Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Hum Genet. 2010 Mar;127(5):513-23. doi: 10.1007/s00439-010-0790-y. Epub 2010 Jan 28.
Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases.
脑血管病和心血管病是全世界范围内导致死亡和残疾的主要原因。它们是由遗传和环境因素相互作用引起的复杂疾病，可能具有一些共同的易感基因。最近的几项研究表明，Kalirin（KALRN）基因的变异与心血管和代谢表型的易感性有关，但在中风患者中尚未进行研究。KALRN 参与了诱导型一氧化氮合酶的抑制、缺血信号转导的调节以及神经元形态发生、可塑性和稳定性。本研究的目的是确定 3q13 上 KALRN 区域（包括 Ropporin 基因（ROPN1）的 SNPs 是否会使葡萄牙患者队列中的缺血性中风（IS）易感性增加。我们对 565 名 IS 患者和 517 名无关对照者的 KALRN 和 ROPN1 染色体区域的 34 个标记 SNPs 进行了基因分型，并对染色体 3 上的 405 个标记进行了基因型推断。我们测试了这些 SNP 与 IS 的单标记关联。ROPN1-KALRN 基因间区的一个 SNP（rs4499545）和 KALRN 中的两个 SNP（rs17286604 和 rs11712619）在等位基因和基因型（未经调整和调整高血压、糖尿病和吸烟状况）方面与 IS 风险显著相关（P<0.05）。32 个推断的 SNP 也在 P<0.05 时显示出关联，对其中三个多态性（rs7620580、rs6438833 和 rs11712039）的实际基因分型验证了它们的关联。此外，rs11712039 与最近一项具有较大效力的全基因组关联研究（Ikram 等人，2009 年）中的 IS 相关（0.001<P<0.01）。这些研究表明，KALRN 基因区域的变异是中风的危险因素，KALRN 可能是血管疾病的共同危险因素。
