DVL2基因多态性与中国汉族人群先天性脊柱侧凸遗传易感性的关联研究

背景：近20年来小鼠的分子胚胎学研究进展获得了大量关于脊椎发育的分子信息,用同线性分析法确立先天性脊柱侧凸的候选基因已成为可能。 目的：通过候选基因DVL2上关键单核苷酸多态性位点的筛查,探索DVL2与中国汉族人群先天性脊柱侧凸及其不同临床表型之间的关联。 方法：采用病例-对照研究,入选127例中国汉族先天性脊柱侧凸患者和127例对照组。根据国际人类基因组单体型图计划提供的基因型数据,应用Haploview 4.1软件选取DVL2的标签和功能单核苷酸多态性。根据椎体畸形特点、畸形部位、畸形受累程度、有无合并肋骨畸形和椎管内畸形将病例组进一步分为不同临床表型。对所有样本应用SNPstream UHT Genotyping系统对所选单核苷酸多态性位点进行基因型鉴定;进一步进行基于基因型/等位基因频率的关联分析,并用Haploview 4.1软件分析对照组单核苷酸多态性位点间是否存在连锁不平衡。 结果与结论：共筛选5个位点：单核苷酸多态性1(rs2074222)、单核苷酸多态性2(rs222837)、单核苷酸多态性3(rs222835)、单核苷酸多态性4(rs10671352)和单核苷酸多态性5(rs222836),其基因型分布在病例和对照组中均符合Hardy-Weinberg平衡;5个位点处于完全连锁不平衡状态;5个位点的基因型/等位基因/单倍体型与先天性脊柱侧凸的发生风险之间不存在相关性。在进一步与先天性脊柱侧凸临床表型的关联分析中没有发现阳性位点。提示在中国汉族人群中DVL2基因可能不是引起先天性脊柱侧凸及其不同临床表型的主要因素,有待于进一步深入研究。     

白细胞介素16基因多态性与广西地区汉族女性膝关节原发性骨性关节炎的易感关联

背景：目前的基因研究表明,膝关节原发性骨性关节炎的发病风险与白细胞介素类基因有关联性。 目的：观察白细胞介素16基因多态性与女性膝关节原发性骨性关节炎的相关性。 方法：收集71例Kellgren/Lawrence评分大于2分的膝关节原发性骨性关节炎患者及85例健康对照的广西汉族女性的静脉血标本,采用聚合酶链反应-限制性片段长度多态性技术对两组白细胞介素16的 rs11556218,rs4072111,rs4778889多态位点进行基因分型,计算两组基因型和等位基因的分布差异,分析白细胞介素16基因多态性与膝骨性关节炎的易感关联。 结果与结论：两组3个SNP位点的各基因频数在两组中的分布符合Hardy-Weinberg平衡,等位基因比较差异无显著性意义。单个位点显性模式非条件Logistic回归显示,在rs11556218的3种基因型的比较中,T/G基因型较T/T基因型的膝原发性骨性关节炎的发病风险显著减低(OR=0.41,95%CI：0.21~0.83,P=0.02);在rs4072111中,C/T基因型比C/C基因型的发病风险显著增加(OR=2.36,95%CI：1.19~4.68,P=0.03)。结果证实,广西地区汉族女性人群白细胞介素16的遗传变异与膝关节原发性骨性关节炎的易感性关联。     

基质金属蛋白酶9基因多态性与汉族女性青少年特发性脊柱侧凸的关联分析

目的 探讨基质金属蛋白酶9 (matrix metalloproteinase 9,MMP9)基因多态性与汉族女性青少年特发性脊柱侧凸(adolescent idiopathic scoliosis,AIS)发生和发展的关系.方法 以rs17576、rs2250889、rs1805088 3个标签单核苷酸多态性(single nucleotide polymorphisms,SNPs)作为遗传标记,通过TaqMan荧光探针法对190例AIS患者和190名年龄匹配汉族女性正常对照进行等位基因分型.对结果进行Hardy-Weinberg遗传平衡检验、Pearson x2检验、非条件Logistic回归分析、连锁不平衡检验和单倍型分析,并分析基因型与表型的关系.结果 正常对照组rs17576、rs2250889、rs1805088 3个位点基因型分布符合Hardy-Weinberg平衡(P＞0.05);基因型-表型分析发现rs2250889位点基因型为CC的患者的最大Cobb角(48.50°)大于基因型为GG(25.98°)或GC(28.35°)者(P＜0.05),其侧凸程度较严重.结论 目前尚不能认为MMP9基因是汉族女性AIS的易感基因,但rs2250889纯合变异者脊柱侧凸较严重,提示MMP9异常可导致脊柱侧凸的进展.     

广西百色地区壮族男性人群骨密度与脂联素基因单核苷酸多态性的关系

背景：脂联素可在骨代谢中发挥重要作用。 目的：观察脂联素基因单核苷酸多态性与广西百色地区壮族男性骨密度的关系。 方法：选取广西百色地区壮族男性跟骨骨量减少患者,采用单碱基延伸的单核苷酸多态性分型技术对广西百色地区302例壮族男性的脂联素基因的5个单核苷酸多态性位点(rs1063539、rs12495941、rs266729和rs3774261)进行了基因分型。 结果与结论：以5个多态性位点作为自变量的多元 Logistic回归检测结果显示,仅rs3774261多态性与跟骨超声振幅衰减显著相关(OR=1.948,95%CI：1.184~3.203,P < 0.01),并独立于骨量减少的传统危险因素。对基因型进行纯合子与杂合子合并后的协方差分析显示,仅rs3774261的AG+GG与AA基因型的跟骨超声振幅衰减值差异有显著性意义(P < 0.05),AG+GG型对骨密度具有一定的保护作用,AA型是骨密度降低的危险因素。结果证实,脂联素基因第2内含子rs3774261位点多态性与中国百色地区壮族男性骨密度有一定关联。     

中国北方汉族人群中载脂蛋白M基因多态性分布特征及连锁不平衡分析

目的研究中国北方汉族人群中载脂蛋白M基因（apolipoprotein M,APOM）多态性分布特征及其连锁不平衡关系。方法采用PCR扩增基因组DNA直接测序法结合PCR-限制性片段长度多态方法对330名中国北方汉族健康人群的APOM基因单核苷酸多态性（single nucleotide polymorphism,SNP）进行分析。结果中国北方汉族人APOM基因存在1号内含子rs805264位点、5号内含子rs707922位点及rs707921位点3个多态位点,不同种族及地区APOM基因SNP差异有统计学意义。APOM基因rs805264位点、rs707922位点及rs707921位点SNP在中国北方汉族人群中呈现明显的连锁不平衡,主要有G-G-C、A-T-A两种单体型。结论APOM基因SNP在中国北方汉族人群中存在显著连锁不平衡。     

Interleukin-18基因启动子区单核苷酸多态性与肝细胞癌遗传易感性关系的研究

目的探讨白细胞介素18(IL-18)基因启动子区-607C/A(rs1946518)和-137G/C(rs187238)单核苷酸多态性(SNP)与肝细胞癌(肝癌)遗传易感性的关系。方法应用序列特异性引物-聚合酶链反应(PCR-SSP)技术,检测228例肝癌患者和300例健康对照者IL-18基因启动子-607C/A(rs1946518)、-137G/C(rs187238)单核苷酸多态性位点基因型,分析肝癌患者和对照组基因型频率和等位基因频率分布。结果肝癌组SNP位点rs187238 G等位基因的频率明显高于对照组(OR=1.1891,95%CI=1.0106-1.5633,P=0.026)。携带rs187238 GG基因型的肝癌患者较多(OR=1.5168,95%CI=1.1490-1.8322,P=0.010)。分层分析发现,rs1946518位点上AA基因型与肝癌发病的关联在饮酒的肝癌患者中更加显著(P=0.024),而且rs187238位点上GC/CC基因型与肝癌发病的关联在出现肝癌复发的患者中更加显著(P=0.005)。结论 IL-18基因启动子区-137G/C(rs187238)GG基因型与肝癌遗传易感性有关联。而rs1946518位点AA基因型和rs187238位点GC/CC基因型分别与肝癌患者饮酒和肝癌复发有关联。     

白细胞介素10启动子基因多态性与强直性脊柱炎的易感性

背景：在强直性脊柱炎患者中,基因多态性很可能影响细胞因子的分泌模式。 目的：在中国胶东半岛地区汉族人强直性脊柱炎患者中,探讨白细胞介素10启动子基因的单核苷酸多态性和单体型与强直性脊柱炎易感性的相关性。 方法：用酶联免疫吸附测定法测定血清中白细胞介素10的水平,用聚合酶链反应和限制性片段长度多态性方法对白细胞介素10基因启动子中的-1082A/G、-819C/T和-592C/A位点的单核苷酸多态性进行分析。 结果与结论：收集了110例强直性脊柱炎患者和120例同种族的健康人,强直性脊柱炎患者组血清中白细胞介素10水平明显高于健康对照组(Z=10.9,P < 0.001),单核苷酸多态性分析显示：在强直性脊柱炎患者组和健康对照组之间-592A/C位点基因型分布和等位基因频率没有明显差异,该研究中没有发现-1082GG基因型。强直性脊柱炎患者-1082G等位基因频率较健康对照组增加(P=0.047),通过logistic回归分析,强直性脊柱炎患者-1082AG基因型的比值比为1.993(95%CI：1.046-3.800,P=0.034 ),而-819CC基因型的比值比为3.125(95%CI：1.246-7.836,P=0.015),此外,单体型分析显示与ATA 基因型相比,GCC基因型显著增加了患强直性脊柱炎的风险(OR=2.19,95%CI：1.13- 4.26,P= 0.020)。结果表明白细胞介素10的基因单体型与中国胶东半岛地区汉族人强直性脊柱炎的易感因素相关。     

内质网氨基肽酶-1基因(ERAP1)多态性与闽南地区汉族人群强直性脊柱炎关联性研究

本研究探讨内质网氨基肽酶-1基因(endoplasmic reticulum aminopeptidase 1,ERAP1)单核苷酸多态性与闽南地区汉族人群强直性脊柱炎(ankylosing spondylitis,AS)的相关性。选取经纽约诊断标准确诊的闽南地区汉族149例强直性脊柱炎患者(AS组)与150例健康人群(对照组),应用SNaPshot单碱基延伸反应测定所有研究对象ERAP1的10个SNP位点(rs26653、rs7711564、rs27980、rs30187、rs2287987、rs10050860、rs27529、rs17482078、rs27038、rs27044)基因型。结果显示,ERAP1的3个SNP位点rs27044(OR=1.324,P=0.001)、rs30187(OR=1.224,P=0.011)、rs27980(OR=1.220,P=0.005)位点基因型在闽南地区汉族人群AS组和正常对照组之间比较具有显著性差异(P0.05),其罕见等位基因是AS发病的危险因素,rs26653、rs7711564、rs2287987、rs10050860、rs27529、rs17482078、rs27038等SNP位点两组之间比较无统计学差异(P0.05)。本研究表明ERAP1基因单核苷酸多态性rs30187、rs27044、rs27980与闽南地区汉族人群强直性脊柱炎相关,进一步证实了该rs27044位点的等位基因(G)、rs30187位点的等位基因(T)、rs27980位点的等位基因(C)基因是强直性脊柱炎的易感基因。     

4p14区段和CTLA-4基因多态性与Graves病相关

目的探讨中国安徽蚌埠地区汉族人群4p14区段位点rs6832151和CTLA-4基因4个SNPs(单核苷酸多态性)位点基因多态性与Graves病相关性,和基因-基因交互作用对Graves病的影响。方法提取611例诊断明确的GD患者和644名健康对照者的全基因组DNA,用Taq Man探针技术进行基因分型,使用Plink和Haploview等统计软件分析这些位点与蚌埠地区汉族人群Graves病的相关性。结果 4p14区段位点rs6832151的等位基因、基因型频率在GD组和对照组之间有差异(P0.05),CTLA-4基因区域内rs231804和rs231726两个SNP位点基因型在显性模型下差异显著(P0.05);GMDR模型显示CTLA-4基因内rs10197319、rs231726、rs231804、rs1024161位点和4p14区段内rs6832151位点组成的五阶模型(P=0.001)为最佳模型,CTLA-4基因内rs1024161和rs10197319位点之间上位效应分析结果有差异(P0.05)结论 4p14区段rs6832151,CTLA-4基因区域内rs231804和rs231726位点基因多态性与蚌埠地区汉族人群Graves病的遗传易感性相关;rs6832151(4p14区段)和rs10197319、rs231726、rs231804、rs1024161(CTLA-4基因)5个SNP位点间的基因-基因交互作用与Graves病相关,CTLA-4基因内rs1024161和rs10197319位点之间存在上位效应。     

抑郁症与cAMP反应元件结合蛋白基因的关联研究

目的 探讨cAMP反应元件结合蛋白(cyclic adenosine monophosphate response elementbinding protein,CREB1)基因与抑郁症的关联关系.方法 采用聚合酶链反应-限制性片段长度多态性方法检测105个抑郁症核心家系CREB1基因上单核苷酸多态性(single nucleotide polymorphisms,SNP)rs10932201和rs6740584的等位基因与基因型分布情况.进行单位点及单倍型的传递/不平衡检验(transmission disequilibrium test,TDT).结果 CREB1基因上SNP位点rs10932201和rs6740584与抑郁症均无显著性关联,TDT χ2 值分别为2.700(P=0.1004)和0.458(P=0.4986),差异均无统计学意义.单倍型TDT分析结果显示由rs10932201和rs6740584构成的单倍型与抑郁症存在显著性关联,差异有统计学意义(总χ2=23.458,df=3,P=0.00003241).单个单倍型A-C和A-T与抑郁症也均有显著性关联,差异有统计学意义(χ2 值分别为5.405和13.623,P值分别为0.020和0.00022).结论 CREB1基因上SNP位点rs10932201和rs6740584与抑郁症均无显著性关联,但由这2个SNP位点构成的单倍型与抑郁症存在显著性关联,提示CREB1基因rs10932201-rs6740584单倍型可能在抑郁症的遗传学发病机制中具有重要作用.     

A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility

Genome-wide association studies for breast cancer have identified over 40 single-nucleotide polymorphisms (SNPs), a subset of which remains statistically significant after genome-wide correction. Improved strategies for mining of genome-wide association data have been suggested to address heritable component of genetic risk in breast cancer. In this study, we attempted a two-stage association design using markers from a genome-wide study (stage 1, Affymetrix Human SNP 6.0 array, cases=302, controls=321). We restricted our analysis to DNA repair/modifications/metabolism pathway related gene polymorphisms for their obvious role in carcinogenesis in general and for their known protein-protein interactions vis-à-vis, potential epistatic effects. We selected 22 SNPs based on linkage disequilibrium patterns and high statistical significance. Genotyping assays in an independent replication study of 1178 cases and 1314 controls were attempted using Sequenom iPLEX Gold platform (stage 2). Six SNPs (rs8094493, rs4041245, rs7614, rs13250873, rs1556459 and rs2297381) showed consistent and statistically significant associations with breast cancer risk in both stages, with allelic odds ratios (and P-values) of 0.85 (0.0021), 0.86 (0.0026), 0.86 (0.0041), 1.17 (0.0043), 1.20 (0.0103) and 1.13 (0.0154), respectively, in combined analysis (N=3115). Of these, three polymorphisms were located in methyl-CpG-binding domain protein 2 gene regions and were in strong linkage disequilibrium. The remaining three SNPs were in proximity to RAD21 homolog (S. pombe), O-6-methylguanine-DNA methyltransferase and RNA polymerase II-associated protein 1. The identified markers may be relevant to breast cancer susceptibility in populations if these findings are confirmed in independent cohorts.     

经典中医古方治疗骨质疏松症的系统评价

背景：经典中医古方在针对骨质疏松症的治疗中有着较好的疗效,但以系统科学方法进行Meta分析以明确其总体疗效的报道不多。 目的：系统评价中医经典古方在治疗骨质疏松症的疗效性和安全性,为经典古方在骨质疏松症中的应用提供依据。 方法：计算机检索中国期刊全文数据库(2001/2010)、中国重要会议论文全文数据库(2001/2010)、维普数据库(2001/2010)等国内各大数据库,手工检索所有纳入文献的参考文献。纳入经典中医古方治疗骨质疏松症的随机对照试验(RCT)。评价纳入研究的方法学质量并进行资料提取后,采用RevMan4.2软件进行Meta分析。 结果与结论：共纳入包括1 235例受试者在内的随机对照试验17个,Jadad评分4个2分,其余均为1分,且所有研究均处于C级,质量不高。经典古方与单纯西药治疗相比,总体疗效合并OR=3.82, 95%CI[2.70~5.41];症状积分WMD=-1.95,95%CI[-2.19~1.72];腰椎骨密度WMD=0.04,95%CI[0.03~0.06],其他部分骨密度WMD=0.04,95%CI[0.03~0.06]。经典古方加西药对比西药,总有效率OR=3.09,95%CI[1.58~6.07]。提示现有临床研究证据表明中医经典古方在治疗骨质疏松症方面存在一定的优势,未见明显不良反应的报道。     

非手术与手术修复急性闭合性跟腱断裂的Meta分析

背景：关于非手术及手术修复急性跟腱断裂一直存在争议,相关研究多为回顾性分析,缺乏高等级循证医学证据。 目的：系统评价非手术与手术修复急性闭合性跟腱断裂临床疗效。 方法：计算机检索 PubMed、EMbase、The Cochrane Library(2014年第1期)、CBM、CNKI、Ovid及WanFang Data,手工检索相关杂志,检索时限均从建库或建刊至2014年2月,纳入非手术治疗与手术治疗急性闭合性跟腱断裂的随机对照试验,由2名研究人员独立提取文献数据及质量评价后,用RevMan 5.2软件进行系统评价。 结果与结论：最终纳入9篇随机对照文献,患者共874例,非手术组441例,手术组433例。Meta分析结果显示,与手术组相比较,非手术组总的并发症率更低[OR=0.41,95%CI(0.26,0.63),P < 0.000 1],但跟腱再断裂率高[OR=2.86,95%CI(1.62,5.02),P=0.000 2],瘢痕粘连=0.07,95%CI(0.03,0.19),P < 0.000 1]。而两者在患者满意度、浅表感染、恢复正常运动、深部感染等方面,差异均无显著性意义(P > 0.05)。非手术修复与手术修复急性闭合性跟腱断裂相比,可有效降低总的并发症及瘢痕粘连率,但跟腱再断裂率较高。受样本量及方法质量学的限制,以上结论需要更多大样本、多中心、高质量的随机对照试验验证。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder.

Synaptosomal-associated protein of 25 kDa (SNAP-25), a protein involved in presynaptic neurotransmitter release, is a candidate gene for attention deficit/hyperactivity disorder (ADHD). Previous investigators have reported association initially with two single nucleotide polymorphisms (SNPs) (rs3746544, rs1051312) and their associated haplotypes. Subsequently, additional SNPs across the region were also reported to be associated with ADHD. We attempted to replicate these observations in a sample of 229 families with ADHD offspring by genotyping 61 SNPs spanning the region containing SNAP-25. A single SNP (rs3787283) which is in strong linkage disequilibrium (LD) with rs3746544 and rs1051312 (D' = 0.89-0.94) resulted in a nominally significant association (P = 0.002). When we pooled our data with those from prior studies, results were modestly significant for rs3746544 (P = 0.048) and rs6077690 (P = 0.031). As an attempt to determine if specific ADHD-related phenotypes may be more relevant to SNAP-25 than the categorical diagnosis, we carried out exploratory subgroup analysis in our ADHD sample according to co-morbid status. We found the strongest association result in the ADHD patients with co-morbid major depressive disorder (MDD). Six SNPs were nominally associated with the ADHD and co-morbid MDD cases (P = 0.012-0.045). Furthermore, a haplotype block located 11 kb 3' of the gene showed positive evidence for association with this phenotype (global P = 0.013). In conclusion, we report some evidence supporting the association of previously implicated SNPs (rs3746544, rs1051312) of SNAP-25 to ADHD. We further suggest that co-morbidity with MDD may enhance detection of the association between SNAP-25 and ADHD.     

Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia.

The glutamatergic dysfunction has been implicated in pathophysiology of schizophrenia. The Group III metabotropic glutamate receptor 4 (mGluR4), 6, 7, and 8 are thought to modulate glutamatergic transmission in the brain by inhibiting glutamate release at the synapse. We tested association of schizophrenia with GRM8 using 22 single nucleofide polymorphisms (SNPs) with the average intervals of 40.3 kb in the GRM8 region in 100 case-control pairs for the SNPs. Although we observed significant associations of schizophrenia with two SNPs, SNP18 (rs2237748, allele: P = 0.0279; genotype: P = 0.0124) and SNP19 (rs2299472, allele: P = 0.0302; genotype: P = 0.0127), none of two SNPs showed significant association with disease after Bonferroni correction. Both SNP18 and SNP19 were included in a large region (>330 kb) in which SNPs are in linkage disequilibrium (LD) at the 3' region of GRM8. We also tested haplotype association of schizophrenia with constructed haplotypes of the SNPs in LD. Significant associations were detected for the combinations of SNP5-SNP6 (chi(2) = 18.12, df = 3, P = 0.0004, P corr = 0.0924 with Bonferroni correction), SNP4-SNP5-SNP6 (chi(2) = 27.50, df = 7, P = 0.0075, P corr = 0.015 with Bonferroni correction), and SNP5-SNP6-SNP7 (chi(2) = 23.92, df = 7, P = 0.0011, P corr = 0.0022 with Bonferroni correction). Thus, we conclude that at least one susceptibility locus for schizophrenia is located within the GRM8 region in Japanese.     

Polymorphism in the insulin-like growth factor 1 gene is associated with age at menarche in caucasian females

BACKGROUND: The insulin-like growth factor 1 (IGF1) gene, which plays a crucial role in hypothalamic-pituitary-ovarian hormone-controlled metabolic processes, may influence the onset of menarche. Our study aimed to test association between IGF1 polymorphisms with the variation of age at menarche (AAM) in Caucasian females. METHODS: We recruited a sample of 1048 females from 354 Caucasian nuclear families and genotyped 19 single-nucleotide polymorphisms (SNPs) spanning the entire IGF1 gene. Pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both single SNP markers and haplotypes were tested for association with AAM using the quantitative transmission disequilibrium test. RESULTS: Significant association (P = 0.0153) between AAM and SNP3 (rs6214) in block1 was detected. CONCLUSIONS: Our results suggested a potential effect of SNP3 in the IGF1 gene on AAM variation in Caucasian women for the first time. However, further independent studies are needed to confirm our findings.     

SOD2 V16A SNP in the Mitochondrial Targeting Sequence is Associated with Noise Induced Hearing Loss in Chinese Workers

Objective: To investigate whether single nucleotide polymorphisms (SNPs) in the Mn-superoxide dismutase gene (SOD2) underlie the susceptibility to noise-induced hearing loss (NIHL). Methods: Audiometric data from 2400 Chinese Han workers who exposed to occupational noise were analyzed. DNA samples were collected from the 10% most susceptible and the 10% most resistant individuals, and five SNPs (SOD2 rs2842980, rs5746136, rs2758331, rs4880 and rs5746092) were genotyped by Taqman SNP Genotyping Kits. The SNP main effects and interactions between noise exposure and SNP were analyzed using logistic regression. Haplotypes were analyzed by using Haploview software. Results: The CT genotype of rs4880 (SOD2 V16A SNP) was associated with a higher risk of NIHL (covariates-adjusted OR, 2.18; 95% CI, 1.34–3.54, P = 0.002). Haplotype analysis revealed that the frequency of AGCCG at the five SNP loci was significantly higher in the susceptible group (P = 0.020). With AGCTG as the reference, the OR (95% CI) was 2.63 (1.14, 6.06). The rs4880 polymorphisms imposed larger effects when the carriers were exposed to higher levels of noise, indicating the interaction between SNP and noise exposure. Conclusions: Our results suggest that SOD2 V16A SNP in the mitochondrial targeting sequence is associated with noise induced hearing loss in Chinese workers, and this effect was enhanced by higher levels of noise exposure.