Patient Genotypes Impact Survival After Surgery for Isolated Congenital Heart Disease
Patient Genotypes Impact Survival After Surgery for Isolated Congenital Heart Disease
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DOI：
10.1016/j.athoracsur.2014.03.017
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发表时间：
2014-07-01
影响因子：
4.6
通讯作者：
Jarvik, Gail P.
中科院分区：
文献类型：
--
作者：
Kim, Daniel Seung;Kim, Jerry H.;Jarvik, Gail P.
背景。婴儿期心脏手术后的生存需要氧化应激管理和血管调节途径的适应性反应。我们对这些途径的遗传变异影响非综合征先天性心脏病患儿术后生存的假设进行了检验。这是一项对6个月前接受心脏手术合并体外循环的非综合征性先天性心脏病患者的队列分析（n = 422）。通过先验文献检索，鉴定了6个参与氧化应激和血管反应途径的基因中的6个单核苷酸多态性（snp），以检测其对无移植生存的影响。采用Cox比例风险模型计算经混杂协变量调整后的生存曲线。长期生存率与血管内皮生长因子A基因SNP rs833069 （p = 7.03 × 10(-4)）和超氧化物歧化酶2基因SNP rs2758331 （p = 0.019）密切相关。为了检验这两种snp对无移植生存的共同影响，对基因型进行分组，形成反映风险等位基因累积数量的风险评分（每位患者0至4个等位基因）。混杂校正后，基于VEGFA和SOD2 SNP基因型的较高风险评分与较差的无移植生存相关（p = 3.02x10(-4)）。风险等位基因的总负担是加性的；风险评分最高的受试者为4分（n = 59例，占队列的14.2%），其无移植生存较差的总协变量校正风险比为15.64。心脏手术后，VEGFA和SOD2 snp高危等位基因纯合子的婴儿死亡或心脏移植的风险增加约16倍，这表明遗传变异是先天性心脏病手术后生存的重要修饰因素。(C) 2014年由胸外科医师协会发布
Background. Survival after cardiac surgery in infancy requires adaptive responses from oxidative stress management and vascular regulation pathways. We tested the hypothesis that genetic variation in these pathways influences postoperative survival in nonsyndromic congenital heart disease children.Methods. This is an analysis of a cohort of nonsyndromic congenital heart disease patients who underwent cardiac surgery with cardiopulmonary bypass before 6 months of age (n = 422). Six single nucleotide polymorphisms (SNPs) in six genes involved in oxidative stress and vascular response pathways, identified through a priori literature search, were tested for effects on transplant-free survival. Survival curves, adjusting for confounding covariates, were calculated using the Cox proportional hazard models.Results. Long-term survival was strongly associated with vascular endothelial growth factor A gene SNP rs833069 (p = 7.03x10(-4)) and superoxide dismutase 2 gene SNP rs2758331 (p = 0.019). To test for joint effects of the two SNPs on transplant-free survival, the genotypes were grouped to form a risk score reflecting the cumulative number of risk alleles (0 to 4 alleles per patient). A higher risk score based on the VEGFA and SOD2 SNP genotypes was associated with worse transplant-free survival (p = 3.02x10(-4)) after confounder adjustment. The total burden of risk alleles was additive; subjects with the highest risk score of 4 (n = 59 subjects, 14.2% of the cohort) had a total covariate-adjusted hazard ratio of 15.64 for worse transplant-free survival.Conclusions. After cardiac surgery, infants who are homozygous for the high-risk alleles for both the VEGFA and SOD2 SNPs have an approximately 16-fold increased risk of death or heart transplant, suggesting that genetic variants are important modifiers of survival after surgery for congenital heart disease. (C) 2014 by The Society of Thoracic Surgeons