| Abstract: | 研究背景
冠狀動脈疾病(coronary artery disease, CAD)已經成為現今各國所面臨的重要健康問題，而心血管疾病危險因子的評估，與疾病的治療和公衛政策息息相關。近十多年來，隨著單核苷酸的基因多型性 (Single Nucleotide Polymorphism, SNP) 和全基因組的關聯研究( Genome-wide Association Study, GWAS ) 的蓬勃發展，CAD 和類幾丁質酶(YKL-40)的研究結果應運而生。YKL-40為一肝素、幾丁質結合的糖蛋白，分子量為40K Da，由於它有3個N 端的胺機酸，tyrosine (Y)、lysine (K)、Leucine(L)，故定名為YKL-40。YKL-40為chitinase-3-like protein1 (CHI3L1)基因所調控，由巨噬細胞分泌並影響其成熟。在許多之前的研究顯示YKL-40 和腫瘤的複發及預後、冠狀動脈心臟病的死亡率、中風的風險、敗血症的預後、氣喘治療的效果皆息息相關。因此本研究主題即收集胸痛病患，並經由冠狀動脈心導管攝影作為冠狀動脈心臟病的確診，區分為病例組和控制組， 並檢測YKL-40 的四個單核苷酸基因多型性 (rs6691378, rs10399805, rs4950928, rs880633)與冠狀動脈心臟病的臨床關聯性，希望作為心血管疾病的另一預測因子。
材料與方法
我們收集576位因胸痛而先接受非侵入性檢查的病患，包括：運動心電圖(treadmill exercise test)、心臟核子醫學掃描(myocardial perfusion scan)，多切面電腦斷層(multislice computer computed tomography)、心臟超音波、心臟酵素檢測。病患基本收集的資料包括性別、年齡、症狀、病史及生化檢查數值。最後，這些病患皆安排心臟冠狀動脈血管攝影。收案時間為西元2007年四月~2013年三月。根據冠狀動脈血管攝影檢查之結果，分成有冠狀動脈疾病組(病例組，N=373，coronary artery stenosis> 50%) 和無冠狀動脈疾病組(控制組，N=203，coronary stenosis< 50%)，並採用即時-聚合酶鏈反應（real time-PCR）的方法，來分析兩組的臨床特性和的四個單核苷酸基因多型性SNP rs6691378(-1371G/A)、SNP rs10399805(-247G/A)、SNP rs4950928(-131C/G)、SNP rs880633(+2950T/C)之關係，並經由多變項分析的結果，找出女性次族群最相關之基因多型性的分析結果。
研究結果
在所有族群中，YKL-40 rs4950928的CG/GG基因型相較於CC基因型，在CAD的族群中對比於非CAD族群有較低的比率(p=0.039, odds ratio(OR)=0.677)。在女性族群中，YKL-40 rs6691378的GA/AA 基因型相較於GG基因型，在CAD的族群中有較高的比率(p=0.008, odds ratio(OR)=2.267)。YKL-40 rs10399805的GA/AA 基因型相較於GG基因型，在CAD的族群中也有較高的比率(p=0.004, odds ratio(OR)=2.421)。另外在女性族群的臨床表現上，YKL-40 rs6691378的GA/AA 基因型相較於GG基因型，有較高急性心肌梗塞的比率(p=0.010, odds ratio(OR)=2.925)；而YKL-40 rs10399805的GA/AA 基因型相較於GG基因型，亦有呈現較高急性心肌梗塞的趨勢(p=0.051, odds ratio(OR)=2.249)。再經由多變項分析之結果發現，高血壓、近24小時內有胸悶症狀、心臟酵素上升、YKL-40 rs10399805的GA/AA 基因型，為女性族群中CAD的獨立預測因子。
結論
在女性此一冠心症臨床症狀較不典型之族群，YKL-40 rs10399805(-247G/A)的基因多型性無疑是提供了一個更佳的預測及檢測工具。而在所有族群中，YKL-40 rs4950928(-131C/G)則呈現出 G等位基因具有保護冠心症之結果。因此，本研究在YKL-40基因多型性與台灣族群冠心症的研究中，建立一重要之里程碑。 Background YKL-40, released by human activated macrophages, neutrophils and vascular smooth muscle cells, plays a role in the pathogenesis of endothelial dysfunction, atherosclerosis and abnormal angiogenesis. However, the association of single nucleotide polymorphisms (SNPs) of YKL-40 with coronary artery disease (CAD) has not been clear in the Taiwan population and needed to be investigated. Materials and methods Five hundred and seventy-six unrelated Taiwanese patients (male 397, female 179), receiving coronary angiography because of chest pain at Chung Shan Medical University Hospital were recruited from April 2007 to March 2013. The blood samples were obtained for the analysis of YKL-40 SNPs rs6691378, rs10399805, rs4950928, rs880633 using real time PCR assay from CAD case group (373 patients) and non-CAD control group (203 controls). Results In the female population, the frequencies of YKL-40 rs6691378 with GA/AA genotype [P=0.008, odds ratio (OR)=2.267] and rs10399805 with GA/AA genotype (P=0.004, OR=2.421,) were higher, as compared to their wild GG genotypes in CAD than non-CAD groups After multivariate analysis for YKL-40 SNPs and clinical features in the female group. In addition to, recent 24 hours severe angina and elevated cardiac enzyme, YKL-40 SNP rs10399805 GA/AA (P=0.009, OR=2.524, 95% confidence interval =1.254-5.078) was an independent factors for CAD. Conclusion YKL-40 -131C/G (rs4950928) SNP may decrease the genetic susceptibility to CAD, as shown in the study participants. In the female patients, YKL-40 SNP -1371G/A (rs6691378) with the GA/AA genotype or the A allele was associated with CAD. In addition, YKL-40 SNP -247G/A (rs10399805) with the GA/AA genotype or the A allele can increase the genetic susceptibility to CAD. More important, YKL-40 rs10399805 GA/AA may serve as an independent risk factor for CAD in Taiwanese women. |
