Diabetes mellitus and late‐onset hypogonadism: the role of Glu298Asp endothelial nitric oxide synthase polymorphism

Nitric oxide has been associated with insulin resistance and type 2 diabetes mellitus (DM). An association has been suggested between a single nucleotide polymorphism (Glu298Asp variant) of the endothelial nitric oxide synthase (eNOS) gene and increased risk of DM. However, the role of this polymorphism in favouring DM has not been investigated in hypogonadism, in which low testosterone and obesity are believed to play the major role. We aimed to evaluate whether eNOS gene single nucleotide polymorphism (Glu298Asp variant) might give a relevant contribution also to the onset of hypogonadism‐associated DM. 110 men affected by late‐onset hypogonadism were retrospectively reviewed. Patients were clinically and biochemically evaluated. Detection of eNOS Glu298Asp polymorphism was performed. After splitting the sample according to the three genetic variants (i.e. eNOS_GG, eNOS_GT, eNOS_TT), no difference was evident in age, body mass index (BMI) and total testosterone. Conversely, DM prevalence, glycaemia and glycated haemoglobin were significantly higher in eNOS_TT than in eNOS_GT and eNOS_GG. Logistic regression analysis showed that, after adjustment for age, BMI and total testosterone, eNOS_TT was positively and significantly associated with DM. Our study suggests that Glu298Asp single nucleotide polymorphism of the eNOS gene may be an independent risk factor for hypogonadism‐associated type 2 DM.     

Fetal programming of polycystic ovary syndrome

Polycystic ovary syndrome(PCOS) is a common endocrine disorder that affects up to 6.8% of reproductive age women.Experimental research and clinical observations suggest that PCOS may originate in the very early stages of development,possibly even during intrauterine life.This suggests that PCOS is either genetically-transmittedor is due to epigenetic alterations that develop in the intrauterine microenvironment.Although familial cases support the role of genetic factors,no specific genetic pattern has been defined in PCOS.Several candidate genes have been implicated in its pathogenesis,but none can specifically be implicated in PCOS development.Hypotheses based on the impact of the intrauterine environment on PCOS development can be grouped into two categories.The first is the "thrifty" phenotype hypothesis,which states that intrauterine nutritional restriction in fetuses causes decreased insulin secretion and,as a compensatory mechanism,insulin resistance.Additionally,an impaired nutritional environment can affect the methylation of some specific genes,which can also trigger PCOS.The second hypothesis postulates that fetal exposure to excess androgen can induce changes in differentiating tissues,causing the PCOS phenotype to develop in adult life.This review aimed to examine the role of fetal programming in development of PCOS.     

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

BackgroundFamily history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.ObjectiveTo detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.Design, setting, and participantsA two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.Outcome measurements and statistical analysisFrequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.Results and limitationsEleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.ConclusionsOur approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.Patient summaryMultiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.     

肾移植术后Ⅰ型原发性高草酸尿症复发致移植肾功能不全的多学科综合诊疗

目的  探讨肾移植术后Ⅰ型原发性高草酸尿症（PH）复发的临床特点和多学科综合诊疗（MDT）的经验。方法  对1例接受同种异体肾移植手术后不明原因移植肾功能短期内迅速下降的病例进行MDT讨论,总结MDT在诊断罕见遗传性疾病以及提高肾移植受者长期存活中的作用。结果  经MDT讨论,患者确诊为Ⅰ型PH复发,排除排斥反应后恢复常规免疫抑制方案,嘱大量饮水,予优质蛋白和低磷饮食、维生素B6、钙剂等保守治疗措施并积极防治并发症。患者移植肾功能恶化延缓,但仍在肾移植术后5个月恢复规律血液透析至投稿日。结论肾移植术后Ⅰ型PH复发较为罕见,临床主要表现为复发性肾结石,移植肾功能下降,且并发症多,患者预后不良。通过MDT讨论患者病情,明确诊断,确定最佳治疗方案,延缓了病情进展,改善了患者预后。     

Analysis of association between the 5‐HTTLPR and STin2 polymorphisms in the serotonin‐transporter gene and clinical response to a selective serotonin reuptake inhibitor (sertraline) in patients with premature ejaculation

Study Type – Therapy (cohort)
Level of Evidence 2b

OBJECTIVE

To test the hypothesis that polymorphism within the gene‐linked polymorphic region (5‐HTTLPR) and second intron of SLC6A4 gene (STin2) is associated with selective serotonin‐reuptake inhibitors (SSRIs) response in subjects with premature ejaculation (PE).

PATIENTS AND METHODS

In all, 246 men with PE were recruited in this study. They were asked to take sertraline 50 mg daily for 2 weeks, and thereafter 100 mg daily, for a 12‐week treatment period. Pretreatment evaluation included history and physical examination, intravaginal ejaculatory latency time (IELT), and International Index of Erectile Function (IIEF). The efficacy of treatment was assessed using responses to IIEF, and geometric mean IELT evaluation. 5‐HTTLPR was genotyped using polymerase chain reaction techniques. A repeated‐measures analysis of variance of geometric mean IELT was done to test a genotype effect on treatment outcome with SSRI (sertraline).

RESULTS

Of 227 participants who completed the study, 175 (77.1%) responded to sertraline (IELT >1 min). Overall the patients had a 3.7‐fold (95% confidence interval, CI, 1.72–5.46) increase of the geometric mean IELT (P = 0.001). The results showed that responses were significantly better for the L_A/L_A genotype of the 5‐HTTLPR polymorphism than for S‐allele carriers (P = 0.001). The STin2 12/12 genotype was found more often in those responding to sertraline than in those not responding (P = 0.001). The probability of patients responding sufficiently to sertraline with an L_A/L_A genotype was highest (odds ratio 4.66, 95% CI, 2.48–6.14).

CONCLUSIONS

These findings indicate that the genotype of 5‐HTT contributes in unique ways to the variation in the outcome of PE treatment with SSRIs.     

Prognostic significance of thymidylate synthase polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy

Aim There is a lack of prognostic factors of preoperative chemoradiation for locally advanced rectal cancer. Thymidylate synthase (TS) is the most important target of 5‐fluorouracil; three main genetic polymorphisms of TS have been described. We analysed the prognostic value of these in patients with locally advanced rectal cancer treated with fluoropyrimidine‐based chemoradiation. Method Ninety‐nine patients treated between November 2001 and March 2009 were included. All were treated by radiotherapy (5040 cGy) and concomitant fluoropyrimidine‐based chemotherapy. Three polymorphisms were analysed: (i) a double (2R) or triple (3R) repeat of a 28 base pair (bp) tandem sequence upstream of the ATG codon initiation site in the 5′‐terminal regulatory region, (ii) a functional G > C single nucleotide polymorphism present in the second repeat of the 3R alleles and (iii) a 6 bp deletion at nucleotide 1494 in the 3′‐untranslated region. DNA was extracted from paraffin‐embedded core biopsies taken from the tumour and the genotype was analysed using polymerase chain reaction restriction fragment length polymorphism. Results The 6 bp polymorphism was significantly associated with disease‐free survival (+ 6 bp/+ 6 bp vs?6 bp/?6 bp, P = 0.032 logistic regression). No differences were found in disease‐free survival according to the other polymorphisms studied. No relationship was observed between the different TS genotypes and pathological regression. Conclusion The study suggests that the TS 6 bp polymorphism may be a predictor of disease‐free survival in patients with locally advanced rectal cancer treated with fluoropyrimidine‐based chemoradiation.     

Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

Background

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.

Objective

To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.

Design, setting, and participants

Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).

Outcome measurements and statistical analysis

Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.

Results and limitations

Eleven of 177 patients with MSH2 mutations (6.21%, p < 0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p > 0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p < 0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.

Conclusions

LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.     

Expression profiles and single-nucleotide polymorphism analysis of human HANP1/H1T2 encoding a histone H1-like protein

Recently we cloned the Hanp1 cDNA that encodes a histone H1-like haploid germ cell-specific nuclear protein in the mouse. Homozygous Hanp1 mutant male mice were infertile, while females were fertile. Although a substantial number of sperm were recovered from the epididymis, their shape and function were abnormal. Hanp1 protein is essential for nuclear formation in functional spermatozoa, and is specifically involved in the replacement of histones with protamines during spermiogenesis. To investigate the roles of human HANP1 (h-HANP1) and its relation to male infertility, we isolated h-HANP1 cDNA from a human cDNA plasmid library using mouse Hanp1 cDNA as a probe. h-HANP1 is expressed in the testes and its genomic construct also intronless as mouse Hanp1. We found that the h-HANP1 coding region have 5 single-nucleotide polymorphisms in Japanese men.     

CYP2C19基因多态性对质子泵抑制剂治疗胃食管反流病疗效影响的Meta分析

目的：系统评价药物代谢酶CYP2C19基因多态性与质子泵抑制剂治疗胃食管反流病疗效的关系,以期为临床治疗提供循证参考。方法检索PubMed、Embase、CBM、CNKI、WanFang data、CQVIP等数据库,收集CYP2C19基因多态性与质子泵抑制剂治疗胃食管反流病的临床文献。根据纳入和排除标准筛选文献、评价和提取数据后,采用RevMan 5.3软件进行Meta分析。结果共纳入4篇文献,包含347例对象。 Meta分析结果显示：CYP2C19强代谢型（EM）、中间代谢型（IM）与弱代谢型（PM）的胃食管反流病治愈率不存在统计学差异。结论 CYP2C19基因多态性不影响质子泵抑制剂对胃食管反流病的治愈率。     

染色体芯片检测下胎儿心脏发育异常与遗传学异常相关性

目的探讨研究染色体芯片检测下胎儿心脏发育异常与遗传学异常的相关性。方法选取2017年11月～2018年11月在本院接受产前检查显示异常的308例孕中期孕妇为研究对象,影像学检查心脏超声显示胎儿心脏发育异常孕妇18例为研究组,无胎儿心脏发育异常因高龄合并超声检查显示异常的290例孕妇为对照组,采集羊水行染色体核型分析和芯片分析。结果研究组胎儿复杂性心脏畸形15例,占83.33%,合并多发畸形3例,占16.67%;染色体异常3例,合并多发畸形1例,复杂性心脏畸形2例;芯片异常3例,合并多发畸形1例,复杂性心脏畸形2例。对照组胎儿正常78例,超声检查单发畸形178例,多发畸形34例,两组胎儿畸形率相比,差异有统计学意义(χ2=5.342,P=0.005);研究组染色体异常3例,占16.67%,对染色体正常的心脏发育异常胎儿进行芯片检查,芯片异常3例,芯片检查结果为10号染色体长臂末端片段缺失,对照组染色体均正常。结论胎儿心脏发育异常时合并遗传学异常几率增大,染色体芯片检测可有效诊断胎儿发育异常。