Melton Phillip E, Carless Melanie A, Curran Joanne E, Dyer Thomas D, Göring Harald H H, Kent Jack W, Drigalenko Eugene, Johnson Matthew P, Maccluer Jean W, Moses Eric K, Comuzzie Anthony G, Mahaney Michael C, O'Leary Daniel H, Blangero John, Almasy Laura
Deptartment of Genetics, Texas Biomedical Research Institute, San Antonio, USA.
Circ Cardiovasc Genet. 2013 Apr;6(2):211-21. doi: 10.1161/CIRCGENETICS.113.000079. Epub 2013 Mar 13.
BACKGROUND- Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these 2 arteries; yet, they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components. METHODS AND RESULTS- IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS using 931219 single-nucleotide polymorphisms was undertaken with 6 internal and common carotid artery IMT phenotypes using an additive measured genotype model. The most robust association detected was for 2 single-nucleotide polymorphisms (rs16983261, rs6113474; P=1.60e(-7)) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1. We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at P<5.0e(-6). The genetic correlation between the 2 carotid IMT arterial segments was 0.51. CONCLUSIONS- This study represents the first large-scale GWAS of carotid IMT in a non-European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments, but the moderate genetic correlation implies both common and unique genetic components.
背景——颈总动脉和颈内动脉的内膜中层厚度（IMT）是动脉粥样硬化的既定替代指标，可预测中风和心肌梗死风险。IMT通常作为这两条动脉的平均值来测量；然而，人们认为它们是由不同的生物学机制导致的。本研究的目的是针对IMT开展一项基于家系的全基因组关联研究（GWAS），以识别影响IMT的多态性，并确定不同的颈动脉节段是否受不同的遗传成分影响。
方法与结果——通过B型超声对来自圣安东尼奥家族心脏研究的772名墨西哥裔美国人的颈总动脉和颈内动脉的IMT进行测定。使用加性测量基因型模型，对931219个单核苷酸多态性进行了GWAS，涉及6种颈内动脉和颈总动脉IMT表型。检测到的最显著关联是位于20号染色体p11上与PAX1基因相邻的颈内动脉近壁处的两个处于完全连锁不平衡状态的单核苷酸多态性（rs16983261，rs6113474；P = 1.60e(-7)）。我们还重复了先前在19号染色体q13和7号染色体q22上报道的GWAS区域。我们发现在P<5.0e(-6)时，颈内动脉和颈总动脉表型之间没有重叠关联。两个颈动脉IMT节段之间的遗传相关性为0.51。
结论——本研究是首次在非欧洲人群中对颈动脉IMT进行的大规模GWAS，并鉴定出了几个新的基因座。我们未在颈总动脉和颈内动脉节段之间检测到任何共享的GWAS信号，但中等程度的遗传相关性意味着存在共同和独特的遗传成分。
