基于大家系设计的静息心率与常见慢性病双表型遗传度估计

目的 基于福建省南靖县土楼地区大家系,探索静息心率和常见慢性病(高血压、糖尿病、血脂异常)的单表型遗传度和双表型遗传度。方法 研究对象来源于2015年8月至2017年12月福建省漳州市南靖县土楼地区塔下村、曲江村、南欧村募集的张姓居民及其亲属,以及草坂村、图美村、背岭村募集的陈姓居民及其亲属。研究共纳入了来自452个大家系的1 563名研究对象。家系关系确定依据为家系信息登记及家谱。采用方差组分模型估计连续性变量的单表型、双表型遗传度,采用易患性-阈值模型估计二分类变量的单表型、双表型遗传度。结果 家系重建纳入了1个七代家系,2个五代家系,23个四代家系,186个三代家系和240个二代家系。研究对象的平均年龄为57.2岁,男性占39.4%。研究对象的高血压、糖尿病、血脂异常患病率分别为49.2%、10.0%、45.2%。单表型遗传度估计显示,静息心率遗传度为0.263(95%CI: 0.120~0.407),高血压遗传度为0.404(95%CI: 0.135~0.673), 血脂异常遗传度为0.799(95%CI: 0.590~1)。收缩压、舒张压、血糖、总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白的遗传度分别为0.379、0.306、0.393、0.452、0.568、0.852、0.387。双表型遗传度分析显示,静息心率与高血压、糖尿病、舒张压、血糖、甘油三酯存在表型相关性。双表型遗传度显示,静息心率与血糖(遗传相关性0.485,95%CI: 0.120~1,P<0.05)和糖尿病(遗传相关性0.795,95%CI: 0.181~0.788,P<0.05)具有较强的遗传相关性。结论 静息心率是一个可遗传性状,其与常见慢性病及其相关指标存在相关性。静息心率与糖尿病和血糖值具有较强的遗传相关性,提示静息心率与糖尿病和血糖之间可能存在共同的遗传基础。     

2型糖尿病家系遗传特征的初步分析

目的 对2型糖尿病(T2DM)家系的遗传特征进行初步分析.方法 对有2例或2例以上T2DM患者的715个家系共4468名成员(包括配偶),由专门小组调查并采血样进行分析.结果 4468名成员中T2DM和糖调节受损(IGR)总患病率为47.62%,新检出T2DM患者218例,IGR患者422例.一级亲属中同胞T2DM、IGR的患病率分别为38.33%、14.25%,父母分别为56.81%、12.58%,均高于二级亲属(9.55%、6.10%)及无T2DM家族史的配偶患病率(10.57%、9.55%,均P＜0.01).先证者的子女IGR患病率及新检出率(12.46%、11.73%)明显高于配偶(9.55%、9.55%,均P＜0.01).结论 T2DM的发病具有明显的家族聚集性,其一级亲属是T2DM和IGR的高危人群,对该人群宜开展早期筛查及长期监测.     

2型糖尿病家系一级亲属同胞腰臀股围的变化

目的：研究2型糖尿病家系一级亲属同胞糖代谢异常及糖耐量正常者的腰、臀、股围变化及其意义。方法：在560个临床表现为2型糖尿病的家系中，去除1型糖尿病、线粒体糖尿病和收集标本数少的家系后，得406个2型糖尿病家系，将其家系一级亲属同胞成员分为正常糖耐量组（NGT组，425例）、糖耐量减退组（IGT组，79例）、糖尿病组（DM组，694例），并以同胞配偶中的无糖尿病家族史的正常糖耐量者作为对照组（C组，429例），比较各组间腰、臀、股围及其各个比值的6个参数的差异。结果：DM组腰围、腰臀比、腰股比、臀股比高于C组，臀围、股围低于C组（腰围P＝0．0059，余均＜0．001）。NGT组腰臀比，腰股比大于C组（P分别显0．0009，0．0045），股围小于C组（P＝0．0321），均有显著差异。腰围、腰臀比、腰股比在X组、NGT组、IGT组、DM组有逐渐增高趋势，臀围、股围在四组有逐渐减低趋势。去除用胰岛素治疗，或体重指数＜20kg/m^2或空腹血糖＞14mmol/L者比较6个参数在4组中的差异，显示上述变化趋势更显著。结论：糖代谢异常患者，随着糖代谢异常的加重，其体脂有重新分布，逐渐向中心性肥胖发展的趋势。即腹围渐大，臀围，尤其是股围有逐渐相对缩小的趋势。值得注意的是2型糖尿病家系同胞一级亲属中的糖耐量正常者已不同于群体中的糖代谢正常者，开始出现此种变化趋势，可能与遗传因素有关。     

心肌梗死家系女性成员血清雌激素、睾酮及其比值的变化

目的探讨心肌梗死家系女性成员雌激素、睾酮及其比值变化,以及其在心肌梗死家系这组特殊人群中女性冠心病发病机制中的作用。方法将15个合格心肌梗死家系中女性成员分为冠心病组和一级亲属健康组,设立健康对照组。应用放射免疫法测量每个受试对象血清雌激素和睾酮的水平,并对血清雌激素/睾酮与血脂各项指标进行相关性分析。结果与对照组相比,各组之间年龄和血压等无统计学意义上的差异,心肌梗死家系中冠心病组雌激素水平与对照组及一级亲属健康组无统计学上的差异,但是睾酮水平高于一级亲属健康组及对照组(分别为18.07比13.27比13.08 mol/L,P<0.05);冠心病组血清雌激素/睾酮比值显著低于一级亲属健康组及对照组(分别为16.71比23.25比24.87,P<0.05),而一级亲属健康组与对照组之间差异无显著性(P>0.05)。相关性分析显示,血清雌激素/睾酮比值与高密度脂蛋白胆固醇呈正相关,与胆固醇、低密度脂蛋白胆固醇和甘油三酯呈负相关。结论在心肌梗死家系这个特殊人群中女性内源性雌激素水平与心绞痛、心肌梗死之间未见相关性,而内源性雄激素水平与之则可能有正相关性,高睾酮血症及低血清雌激素/睾酮比值可能通过对血脂代谢来影响和促进冠心病的发生、发展。     

Expression of green fluorescent protein under the regulation of human locus control region elements HS2 and HS3 in transgenic mice

Human beta-globin locus control region (LCR) is composed of five DNase I hypersensitive sites (HSs). We previously demonstrated that when HS2 and HS3 were constructed together in one vector and integrated into one position in transgenic mice, the two cis-elements showed a marked synergy in regulating the spatial and temporal expression of beta-globin transgene. This study is to investigate whether these two elements still show a synergy or superposition when they are not located in one construct. HS2/GFP and HS3/GFP transgenic mice, with the transgene encoding green fluorescent protein (GFP) driven by beta-globin promoter and under the control of HS2 (HS2/GFP mice) and HS3 (HS3/GFP mice), were mated to generate double-heterozygotes (HS2/GFP + HS3/GFP mice). The expression and integration status of GFP genes in transgenic mice were analyzed. Our data showed that there was no difference in the percentages of GFP positive cells in peripheral blood between double-heterozygotes and their corresponding founders (HS2/GFP or HS3/GFP). Interestingly, it was observed that exogenous GFP genes were highly expressed in another transgenic mouse pedigree with HS2 element integrated twice into the same chromosome at two different loci. However, when one site was lost in some offspring because of recombination, the percentages of GFP positive cells in peripheral blood as well as in some erythroid tissues were decreased obviously. These results demonstrated that HS2 and HS3 elements would not show any synergy or superposition if they were located on different chromosomes in transgenic mice, and that HS2 element containing the core and flanking sequences might not be able to overcome the position effects and control position dependent expression of linked genes in transgenic mice.     

Best卵黄样黄斑营养不良一家系的基因突变型及临床表型

目的探究Best卵黄样黄斑营养不良(Best vitelliform macular dystrophy,BVMD)一家系的基因突变表型及临床特点方法回顾性分析BVMD一家系所有患者详细病史资料及检查结果,眼部检查包括视力、色觉、裂隙灯、散瞳眼底检查、光学相干断层扫描等,根据眼底表现对BVMD病变进行分期,了解BVMD中儿童及成人发病特点的相关差异。对家系中有关直系亲属取外周静脉血行基因分析,通过靶向捕获高通量测序,对BVMD致病基因进行分析,寻找可能致病突变。结果 8名家庭成员中5例为BVMD患者,其中1例2眼为Ⅱ期,3例5眼为Ⅲ期,1例1眼为Ⅳ期,1例2眼为V期。基因检查结果为常染色体显性遗传,BEST1 (OMIM607854)基因c.238T>C;p.Phe80Leu杂合突变。结论此家系呈现常染色体显性遗传,基因检测对于BVMD的诊断及遗传学咨询具有重要作用。在同一分期中儿童患者眼底表现较重,需更密切的随访监测。OCT可作为此类疾病随访的监测指标。     

细胞色素P450氧化酶基因MSP1位点多态性与早产的关联性研究

目的:探讨早产与母、婴细胞色素P450氧化酶基因(CYP1A1)MSP1位点多态性的关系.方法:于1999年到2001年,采用病例对照及核心家系的研究设计,在安徽省安庆市调查了496个核心家系,包括247个正常孕周出生的核心家系(对照核心家系)和249个早产核心家系.采用盐沉淀法提取基因组DNA,通过聚合酶链式反应(PCR)对细胞色素P450氧化酶基因MSP1位点进行基因型鉴定.采用对数-线性回归模型(log-linear model)分析母亲和婴儿CYP1A1基因MSP1位点多态性与早产的关联.观察母亲与婴儿CYPlAl基因之间的联合作用是否对早产有影响,并采用TDT方法检验早产对照核心家系CYPlAl基因MSP1位点、等位基因传递是否平衡.结果:婴儿CYPlAl基因C/C6235基因型能明显增加早产的发生危险性(RR=1.80,95%CI=1.02～3.18).同时,我们也发现母亲CYPlAl基因C/C6235基因型对早产有显著影响(RR=1.82,95%CI=1.11～2.98).母亲与婴儿CYPlAl基因之间无明显联合作用存在.对照核心家系CYPlAI基因MSP1突变等位基因传递符合孟德尔遗传规律.结论:婴儿CYPlAl基因C/C6235基因型和母亲C/C6235基因型均能够明显增加早产发生风险,在早产核心家系中CYPlAl基因MSP1突变等位基因传递不符合孟德尔遗传规律,可能是导致早产的遗传易感位点.     

Pedigree likelihood formulae based on founder and founder couple symmetry and validation of DNA testing software

Pedigree likelihood ratios are widely used in forensic genetics. Linkage of genetic markers affects the pedigree likelihood ratio. In this study, a series of novel formulae was established based on simplification due to founder and founder couple symmetry of the Lander-Green algorithm for dealing with linkage. These new formulae are based on the inheritance vectors and differ from existing formulae that are based on the number of alleles shared identical-by-descent. In contrast to previous formulae, the formulae of this study expand the calculation to more general relationships, which enables specifying the number of typed individuals in pedigrees, and the new formulae are no longer limited to calculation of pairs of linked markers. Alternatively, pedigree likelihood values incorporating multiple linked markers could be obtained by iterating the vector transition probability between pairs of linkage markers and the probability of genotypes of typed individuals given inheritance vectors; the vector transition probability formulae are provided in a table form. To demonstrate utilization of the proposed formulae system, a series of cases were designed based on the relationships to validate GeneVisa software (www.genevisa.net) with frequency data of three linked markers, SE33-D6S1043-D6S474, on chromosome 6. The calculation results were verified with the FamLink software. The results demonstrated that the proposed formulae can correctly obtain the pedigree likelihood ratio, demonstrating the application potential of these formulae to verify effectiveness of DNA testing software.