Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy.
Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy.
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DOI：
10.1161/circgenetics.112.965277
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发表时间：
2013-02
期刊：
影响因子：
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通讯作者：
Huggins GS
中科院分区：
文献类型：
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作者：
Wooten EC;Hebl VB;Wolf MJ;Greytak SR;Orr NM;Draper I;Calvino JE;Kapur NK;Maron MS;Kullo IJ;Ommen SR;Bos JM;Ackerman MJ;Huggins GS
肥厚型心肌病(HCM)的不完全外显和不同表达是很好的认识。可能影响HCM外显性和表达的常见遗传多态变异已经被预测，但还没有得到很好的证实。我们进行了一项病例对照全基因组关联(GWA)研究，以确定常见的HCM相关遗传多态，然后询问这些常见的变异在HCM中是否更具代表性，或者是否可以解释HCM表型的异质性。我们确定了一个内含子Fhod3变异(Rs516514)与肥厚型心肌梗死相关(OR=2.45(95%CI 1.76-3.41，p=1.25×10−7))，并在一个独立的队列中验证了这一发现。接下来，我们检测了FHOD3-V1151I(Rs2303510)，它是部分连锁不平衡(LD)的一个非同义变异，与rs516514有更强的相关性(p=1.76×10−9)。虽然HCM患者更有可能携带这些FHOD3等位基因，但FHOD3-1151I纯合子患者的HCM表型与V1151等位基因携带者相似。在肥厚性肌病的发病过程中，FHOD3的表达增加，在肥厚性肌病切除组织中均检测到FHOD3-V1151I等位基因。以前，FHOD3被发现是肌节形成所必需的，在这里，我们证明了它的苍蝇同源基因是正常成人心脏收缩所必需的。在这里，我们展示了一种常见的非同义FHOD3基因变异与HCM的关联。这一发现进一步加强了改变肌节蛋白和HCM的氨基酸序列的基因突变和多态的潜在作用。
Incomplete penetrance and variable expression of Hypertrophic Cardiomyopathy (HCM) is well appreciated. Common genetic polymorphisms variants that may affect HCM penetrance and expression have been predicted but are not well established. We performed a case-control genome wide association (GWA) study to identify common HCM-associated genetic polymorphisms and then asked whether such common variants were more represented in HCM or could explain the heterogeneity of HCM phenotypes. We identified an intronic FHOD3 variant (rs516514) associated with HCM (OR = 2.45 (95% CI 1.76–3.41), p=1.25 × 10−7) and validated this finding in an independent cohort. Next, we tested FHOD3-V1151I (rs2303510), a non-synonymous variant in partial linkage disequilibrium (LD) with rs516514, and we detected an even stronger association with HCM (p=1.76 × 10−9). While HCM patients were more likely to carry these FHOD3 alleles subjects homozygous for FHOD3-1151I had similar HCM phenotypes as carriers of the V1151 allele. FHOD3 expression is increased in the setting of HCM and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue. Previously FHOD3 was found to be required for formation of the sarcomere and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction. Here we demonstrate the association of a common non-synonymous FHOD3 genetic variant with HCM. This discovery further strengthens the potential role of gene mutations and polymorphisms that alter the amino acid sequence of sarcomere proteins and HCM.