Dueker Nicole D, Beecham Ashley, Wang Liyong, Blanton Susan H, Guo Shengru, Rundek Tatjana, Sacco Ralph L
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, United States of America.
PLoS One. 2016 Dec 9;11(12):e0167202. doi: 10.1371/journal.pone.0167202. eCollection 2016.
Cardiovascular disorders including ischemic stroke (IS) and myocardial infarction (MI) are heritable; however, few replicated loci have been identified. One strategy to identify loci influencing these complex disorders is to study subclinical phenotypes, such as carotid bifurcation intima-media thickness (bIMT). We have previously shown bIMT to be heritable and found evidence for linkage and association with common variants on chromosome 7p for bIMT. In this study, we aimed to characterize contributions of rare variants (RVs) in 7p to bIMT. To achieve this aim, we sequenced the 1 LOD unit down region on 7p in nine extended families from the Dominican Republic (DR) with strong evidence for linkage to bIMT. We then performed the family-based sequence kernel association test (famSKAT) on genes within the 7p region. Analyses were restricted to single nucleotide variants (SNVs) with population based minor allele frequency (MAF) <5%. We first analyzed all exonic RVs and then the subset of only non-synonymous RVs. There were 68 genes in our analyses. Nucleotide-binding oligomerization domain (NOD1) was the most significantly associated gene when analyzing exonic RVs (famSKAT p = 9.2x10-4; number of SNVs = 14). We achieved suggestive replication of NOD1 in an independent sample of twelve extended families from the DR (p = 0.055). Our study provides suggestive statistical evidence for a role of rare variants in NOD1 in bIMT. Studies in mice have shown Nod1 to play a role in heart function and atherosclerosis, providing biologic plausibility for a role in bIMT thus making NOD1 an excellent bIMT candidate.
包括缺血性中风（IS）和心肌梗死（MI）在内的心血管疾病具有遗传性；然而，已确定的可重复位点很少。识别影响这些复杂疾病的位点的一种策略是研究亚临床表型，如颈动脉分叉内膜中层厚度（bIMT）。我们之前已证明bIMT具有遗传性，并发现了7号染色体p臂上的常见变异与bIMT存在连锁和关联的证据。在本研究中，我们旨在确定7号染色体p臂上的罕见变异（RVs）对bIMT的影响。为实现这一目标，我们对来自多米尼加共和国（DR）的9个与bIMT有强连锁证据的大家庭中7号染色体p臂上1个LOD单位下限区域进行了测序。然后，我们对7号染色体p臂区域内的基因进行了基于家系的序列核关联检验（famSKAT）。分析仅限于基于人群的次要等位基因频率（MAF）<5%的单核苷酸变异（SNV）。我们首先分析了所有外显子RVs，然后分析了仅非同义RVs的子集。我们的分析中有68个基因。在分析外显子RVs时，核苷酸结合寡聚化结构域（NOD1）是最显著相关的基因（famSKAT p = 9.2x10-4；SNV数量 = 14）。我们在来自DR的12个大家庭的独立样本中实现了对NOD1的提示性重复验证（p = 0.055）。我们的研究为NOD1中的罕见变异在bIMT中的作用提供了提示性统计证据。对小鼠的研究表明Nod1在心脏功能和动脉粥样硬化中起作用，为其在bIMT中的作用提供了生物学合理性，因此使NOD1成为bIMT的一个优秀候选基因。
