 95% CI 0.59, 0.91) with ER?/PR? tumors. These data provide support for an association between TL and TL‐related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry. © 2013 Wiley Periodicals, Inc.     

Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas

Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.     

Genetic polymorphisms of TP53-binding protein 1 (TP53BP1) gene and association with breast cancer risk

In the present study, we evaluated the association between the TP53BP1 Glu353Asp and T-885G polymorphisms and breast cancer risk as well as with the clinicopathological characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using PCR-RFLP method in a hospital-based Malaysian population. Breast cancer risk was not observed among women who were heterozygous (OR(adj) = 0.887; 95% CI, 0.632-1.245) or homozygous (OR(adj) = 1.083; 95% CI, 0.595-1.969) for Asp allele, and those carriers of Asp allele (OR(adj) = 0.979; 95% CI, 0.771-1.243). Similarly, women who were TG heterozygotes (OR(adj) = 1.181; 95% CI, 0.842-1.658) or GG homozygotes (OR(adj) = 1.362; 95% CI, 0.746-2.486) and carriers of G allele (OR(adj) = 1.147; 95% CI, 0.903-1.458) were not associated with increased risk of breast cancer. Asp allele genotype was significantly associated with ER negativity (p = 0.0015) and poorly differentiated tumours (p = 0.008), but G allele genotype was not associated with the clinicopathological characteristics. In conclusion, Glu353Asp and T-885G polymorphic variants might not have an influence on breast cancer risk, thus might not be potential candidates for cancer susceptibility. Glu353Asp variant might be associated with tumour aggressiveness as defined by its association with ER negativity and poorly differentiated tumours.     

Androgen receptor amplification is associated with increased cell proliferation in prostate cancer

Mechanisms of prostate cancer progression during hormonal therapy and the pathobiologic consequences of androgen receptor (AR) gene amplification are inadequately known. To further investigate the hypothesis that AR gene amplification is associated with increased cell proliferation, we analyzed 123 paraffin-embedded prostate cancer specimens from men who experienced tumor relapse during androgen withdrawal therapy. We used fluorescence in situ hybridization to quantify AR gene copy number and Ki-67 immunohistochemistry to determine cell proliferation. One third of the tumors showed AR gene amplification. Among tumors with AR amplification, the mean cell proliferation rate was 19.8 (SD, 12.3; 95% confidence interval [CI], 15.4-24.1), whereas it was 13.0 (SD, 15.9; 95% CI, 9.1-16.8) in tumors without amplification (P = .032). In the best fitting logistic regression model, only proliferation remained significant (P = .040). When the median Ki-67 labeling index (6.7%) of all tumors was used as a cutoff point, the tumors with AR amplification were more frequently highly proliferating than tumors with no amplification (P = .010; odds ratio, 3.4; 95% CI, 1.4-8.3). Our results imply that progression of prostate cancer during androgen withdrawal therapy is associated with AR gene amplification and increased cell proliferation rate in one third of tumors. We suggest that AR gene amplification is an important molecular mechanism underlying the increase in proliferation rate of a substantial fraction of recurrent prostate carcinomas. However, efforts should be targeted to develop prostate cancer cell lines to study causal relationships between AR gene amplification and various biologic variables.     

Caspase 9 promoter polymorphisms and risk of primary lung cancer

Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the CASP-9 gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [-1263A>G, -905T>G, -712C>T and -293_-275delCGTGAGGTCAGTGCGGGGA (-293del)] in the CASP-9 promoter with the risk of lung cancer in a Korean population. The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The -1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the -1263 AA genotype or combined -1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42-0.98, P=0.04 and adjusted OR=0.67, 95% CI=0.46-0.97, P=0.01, respectively]. For the -712C>T polymorphism, individuals with at least one -712T allele were at a significantly increased risk of lung cancer compared with those harboring the -712 CC genotype (adjusted OR=1.42, 95% CI=1.06-1.89, P=0.02). Consistent with the results of genotype analyses, the -1263G/-712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47-0.75, P and Bonferroni corrected P (Pc)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45-0.81, P=0.0007 and Pc=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17-0.68, P=0.0023 and Pc=0.0046 for the G-C homozygotes; P(trend)<0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the -1263G/-712T and -1263A/-712C haplotypes. These results suggest that CASP-9 promoter polymorphisms affect CASP-9 expression and contribute to genetic susceptibility to lung cancer.     

The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis

Associations with disease identified by genome-wide association studies (GWAS) must be replicated and refined to validate causative variants. In the Wellcome Trust Case Control Consortium (WTCCC) GWAS using 14?500 non-synonymous single nucleotide polymorphisms (nsSNP), rs11062385 (a nsSNP in JARID1A) showed nominal association with ankylosing spondylitis (AS) (P=0.0006, odds ratio (OR)=1.26, 95% confidence interval (95% CI)=1.1-1.4). To replicate and refine the association of JARID1A, rs11062385 was genotyped in 730 further cases and compared with allele frequencies in non-AS disease cohorts typed by WTCCC. We replicated the initial association (P=0.04, OR=1.16, 95% CI=1.01-1.34) and identified a strengthened association with AS in a meta-analysis of this new study combined with the original WTCCC study (P=0.0001, OR=1.21, 95% CI=1.10-1.33). We also genotyped nine further intronic tagging SNPs in JARID1A in 1604 AS cases and 1020 new control samples, but none was associated with AS. JARID1A or a locus in strong linkage disequilibrium with it is a positional candidate for susceptibility to AS.     

Predictive factors for age at menopause in Caucasian females

OBJECTIVE: Early onset of menopause results in the premature exposure to low estrogen levels and is associated with a number of postmenopausal health problems and higher risk of mortality. The aim of this study was to determine genetic and environmental factors associated with age at natural and surgical menopause. METHODS: Multiple regression analysis using a sample of Caucasians composed of 154 females with surgical and 248 with natural menopause. RESULTS: Breastfeeding is a significant predictor of earlier natural menopause (P<0.05). Use of oral contraceptives and smoking were not significantly associated with age at menopause. Females who did not have history of pregnancies are at significantly higher risk (P<0.001) of getting early surgical menopause than those who did. We also tested the association of seven single nucleotide polymorphisms (SNPs) of the estrogen receptor alpha (ER-alpha) gene with age at menopause. No association was observed with age at menopause but the PvuII p allele was overrepresented in women with surgical menopause and associated with menopause per se (P=0.029; OR=1.8, 95% CI=1.1-3.0). CONCLUSIONS: Breastfeeding and alcohol consumption are significantly associated with earlier natural menopause. No significant effects of the ER-alpha genotypes were observed on the age of menopause. Given the important role of the ER-alpha in estrogen signaling, which directly influences the menopausal process, further studies are required to better define the relationship between this gene and age at menopause.     

IL-10 genotype analysis in patients with Behçet's disease

Beh?et's disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation, and skin lesions. The etiology of the disease is currently unknown but evidence suggests that there is a strong genetic component mediating the chronicity of the disorder. We have examined the association between polymorphisms at position -1082, and -819 in the promoter region of the gene encoding IL-10 in patients with Beh?et's disease from two distinct patient populations. The IL-10 -1082AA genotype was weakly associated with BD when all patients were analyzed as a group (pc = 0.04, OR 1.4, 95% CI 1.1-1.9), but not in the UK or Middle Eastern (ME) cohorts of patients alone compared to local controls. An association with IL-10 -819T was evident in all BD patients, (pc = 0.02, OR 1.5, 95% CI 1.1-2.0), and this was because of an association in the UK but not ME patients (pc = 0.0004, OR 2.1, 95% CI 1.4-3.3). The -1082A/-819T haplotype, which is linked to low production of this cytokine, was not significantly associated with Beh?et's disease. This link between BD, a chronic, relapsing, autoinflammatory condition, and a genotype associated with low IL-10 production provides evidence that abnormalities in the genetic control of cytokine levels may be relevant in influencing the immune response in Beh?et's disease in some patient groups.     

The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease

Background: It has been reported that one single nucleotide polymorphisms (SNPs) rs5743708 in TLR2 gene might be associated with the susceptibility to tuberculosis disease. Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease. Methods: A systematic search of studies on the association of the rs5743708 gene polymorphism in the TLR2 gene with susceptibility to tuberculosis disease was conducted in PubMed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. Results: A total of nineteen case-control studies from 13 articles on rs2910164 and 3 studies on the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease were included. A significant relationship between the rs5743708 gene polymorphism in the TLR2 gene and tuberculosis disease was discovered in an allelic genetic model (OR: 2.801, 95% CI: 2.130-3.683, P=0.000), a homozygote model (OR: 5.795, 95% CI: 1.982-16.941, P=0.001), a heterozygote model (OR: 2.628, 95% CI: 1.888-3.569, P=0.000), a dominant genetic model (OR: 2.786, 95% CI: 2.003-3.877, P=0.000) and a recessive genetic model OR: (5.568, 95% CI: 1.907-16.255, P=0.002). In sub-group analysis base on ethnicity, significance was observed between the Caucasian group and the Asian group. Conclusions: The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease. Individuals with the rs5743708 gene polymorphism in the TLR2 gene are under a higher risk for tuberculosis disease.     

广东汉族女性TRIM31基因单核苷酸多态性与乳腺癌易感性的相关性研究

目的:探讨TRIM31(Tripartite motif containing 31)基因rs1116221位点单核苷酸多态性(Single nucleotide poly-morphisms,SNP)与广东汉族女性乳腺癌易感性的关系。方法:利用MassARRAY-IPLEX SNP分型技术,对南方医科大学南方医院的216例广东汉族乳腺癌患者及216例同期健康体检者TRIM31基因的多态性位点rs1116221进行基因分型,采用χ2检验方法统计分析病例组与对照组的基因型分布频率的差异,采用非条件Logistic回归计算比数比(Odds ratio,OR)和95%可信区间(Confidence interval,CI)对该位点多态性与乳腺癌易感性的相关性进行评价。在此基础上,在病例组中根据临床雌激素受体(Estrogen receptor,ER)和孕激素受体(Progesterone receptor,PR)的免疫组化结果进一步分层分析。结果:TRIM31基因位点rs1116221在广东汉族女性中存在CC、CT、TT 3种多态性,病例-对照分析显示,该位点基因型分布频率在两组中无统计学差异(P>0.05);进一步分层分析发现,该位点的基因型分布在ER阳性/阴性(+/-)分组中存在差异,且具有统计学意义(P=0.034),携带杂合基因型CT的个体更倾向于ER(+)乳腺癌(OR=2.67,95%CI:1.02～7.02);而在PR阳性/阴性(+/-)分组中无统计学差异。结论:基因TRIM31的rs1116221位点多态性与乳腺癌患病风险之间无明显相关性,但该位点的杂合基因型与乳腺癌ER阳性(+)明显相关。     

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.     

BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis

A meta-analysis regarding BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and their associations with osteoporosis in females is reported. The meta-analysis involved 14, seven, seven and three studies for BsmI, TaqI, ApaI and FokI polymorphisms, respectively. The studies were association studies with osteoporotic cases and controls free of osteoporosis that provided the genotype distribution of individual cases and controls. For the BsmI polymorphism, the allele contrast b vs. B showed heterogeneity among studies (p< 0.01, I2> 50%) and the random effects (RE) pooled odds ratio (OR) was non-significant: 0.94 [95% confidence interval (CI) 0.63-1.38]. Caucasians, postmenopausal cases and studies with WHO diagnostic criteria showed no association under any genetic contrast. However, in East Asians, the OR for the dominant model [fixed effects OR=0.14 (95% CI 0.04-0.50) and RE OR=0.16 (95% CI 0.03-0.84)] was significant, indicating prevention. Overall, for the TaqI, ApaI and FokI polymorphisms, the allele contrast showed heterogeneity and the pooled RE ORs were non-significant [OR=1.06 (95% CI 0.71-1.60), OR=0.99 (95% CI 0.72-1.37) and OR=1.17 (95% CI 0.76-1.80), respectively]. The allele contrast for Caucasians, East Asians, postmenopausal cases and studies with WHO diagnostic criteria showed no association for TaqI, ApaI, and FokI. The allele contrast of homozygotes, and the recessive and dominant models the results followed the same pattern as the allele contrast. Therefore, the relationship between the VDR polymorphisms and osteoporosis remains an unresolved issue and other probable genetic-environmental risk factors interacting with the above polymorphisms should be investigated.