O'Halloran A M, Patterson C C, Horan P, Maree A, Curtin R, Stanton A, McKeown P P, Shields D C
School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
J Thromb Thrombolysis. 2009 Feb;27(2):175-84. doi: 10.1007/s11239-008-0196-z. Epub 2008 Feb 8.
Both platelet function and heart disease show strong genetic components, many of which remain to be elucidated.
The roles of candidate polymorphisms in ten platelet-associated genes were compared between 1,237 Acute Coronary Syndrome (ACS) cases (with myocardial infarction and unstable angina) and 386 controls, from an Irish Caucasian population. Additionally, 361 stable angina patients were investigated. Two genes of interest were followed up in a separate Irish study of 1,484 individuals (577 with IHD and 907 unaffected).
The GALNT4 (N-acetyl galactosaminyl transferase 4) 506I allele was significantly underrepresented in ACS (OR = 0.66, CI = 0.52-0.84; P = 0.001; P = 0.01 after correction for multiple testing), while the SULT1A1 (Sulphotransferase 1A1) 213H allele was associated with risk of ACS (OR = 1.37, CI = 1.08-1.74; P = 0.01; P = 0.1 after correction for multiple testing). Subsequent genotyping of further SNPs in GALNT4 in the family-based (IHD) group revealed that the 506I allele showed the same trend towards protecting against ACS but the haplotypic test over the four commonest haplotypes was not significant (P = 0.55). In contrast, the SULT1A1/SULT1A2 gene complex showed suggestive haplotypic association in the family-based study (P = 0.07), with the greatest increase in risk conferred by the SULT1A2 235T allele (P = 0.025).
We have identified two risk genes for cardiovascular disease, one of whose (GALNT4) effects may be on either platelet or endothelial function through modifications of PSGL1 or other important glycosylated proteins. The role of sulphotransferases (SULT1A1/2) in cardiovascular disease requires further exploration. Further validation of cardiovascular risks conferred by both genes in other populations (including gene copy number variation) is warranted.
血小板功能和心脏病都显示出很强的遗传成分，其中许多成分仍有待阐明。
在来自爱尔兰白种人群体的1237例急性冠状动脉综合征（ACS，包括心肌梗死和不稳定型心绞痛）病例和386例对照中，比较了10个血小板相关基因中候选多态性的作用。此外，还对361例稳定型心绞痛患者进行了研究。在另一项对1484名个体（577例患有缺血性心脏病，907例未受影响）的爱尔兰研究中，对两个感兴趣的基因进行了后续研究。
GALNT4（N-乙酰半乳糖胺基转移酶4）506I等位基因在ACS患者中显著减少（比值比=0.66，置信区间=0.52-0.84；P=0.001；多重检验校正后P=0.01），而SULT1A1（磺基转移酶1A1）213H等位基因与ACS风险相关（比值比=1.37，置信区间=1.08-1.74；P=0.01；多重检验校正后P=0.1）。在基于家系的（缺血性心脏病）组中对GALNT4中更多单核苷酸多态性进行后续基因分型显示，506I等位基因在预防ACS方面呈现相同趋势，但对四种最常见单倍型进行的单倍型检验无显著性差异（P=0.55）。相比之下，在基于家系的研究中，SULT1A1/SULT1A2基因复合体显示出提示性的单倍型关联（P=0.07），SULT1A2 235T等位基因带来的风险增加最大（P=0.025）。
我们确定了两个心血管疾病风险基因，其中一个（GALNT4）的作用可能是通过修饰PSGL1或其他重要的糖基化蛋白来影响血小板或内皮功能。磺基转移酶（SULT1A1/2）在心血管疾病中的作用需要进一步探索。有必要在其他人群中对这两个基因赋予的心血管风险进行进一步验证（包括基因拷贝数变异）。
