家族性高甘油三酯血症家系的候选基因位点连锁分析

摘要

Objective To perform linkage analysis and mutation screening in a Chinese family with familial hpertriglyceridemia (FHTG). Method Thirty two family members including 12 hypertriglyceridemia patients participated in the study. Genotyping and haplotype analysis for 22 subjects were performed using short tandem repeat (STR) microsatellite polymorphism markers on 16 candidate genes and/or loci related to lipid metabolism. Two of the sixteen known candidate genes, APOA2 and USF1 were screened for mutation by direct DNA sequencing. Result No linkage was found between the candidate genes/loci of APOA5, LIPI, RP1, APOC2, ABC1, LMF1, APOA1-APOC3-APOA4, LPL, APOB,CETP, LCAT, LDLR, APOE and the phenotype in this family. The two-point Lod scores (θ=0) were all less than-1.0 for all the markers tested. Linkage analysis suggested linkage to chromosome 1q23.3-24.2 between the disease phenotype and STR marker D1S194 with a two-point maximum Lod score of 2.44 at θ=0. Fine mapping indicated that the disease gene was localized to a 5.87 cM interval between D1S104 and D1S196. No disease-causing mutation was detected in the APOA2 and USF1 genes. Conclusion The above mentioned candidate genes were excluded as the disease causing genes for this family. The results implied that there might be a novel gene/locus for FHTG on chromosome 1q23.3-1q24.2.%目的 对一个家族性高甘油三酯血症(familial hypertriglyceridemia,FHTG)家系进行遗传连锁定位及基因突变分析.方法 32名家系成员,其中12例为高甘油三酯血症(hypertriglyceridemia)患者.应用短串联重复(short tandem repeat,STR)片段微卫星标记物对其中的22名成员进行了16个与脂代谢有关的候选基因和(或)位点的遗传连锁分析和单倍型分析,并对其中的两个候选基因APOA2和USF1直接测序以筛查突变.结果 APOA5、LIPI、RP1、APOC2、ABC1,LMF1、APOA1-APOC3-APOA4、LPL,APOB、CETP、LCAT,LDLR,APOE等候选基因位点与该家系表型不连锁,Lod值均小于-1.0(θ=0).遗传连锁分析提示位于1q23.3-24.2染色体区域,疾病表型在D1S104至D1S196之间(遗传间距为5.87 cM)存在连锁,其中D1S194两点间最大Lod值为2.44(θ=0).对APOA2和USF1基因的序列分析未发现致病突变.结论 排除了上述候选基因为本家系的致病基因;提示在1q23.3-1q24.2染色体区域可能存在一个新的与FHTG相关的基因.