Foroud Tatiana, Sauerbeck Laura, Brown Robert, Anderson Craig, Woo Daniel, Kleindorfer Dawn, Flaherty Matthew L, Deka Ranjan, Hornung Richard, Meissner Irene, Bailey-Wilson Joan E, Rouleau Guy, Connolly E Sander, Lai Dongbing, Koller Daniel L, Huston John, Broderick Joseph P
Indiana University School of Medicine, Health Information and Translational Sciences Building - HS 4000, 410 West 10th Street, Indianapolis, IN 46202-3002, USA.
Stroke. 2008 May;39(5):1434-40. doi: 10.1161/STROKEAHA.107.502930. Epub 2008 Mar 6.
Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA.
Multiplex families having at least 2 individuals with "definite" or "probable" IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene x smoking (pack-years) interaction.
The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking.
We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene x smoking interaction with 3 of the loci.
有证据表明遗传因素在很大程度上影响颅内动脉瘤（IA）的发病风险。本研究旨在确定可能携带有影响IA发病风险基因的染色体区域。
通过一个国际联盟确定了至少有2名患有“确诊”或“疑似”IA的个体的多重家庭。因高血压病史或当前吸烟而IA发病风险增加的IA患者的一级亲属接受了脑磁共振血管造影检查。使用Illumina 6K SNP系统完成了基因组筛查，并对来自192个家庭、包含1155名基因分型个体的结果数据进行了分析。在使用多点模型独立方法进行连锁检验时，采用了狭义和广义疾病定义。进行有序子集分析以检验基因与吸烟（包年数）的相互作用。
使用广义疾病定义时，在4号染色体（LOD = 2.5；156 cM）、7号染色体（LOD = 1.7；183 cM）、8号染色体（LOD = 1.9；70 cM）和12号染色体（LOD = 1.6；102 cM）上发现了最强的连锁证据。利用每个家庭中受影响个体的平均吸烟包年数，4号染色体（LOD = 3.5；P = 0.03）、7号染色体（LOD = 4.1；P = 0.01）和12号染色体（LOD = 3.6；P = 0.02）上的基因似乎都受到家庭中受影响成员吸烟程度的调节。在8号染色体上，将吸烟作为协变量纳入并未显著增强连锁证据，表明该区域的基因座与吸烟之间没有相互作用。
我们检测到与4个染色体区域连锁的可能证据。有潜在证据表明3个基因座存在基因与吸烟的相互作用。
