摘要
人类正致力于对各种疾病致病基因的研究,试图找到各种疾病的致病基因,研究其发病机理的分子机制,从而达到对疾病的预防和控制。迄今为止,已有大部分疾病的致病基因被报道,甚至在心血管疾病领域,已有超过30种疾病的致病基因通过分子克隆方式被发现。但是,危险人类生命的众多疾病通常是复杂性疾病,例如糖尿病、冠心病等,通常与复杂性疾病有关的,还有许多数量性的生理、生化指标。这类疾病或者指标,通常并非由单一基因所调控,而是由多个基因所调控。因此,这种多基因调控的复杂性疾病和相关指标的研究对方,通常是以下两种：1,由核心家系组成的人群；2,散发人群。两种人群各具优势：核心家信组成的人群,更强调遗传背景,但取样较难；散发人群却取样较为简单,通常容易获得大样本量。复杂性多基因疾病的现代分子医学遗传学方法主要也由两种：1,连锁分析；2,关联分析。连锁分析通常选用微卫星标记,具有多种等位基因,但密度小；相对来说,关联分析使用的是单核苷酸多态性分子标记(SNP),一个SNP只带有两个等位基因,但SNP密度大,能对SNP进行分型的技术手段多。
本文主要研究了冠心病的两个主要影响因子——HDL-C和甘油三脂的数量性状位点,用到了上文所述的两种人群和两种分析方法,发现了迄今为止最为显著的影响HDL-C水平的新位点,有利于今后对影响HDL-C水平的多态和基因的发现,希望对冠心病的预防和治疗,起到积极功效。
在第一部分中,本研究首先对一个388个早发冠心病核心家系(共714个个体)进行了连锁分析,通过全基因组连锁分析,找到了两个同HDL-c显著相关的数量性状位点(QTL)：7p22以及15q25,最高多点LOD值分别为3.76和6.69。之后我们使用微卫星标记和单核苷酸多态标记对以上两个位点进行了精细定位,结果显示,7p22位点的最高多点LOD值降到了3.09,达不到显著标准,因此不是一个与HDL-C显著相关的QTL；15q25位点经过精细定位之后,被分割成了两个相连QTLs——15q22(LOD值2.73)和15q25(LOD值5.63)。其中,15q22QTL下有LIPC基因,基因启动子区SNP rs1800588通过QTDT计算被证明在我们的人群中与HDL-C水平显著相关(P=0.0067),表明15q22 QTL可能是由rs1800588所导致的。15q25位点则是迄今为止被发现的最为显著的影响HDL-C水平的QTL,这个位点的发现,也为今后对HDL-C调节机制的研究提供了新的线索。
文章第二部分,新近被报道的3个与HDL-C相关的SNPs和6个与甘油三酯相关的SNPs (rs1323432、rs2338104、rs4846914、rs16996148、rsl7321515、rs17145738、rsl748195、rs12130333),亟待在其他人群中得以验证。本研究采用1231个心肌梗塞病人和560个正常对照,对以上8个SNPs进行了基因分型,对于所得结果,运用General linear model进行统计学计算,以期在我们的1231心梗病人和560正常人中验证以上SNPs。结果显示,3个在全基因组关联分析中与HDL-C显著相关SNPs:rs1323432、rs2338104和rs4846914,无论是在1231心梗病人群体中,还是560正常人群中,亦或是合并人群中,均与HDL-C的水平不相关；6个在全基因组关联分析中与HDL-C显著相关SNPs:rs4846914、rs16996148、rs17321515、rs17145738、rs1748195、rs12130333也显示了类似的结果,在我们的1231心梗病人群体、560正常对照群体以及合并群体中,均与甘油三酯水平不相关。之后,我们开展了这8个SNPs与心肌梗死的关联分析,结果显示,rs12130333 SNP有可能与心肌梗塞有关(P=0.007,OR=0.773),但仍然达不到显著标准。
Today, molecular genetic technology can identify disease-causing genes for essentially all types of human diseases, which immediately provide the molecular mechanisms underlying the pathogenesis of the disease, and lead to development of new methods for diagnosis and treatment. Positional cloning based on genome-wide linkage analysis is the most efficient method for identifying genes for single gene disorders or monogenic diseases, and has led to identification of many human disease genes, for example, long QT syndrome, atrial fibrillation, retinitis pigmentosa, and many others.
However, the most common diseases that threaten human health and burden the society are the complex diseases caused by multiple genes (not a single gene) and environment factors. The examples are coronary artery disease and myocardial infarction, diabetes, and hypertension. Complex diseases are different from monogenic disorders in that the pattern of the disease can not be simply determined to be either dominant or recessive. As a result, genome-wide linkage analysis of common complex diseases or traits usually requires hundreds of small families. After linkage is found, candidate genes within the linked chromosomal region can be analyzed for association with the trait. Alternatively, a candidate association study can be used to identify risk factors or genes for a complex disease or trait. In this case, a candidate variant or gene is selected and its frequency is compared between a group of patients (or people with a trait under study) and a group of controls without the disease or trait. A significant difference suggests that a specific variant is associated with the disease or trait.
In our study, using differents populations, we applied linkage anaylsis and association astudy on the two important traits of CAD:HDL and triglyceride, and finally found the most significant QTL of HDL:15q25. The result may help researcher to find the real variant or gene affecting HDL levels in this locus.
In the first part, We have completed a genome-wide linkage scan for HDL-C in a U.S. cohort consisting 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates (P=5.1×10-4). Two major quantitative trait loci (QTLs) for log-transformed HDL-C adjusted for age and gender were identified onto chromosomes 7p22 and 15q25 with maximum multi-point LOD scores of 3.76 and 6.69 respectively. Fine mapping decreased the 7p22 LOD score to a non-significant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD=2.73) and spanning the LIPC gene, and the other QTL remained at 15q25 (LOD=5.63). A family-based QTDT revealed significant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population (P=0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most significant locus identified for HDL-C to date, and these results provide a framework for the ultimate identification of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism.
In the second part, recent genome wide association studies (GWAS) identified significant associations between single nucleotide polymorphisms (SNPs) rs1323432, rs2338104, and rs4846914 and HDL-C, and between SNPs rs4846914, rs16996148, rs17321515, rs17145738, rsl748195, and rs12130333 and triglyceride, But those results need to be replicated in other populations. In our study, the newly discovered HDL-C and triglyceride SNPs by GWAS were genotyped for 1,231 MI cases and 560 controls from the Cleveland GeneBank by TaqMan SNP genotyping assays. In the result, All eight SNPs, including rsl323432, rs2338104, rs4846914, rsl6996148, rs17321515, rs17145738, rs1748195, and rs12130333, showed a P value of>0.05 for plasma HDL-C and triglyceride concentrations in 1,231 cases,560 controls and a combined 1,791 study subjects. A P value of 0.007 was obtained for association between SNP rs12130333 and MI (odds ratio of 0.773). As a conclution, no significant association could be found between the eight newly-identified HDL-C and triglyceride SNPs by GWAS and HDL-C and triglyceride, at lease in a Cleveland Caucasian population.
引文
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