前列腺癌与代谢酶基因多态性的研究进展

代谢酶基因DNA序列的多态性影响个体对内、外源性化学物的生物转化 ,而影响机体对内、外源性致癌物的易感性 ,结果产生个体肿瘤发病风险的差异。本文就近年来毒物代谢酶基因多态性对人类前列腺癌个体发病风险的研究进展作一综述     

N-乙酰基转移酶2基因多态性与膀胱癌的易感性在亚洲人群中的Meta分析

目的:运用Meta分析的方法综合评价N-乙酰基转移酶2(NAT2)基因多态性与膀胱癌发病的关系。方法:通过文献检索策略对常见的英文和中文数据库进行检索,将检索到的已经发表关于亚洲人群中NAT2基因多态性与膀胱癌关联性的文献进行整合及Meta分析。结果:NAT2慢基因易感性合并OR值及其95%CI为1.67(1.32,2.12)。按亚洲人群进行分层,中国、日本、韩国及印度人群NAT2慢基因易感性合并OR值分别为1.67(1.36~2.05)、2.19(1.71~2.82)、0.78(0.45~1.38)和1.41(0.94~2.12);按是否吸烟进行分层发现吸烟组NAT2慢基因与膀胱癌有关(OR=2.57,95%CI:1.84~3.59),而不吸烟组中未见NAT2慢基因与膀胱癌存在关联(OR=1.36,95%CI:0.92~2.02)。按是否暴露在联苯胺、芳香胺等胺类物质中进行分层发现暴露组中NAT2慢基因与膀胱癌易感性尚不能发现关联(OR=1.99,95%CI:0.49~8.00),而非暴露组中发现NAT2慢基因与膀胱癌易感性存在关联(OR=2.17,95%CI:1.26~3.72)。结论:亚洲人群NAT2基因多态性与膀胱癌易感性存在关联,NAT2基因多态性与膀胱癌易感性的关系在不同地区、不同种族间可能会有所不同。吸烟可能会增加个体患膀胱癌的危险性;而本次研究未发现携带有NAT2慢基因个体暴露在联苯胺、芳香胺等胺类物质中会增加膀胱癌的易感性,可能与研究暴露因素的样本量过少有关。     

南京地区汉族人群TRAIL基因多态性与前列腺癌的易感性研究

目的:探讨南京地区汉族人群中肿瘤坏死因子相关凋亡诱导配体(TRAIL)基因多态性与前列腺癌(PCa)易感性的关系。方法:采用病例对照研究,提取187例PCa患者和237例非PCa健康人(对照组)外周血基因组DNA,应用聚合酶链反应-连接酶特异检测技术(PCR-LDR)分析186例PCa患者和237例对照组TRAIL基因-716位点的多态性,比较不同基因型与PCa易感性的关系。结果:TRAIL基因启动子区存在一个SNP位点(-716A/G),基因型分别为AA型、AG型和GG型;Logistic回归分析显示,携带AG、GG和AG+GG基因型的个体与PCa发病风险之间无明显相关性(OR=0.89,95%CI=0.54～1.47;OR=0.94,95%CI=0.69～1.27;OR=0.87,95%CI=0.54～1.41)。结论:中国南京地区汉族人群中TRAIL基因-716位点基因多态性对PCa易感性无明显影响。     

XPC基因多态性与男性不育的相关性研究

目的:位于XPC基因外显子区域Ala499Val(C>T)和Lys939Gln(A>C)两个非同义突变的单核苷酸多态性位点在人群中研究广泛,具有潜在的功能性,其多态的变化影响到XPC基因的结构和功能,进而影响到DNA损伤修复率。本文探讨了这两个位点基因多态性在中国汉族人群中的分布及其与男性不育发病风险的关联。方法:采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,分析318例男性不育患者和228例正常对照男性中XPC基因两个多态性位点的基因分型和等位基因频率,以及这两个位点单独和联合作用与男性不育的相关性。结果:在Ala499Val(C>T)多态性位点中,CC、CT、TT三种基因型频率在病例和对照组中的分布存在显著性差异(P=0.020)。携带TT基因型的个体罹患男性不育的风险是CC基因型个体的0.49倍(95%CI=0.23～0.88),是(CC+CT)基因型个体的0.39倍(95%CI=0.22～0.71)。Lys939Gln(A>C)多态性位点与男性不育的患病风险无显著性关联。联合两个位点分析,个体携带1～4个危险位点患男性不育的风险是携带零个的2.75倍(95%CI=1.50～5.04)。结论:XPC基因Ala499Val(C>T)基因多态性与男性不育的发病风险存在关联,可能是我国汉族人群男性不育的遗传易感因素之一。     

前列腺癌易感性与丝裂原活化蛋白激酶激酶4基因多态性的关系

目的 探讨苏皖地区汉族人群中丝裂原活化蛋白激酶激酶4(MKK4)基因多态性与前列腺癌(PCa)易感性的关系.方法 采用病例对照研究,提取174例PCa患者和252例健康人(对照组)外周血基因组DNA,应用聚合酶链反应-连接酶特异检测技术(PCR-LDR)分析PCa患者和对照组MKK4基因-1304位点的多态性,比较不同基因型与PCa易感性的关系,并探讨吸烟、饮酒等因素在其中的影响.结果 MKK4基因启动子区存在1个SNP位点(- 1304 T＞G),基因型分别为TT型、TG型和GG型;Logistic回归分析显示,携带TG、GG和TG+GG基因型的个体与PCa发病风险之间无明显相关性[比值比(OR)=0.775,95％可信区间(CI) =0.516～1.164;OR =0.650,95％CI =0.216～1.956;OR =0.763,95％ CI =0.514～1.135].在高龄(＞70岁)和非饮酒人群中,TG+GG基因型的个体发病率明显减少,调整后的OR(95％ CI)分别为0.575(0.348 ～ 0.951)、0.477(0.252 ～0.906).结论 苏皖地区汉族人群中MKK4基因-1304位点基因多态性对PCa易感性无明显影响.     

Toll样受体4的基因多态性与脓毒症

脓毒症是指机体感染微生物后发生的全身炎性反应综合征.在该疾病发生发展中是基因多态性影响着机体对该综合征的遗传易感性.其中Toll样受体4(toll-like receptor4,TLR4)作为识别病原微生物的主要受体之一,在自身免疫中起着重要的作用.已有研究表明TLR4的基因多态性与脓毒症的遗传易感性密切相关,其中TLR4基因的Asp299Gly和Thr399Ile位点的突变与脓毒症的发生发展及预后有关.现就TLR4的功能、信号转导通路及其基因多态性与脓毒症易感性的相关关系作一综述.     

雄激素受体基因多态性与男性不育相关性研究进展

雄激素受体(AR)是一种依赖配体的反式转录调节蛋白,参与雄激素的生理调节功能,其广泛存在于机体的各个组织,属于核受体超家族中的类固醇受体,在精子发生的过程中发挥重要的作用。雄激素通过与AR的结合,启动靶基因的表达,参与精子发生。AR基因多态性会改变自身结构,影响其与雄激素结合的亲和力,使雄激素下游靶基因不能够转录表达蛋白。随着DNA测序技术的发展,研究AR基因多态性与男性不育之间关系成为一大热点。本文主要综述AR基因多态性与男性不育之间的相关性。     

信号传导与转录激活因子-4基因rs7574865位点单核苷酸多态性与类风湿关节炎易感性荟萃分析

目的：综合评价信息传导与转录激活因子-4基因（STAT4基因）rs7574865位点单核苷酸多态性与类风湿关节炎易感性的相关性。方法：计算机检索Pubmed、Embase、中国生物医学文献数据库和万方数据库数据库等,并手工检索相关杂志,收集有关不同人群STAT4基因rs7574865位点单核苷酸多态性的等位基因频率、基因型频率与类风湿性关节炎易感性相关性的研究,采用Stata 12.0软件进行Meta分析;选择的遗传模型包括GT＋TT与GG比较,TT与GT＋GG比较,TT与GG比较以及等位基因T与G之间比较。结果：STAT4基因rs7574865位点T等位基因频率与类风湿性关节炎易感性可能具有相关性（OR=1.259,95%CI=1.202-1.319, P＜0.001）;T等位基因频率与类风湿性关节炎易感性的相关性在欧洲、亚洲、非洲、拉丁美洲人群中有统计学意义;在总体人口中STAT4基因rs7574865位点的基因型与类风湿性关节炎易感性可能具有相关性;在总体人口中STAT4基因rs7574865位点多态性与抗CCP抗体阳性或RF因子阳性类风湿性关节炎易感性仍可能具有相关性。结论：STAT4基因rs7574865位点单核苷酸多态性与类风湿性关节炎易感性可能具有相关性,而且这种相关性可能独立于患者RF因子以及抗CCP抗体水平。     

结直肠癌发病风险与GSTP1基因多态性的关系

谷胱甘肽硫转移酶(glutathione S-transferase,GSTs)是一类具有促进多种亲电子物质、氧化应激产物等与谷胱甘肽的巯基结合而发挥Ⅱ相解毒及抗氧化功能的多基因同工酶家族[1]。本研究旨在探讨结直肠癌发病风险与GSTP1基因多态性的关系。     

维生素D受体基因Apa I多态性与骨质疏松症相关性的研究

目的研究维生素D受体（vitamin Dreceptor,VDR）基因ApaⅠ多态性与原发性骨质疏松症的相关性。方法应用聚合酶链反应-限制性片段长度多态性分析技术测定山东半岛地区155例骨质疏松患者和113例对照者维生素D受体基因ApaⅠ多态性,比较两组基因型和等位基因分布频率。结果两组基因型和等位基因差异有显著性（P〈0.05）。男性及〈65岁骨质疏松组同相应对照组相比差异无显著性,女性及≥65岁骨质疏松组同相应对照组相比差异有显著性（P〈0.05）;≥65岁女性骨质疏松组aa基因型与a等位基因频率高于其对照组。结论山东半岛地区汉族人群中,维生素D受体基因ApaⅠ多态性与原发性骨质疏松症存在相关性,65岁及以上女性a等位基因是易感基因,aa基因型个体存在易感性。     

Genetic risk factors in male infertility

The etiopathogenesis of testicular failure remains unknown in about half of the cases and is referred to as "idiopathic infertility". "Idiopathic" testicular failure is of probable genetic origin since the number of genes involved in human spermatogenesis is likely thousands and only a small proportion of them have been identified and screened in infertile men. In parallel with studies aimed to identify mutations with a clear cause-effect relationship in spermatogenesis candidate genes, there is an increasing interest towards genetic susceptibility factors to male infertility. Despite many efforts, only a few clinically relevant polymorphisms have been identified. This is mainly related to the multifactorial nature of male infertility and to the inappropriate study design of the majority of the studies. The most promising polymorphisms are in genes involved in the endocrine regulation of spermatogenesis and on the Y chromosome, the "gr/gr" deletions. Polymorphisms are generally considered as co-factors. Their final effect on testis function and fertility is probably modulated by the genetic background of each individual and/or by the presence of certain environmental factors. In this review, recent findings concerning some of the most widely studied polymorphisms and male infertility will be discussed.     

CUA Guideline: The workup of azoospermic males

A committee was established at the request of the CUA to determine guidelines for the investigation and management of azoospermia. Members of the committee, all of whom have special expertise in the investigation and management of male infertility, were chosen from different communities across Canada. The members represent different practices in different communities.     

Association of polymorphisms in glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) with idiopathic azoospermia or oligospermia in Sichuan,China

The reported effects of the glutathione S-transferase (GSTs) genes (GSTM1, GSTT1, and GSTP1) on male factor infertility have been inconsistent and even contradictory. Here, we conducted a case-control study to investigate the association between functionally important polymorphisms in GST genes and idiopathic male infertility. The study group consisted of 361 men with idiopathic azoospermia, 118 men with idiopathic oligospermia, and 234 age-matched healthy fertile male controls. Genomic DNA was extracted from the peripheral blood, and analyzed by polymerase chain reaction and restriction fragment length polymorphism analysis. There was a significant association between the GSTP1 variant genotype (Ile/Val + Val/Val) with idiopathic infertility risk (odds ratio [OR]: 1.53; 95% confidence interval [CI]: 1.11–2.11; P = 0.009). Similarly, a higher risk of infertility was noted in individuals carrying a genotype combination of GSTT1-null and GSTP1 (Ile/Val + Val/Val) (OR: 2.17; 95% CI: 1.43–3.31; P = 0.0002). These results suggest an increased risk of the GSTP1 variant genotype (Ile/Val + Val/Val) for developing male factor infertility. Our findings also underrate the significance of the effect of GSTM1 and/or GSTT1 (especially the former) in modulating the risk of male infertility in males from Sichuan, southwest China.     

Psychology of male infertility — a literature survey

Fifty-three articles on the psychology of male infertility published between 1948 and 1985 are reviewed with respect to theoretical backgrounds, methodological approaches and results suggesting an influence of psychological factors on male fertility. Although the data of most empirical studies are found to be incomplete and inconclusive because of conceptual deficiencies and insufficient methods, there is some evidence for stress responses negatively affecting male fertility. The variety of psychological factors presented in the literature indicates the heterogeneity of psychological involvement in male infertility. In conclusion, goals for future research on psychobiological aspects of male infertility are suggested and methodological criteria are outlined.     

男性不育研究新进展

70%以上的男性不育病因不明,即使在已知病因的男性不育中,其发病机制尚未完全阐明,因此男性不育诊治有其复杂性与特殊性。自从1992年发明卵细胞胞质内单精子注射(ICSI)治疗男性不育以来,对难治性男性不育取得突破性进展,但对每一男性不育个体选择治疗时,传统治疗方法应受到重视。男性不育诊治程序的规范化、辅助生殖技术的成功率和安全性等研究将成为男性不育发展的主导方向。     

Methylenetetrahydrofolate reductase C677T polymorphism and the risk of male infertility: a meta-analysis

Several molecular epidemiological studies have been conducted to examine the association between MTHFR C677T polymorphism and male infertility susceptibility, but the results remain inconsistent. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 10 case-control studies, including 2275 cases and 1958 controls, were selected. Crude odds ratios (ORs) with 95% confidence intervals were used to assess the strength of association in the additive model, dominant model and recessive model. In the overall analysis, no significant association between the polymorphism and risk of male infertility was observed. Stratified analysis showed that significantly strong association between MTHFR C677T polymorphism and male infertility were present only in Asians (OR = 1.79 for TT vs. CC genotype; OR = 1.42 for CT/TT vs. CC genotype; OR = 1.50 for TT vs. CC/CT genotype; OR = 1.36 for T vs. C allele), but not in Caucasians. Additionally, MTHFR 677T was associated with a significant increase in the risk of azoospermia in all genetic models. No significantly increased risks of oligoasthenoteratozoospermia were found in any of the genetic models. In conclusion, this meta-analysis supports that MTHFR C677T polymorphism is capable of causing male infertility susceptibility in Asians, but not in Caucasians.     

Association of the methylenetetrahydrofolate reductase gene C677T polymorphism with the risk of male infertility: a meta-analysis

Several molecular epidemiological studies have been conducted to examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility susceptibility, but the results remain inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of 26 case–control studies including 5659 infertility cases and 5528 controls were selected to evaluate the possible association. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association of C677T polymorphism with male infertility in the additive model, dominant model, recessive model and allele-frequency genetic model. In the overall analysis, the frequency of the 677T allele was significantly associated with male infertility susceptibility (OR?=?2.32, 95%CI?=?2.04–2.65 for TT vs. CC genotype; OR?=?1.09, 95%CI?=?1.00–1.19 for CT vs. CC genotype; OR?=?1.19, 95%CI?=?1.10–1.29 for CT/TT vs. CC genotype; OR?=?1.54, 95%CI?=?1.36–1.74 for TT vs. CC/TT genotype; OR?=?1.22, 95%CI?=?1.15–1.30 for T vs. C allele). A subgroup analysis of the subjects showed that significantly strong association between MTHFR C677T polymorphism and male infertility was present only in Asians, but not in Caucasians. Additionally, MTHFR C677T was associated with a significant increase in the risk of azoospermia in all genetic models. Meanwhile, no significantly increased risks of oligoasthenotertozoospermia (OAT) were found in most of the genetic models. In conclusion, this meta-analysis is in favor that the MTHFR C677T polymorphism is capable of causing male infertility susceptibility, especially in Asians and the subgroup of azoospermia.     

Comparative analysis of tests used to assess sperm chromatin integrity and DNA fragmentation

Male infertility has a complex etiology, and many times, the cause is unknown. While routine semen analysis provides an overview of basic semen parameters, such as sperm concentration, motility, viability and morphology, a significant overlap of these parameters has been reported in fertile and infertile men. Moreover, conventional semen parameters do not reveal the cellular or molecular mechanisms of sperm dysfunctions leading to infertility. Therefore, sperm functional parameters, including sperm chromatin integrity, are evaluated to provide information on subtle sperm defects that are not routinely identified. Incomplete or defective sperm chromatin condensation increases the susceptibility of the sperm DNA to oxidative damage or other factors. To evaluate sperm chromatin integrity, different methods with varying degrees of diagnostic and prognostic capabilities are available. Among these assays, SCSA, TUNEL and SCD assays are most commonly used. While these assays rather evaluate the DNA directly for damages, the aniline blue and chromomycin A3 stains test for the quality of chromatin condensation. Thus, this review discusses and compares different methods used to evaluate sperm chromatin integrity and condensation, and their inclusion in the routine evaluation of the male infertility.     

Genetic causes of male infertility

Summary.  Male infertility has often been ascribed to infections, immunologic factors, chemical insults or malformations. About 10% of infertile males have severe defects in sperm production. Lately, research has focused on possible genetic aetiologies. In this review genetic causes of male infertility are discussed. For pragmatic reasons three groups have been defined. In the first group, disorders of sexual differentiation associated with male infertility are considered. In the second group, male infertility is discussed in a context of some genetic diseases. In the third group, genetic causes for isolated defects of sperm production and function are reported.     

Etiologies of sperm DNA damage and its impact on male infertility

Male factor is responsible for up to 50% of infertility cases in the world. Semen analysis is considered the cornerstone of laboratory evaluation of male infertility, but it has its own drawbacks and fails to predict the male fertility potential with high sensitivity and specificity. Different etiologies have been linked with male infertility, of which sperm DNA damage has gained significant attention with extensive research on sperm function tests. The associations between sperm DNA damage and a variety of disorders such as varicocele, obesity, cancer, radiation and lifestyle factors are explored in this review. Furthermore, we discuss the mechanisms of DNA damage as well as its impact in different scenarios of male infertility, associated with spontaneous and assisted reproduction. Finally, we review the clinical applicability of sperm DNA fragmentation testing in the management of male infertility.