Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
PLoS One. 2011;6(8):e23248. doi: 10.1371/journal.pone.0023248. Epub 2011 Aug 12.
The combined thickness of the intima and media of the carotid artery (carotid intima-medial thickness, CIMT) is associated with cardiovascular disease and stroke. Previous studies indicate that carotid intima-medial thickness is a significantly heritable phenotype, but the responsible genes are largely unknown. Hexose-6 phosphate dehydrogenase (H6PDH) is a microsomal enzyme whose activity regulates corticosteroid metabolism in the liver and adipose tissue; variability in measures of corticosteroid metabolism within the normal range have been associated with risk factors for cardiovascular disease. We performed a genetic association study in 854 members of 224 families to assess the relationship between polymorphisms in the gene coding for hexose-6 phosphate dehydrogenase (H6PD) and carotid intima-medial thickness.
Families were ascertained via a hypertensive proband. CIMT was measured using B-mode ultrasound. Single nucleotide polymorphisms (SNPs) tagging common variation in the H6PD gene were genotyped. Association was assessed following adjustment for significant covariates including "classical" cardiovascular risk factors. Functional studies to determine the effect of particular SNPs on H6PDH were performed.
There was evidence of association between the single nucleotide polymorphism rs17368528 in exon five of the H6PD gene, which encodes an amino-acid change from proline to leucine in the H6PDH protein, and mean carotid intima-medial thickness (p = 0.00065). Genotype was associated with a 5% (or 0.04 mm) higher mean carotid intima-medial thickness measurement per allele, and determined 2% of the population variability in the phenotype.
Our results suggest a novel role for the H6PD gene in atherosclerosis susceptibility.
颈总动脉内膜-中层厚度（CIMT）与心血管疾病和中风有关。先前的研究表明，颈动脉内膜-中层厚度是一种具有显著遗传性的表型，但负责的基因在很大程度上是未知的。己糖-6-磷酸脱氢酶（H6PDH）是一种微粒体酶，其活性调节肝脏和脂肪组织中的皮质类固醇代谢；正常范围内皮质类固醇代谢的测量值的变异性与心血管疾病的危险因素有关。我们对 224 个家族的 854 名成员进行了一项遗传关联研究，以评估编码己糖-6-磷酸脱氢酶（H6PD）的基因中的多态性与颈动脉内膜-中层厚度之间的关系。
通过高血压先证者确定家族。使用 B 型超声测量 CIMT。对 H6PD 基因的单核苷酸多态性（SNP）进行基因分型，以标记常见变异。在调整包括“经典”心血管危险因素在内的显著协变量后，评估关联。进行了功能研究以确定特定 SNP 对 H6PDH 的影响。
在 H6PD 基因外显子五的单核苷酸多态性 rs17368528 与颈动脉内膜-中层厚度之间存在关联，该多态性导致 H6PDH 蛋白中的氨基酸从脯氨酸变为亮氨酸（p=0.00065）。基因型与每个等位基因的平均颈动脉内膜-中层厚度测量值增加 5%（或 0.04 毫米）有关，并决定了表型的 2%的人群变异性。
我们的结果表明 H6PD 基因在动脉粥样硬化易感性中具有新的作用。
