Genome screen to detect linkage to intracranial aneurysm susceptibility genes - The Familial Intracranial Aneurysm (FIA) study
Genome screen to detect linkage to intracranial aneurysm susceptibility genes - The Familial Intracranial Aneurysm (FIA) study
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DOI：
10.1161/strokeaha.107.502930
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发表时间：
2008-05-01
期刊：
影响因子：
8.3
通讯作者：
Broderick, Joseph P.
中科院分区：
文献类型：
--
作者：
Foroud, Tatiana;Sauerbeck, Laura;Broderick, Joseph P.
背景和目的--有证据表明，基因对颅内动脉瘤(IA)的风险有实质性的贡献。这项研究的目的是确定可能含有导致IA风险的基因的染色体区域。方法-通过一个国际联合体确定至少有2个个体“确定”或“可能”患有IA的多重家族。IA患者的一级亲属因高血压病史或现在吸烟而增加了IA的风险，他们接受了脑磁共振血管成像检查。使用Illumina 6K SNP系统完成了基因组筛选，并对192个家系的1155个基因分型个体的数据进行了分析。当使用与多点模型无关的方法测试关联时，使用狭义和广义的疾病定义。结果：使用广义疾病定义，在第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)上发现了最大的连锁证据。按每个家系患病个体的平均包年数计算，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族成员吸烟程度的影响。在8号染色体上，吸烟作为一个协变量并没有显著加强连锁证据，这表明该区域的基因座与吸烟之间没有交互作用。结论--我们检测到了可能与4个染色体区域连锁的证据。有潜在证据表明，X基因与其中3个基因座存在交互作用。
Background and Purpose-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.Methods-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.Results-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.Conclusions - 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.