Wang Liyong, Hauser Elizabeth R, Shah Svati H, Pericak-Vance Margaret A, Haynes Carol, Crosslin David, Harris Marco, Nelson Sarah, Hale A Brent, Granger Christopher B, Haines Jonathan L, Jones Christopher J H, Crossman David, Seo David, Gregory Simon G, Kraus William E, Goldschmidt-Clermont Pascal J, Vance Jeffery M
Center for Human Genetics, Department of Medicine, Duke Univeristy Medical Center, Durham, NC, USA.
Am J Hum Genet. 2007 Apr;80(4):650-63. doi: 10.1086/512981. Epub 2007 Feb 8.
A susceptibility locus for coronary artery disease (CAD) has been mapped to chromosome 3q13-21 in a linkage study of early-onset CAD. We completed an association-mapping study across the 1-LOD-unit-down supporting interval, using two independent white case-control data sets (CATHGEN, initial and validation) to evaluate association under the peak. Single-nucleotide polymorphisms (SNPs) evenly spaced at 100-kb intervals were screened in the initial data set (N=468). Promising SNPs (P<.1) were then examined in the validation data set (N=514). Significant findings (P<.05) in the combined initial and validation data sets were further evaluated in multiple independent data sets, including a family-based data set (N=2,954), an African American case-control data set (N=190), and an additional white control data set (N=255). The association between genotype and aortic atherosclerosis was examined in 145 human aortas. The peakwide survey found evidence of association in SNPs from multiple genes. The strongest associations were found in three SNPs from the kalirin (KALRN) gene, especially in patients with early-onset CAD (P=.00001-00028 in the combined CATHGEN data sets). In-depth investigation of the gene found that an intronic SNP, rs9289231, was associated with early-onset CAD in all white data sets examined (P<.05). In the joint analysis of all white early-onset CAD cases (N=332) and controls (N=546), rs9289231 was highly significant (P=.00008), with an odds-ratio estimate of 2.1. Furthermore, the risk allele of this SNP was associated with atherosclerosis burden (P=.03) in 145 human aortas. KALRN is a protein with many functions, including the inhibition of inducible nitric oxide synthase and guanine-exchange-factor activity. KALRN and two other associated genes identified in this study (CDGAP and MYLK) belong to the Rho GTPase-signaling pathway. Our data suggest the importance of the KALRN gene and the Rho GTPase-signaling pathway in the pathogenesis of CAD.
在一项早发性冠心病的连锁研究中，已将冠心病（CAD）的一个易感基因座定位到3号染色体的13-21区。我们在1个LOD单位下降的支持区间内完成了一项关联图谱研究，使用两个独立的白人病例对照数据集（CATHGEN，初始数据集和验证数据集）来评估峰值下的关联性。在初始数据集中（N = 468）筛选了间隔为100 kb的均匀分布的单核苷酸多态性（SNP）。然后在验证数据集中（N = 514）检查有前景的SNP（P <.1）。在包括一个基于家系的数据集（N = 2,954）、一个非裔美国人病例对照数据集（N = 190）和另一个白人对照数据集（N = 255）在内的多个独立数据集中，对初始数据集和验证数据集合并后的显著结果（P <.05）进行了进一步评估。在145个人类主动脉中检查了基因型与主动脉粥样硬化之间 的关联。全峰范围的调查发现多个基因的SNP存在关联证据。在kalirin（KALRN）基因的三个SNP中发现了最强的关联，特别是在早发性CAD患者中（在合并的CATHGEN数据集中P = 0.00001 - 0.00028）。对该基因的深入研究发现，一个内含子SNP，rs9289231，在所有检测的白人数据集中均与早发性CAD相关（P <.05）。在所有白人早发性CAD病例（N = 332）和对照（N = 546）的联合分析中，rs9289231具有高度显著性（P = 0.00008），优势比估计为2.1。此外，该SNP的风险等位基因与145个人类主动脉中的动脉粥样硬化负担相关（P = 0.03）。KALRN是一种具有多种功能的蛋白质，包括抑制诱导型一氧化氮合酶和鸟嘌呤交换因子活性。KALRN以及本研究中鉴定的其他两个相关基因（CDGAP和MYLK）属于Rho GTPase信号通路。我们的数据表明KALRN基因和Rho GTPase信号通路在CAD发病机制中的重要性。
