Goodship Judith A, Hall Darroch, Topf Ana, Mamasoula Chrysovalanto, Griffin Helen, Rahman Thahira J, Glen Elise, Tan Huay, Palomino Doza Julian, Relton Caroline L, Bentham Jamie, Bhattacharya Shoumo, Cosgrove Catherine, Brook David, Granados-Riveron Javier, Bu'Lock Frances A, O'Sullivan John, Stuart A Graham, Parsons Jonathan, Cordell Heather J, Keavney Bernard
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Circ Cardiovasc Genet. 2012 Jun;5(3):287-92. doi: 10.1161/CIRCGENETICS.111.962035. Epub 2012 Apr 13.
Tetralogy of Fallot (TOF) is the commonest cyanotic form of congenital heart disease. In 80% of cases, TOF behaves as a complex genetic condition exhibiting significant heritability. As yet, no common genetic variants influencing TOF risk have been robustly identified.
Two hundred and seven haplotype-tagging single nucleotide polymorphisms in 22 candidate genes were genotyped in a test cohort comprising 362 nonsyndromic British white patients with TOF together with 717 unaffected parents of patients and 183 unrelated healthy controls. Single nucleotide polymorphisms with suggestive evidence of association in the test cohort (P<0.01) were taken forward for genotyping in an independent replication cohort comprising 392 cases of TOF, 218 unaffected parents of patients, and 1319 controls. Significant association was observed for 1 single nucleotide polymorphism, rs11066320 in the PTPN11 gene, in both the test and the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.34 (95% confidence interval [CI], 1.19 to 1.52; P=2.9 × 10(-6)) in the total cohort of TOF cases and controls; this remained highly significant after Bonferroni correction for 207 analyses (corrected P=0.00061). Genotype at rs11066320 was responsible for a population-attributable risk of TOF of approximately 10%.
Common variation in the linkage disequilibrium block including the PTPN11 gene contributes to the risk of nonsyndromic TOF. Rare mutations in PTPN11 are known to cause the autosomal dominant condition Noonan syndrome, which includes congenital heart disease, by upregulating Ras/mitogen-activated protein kinase (MAPK) signaling. Our results suggest a role for milder perturbations in PTPN11 function in sporadic, nonsyndromic congenital heart disease.
法洛四联症（TOF）是最常见的先天性心脏病青紫型。在80%的病例中，TOF表现为一种复杂的遗传疾病，具有显著的遗传度。迄今为止，尚未有力地鉴定出影响TOF风险的常见基因变异。
在一个测试队列中，对22个候选基因中的207个单倍型标签单核苷酸多态性进行基因分型，该队列包括362例非综合征型英国白人TOF患者以及717例未受影响的患者父母和183名无关健康对照。在测试队列中具有提示性关联证据（P<0.01）的单核苷酸多态性被进一步在一个独立的重复队列中进行基因分型，该重复队列包括392例TOF病例、218例未受影响的患者父母以及1319名对照。在测试队列和重复队列中均观察到一个单核苷酸多态性rs11066320（位于PTPN11基因）存在显著关联。在TOF病例和对照的总队列中，rs11066320的基因型与每个等位基因的优势比为1.34（95%置信区间[CI]，1.19至1.52；P=2.9×10⁻⁶）；在对207次分析进行Bonferroni校正后，这一结果仍然高度显著（校正后P=0.00061）。rs11066320的基因型导致TOF的人群归因风险约为10%。
包括PTPN11基因在内的连锁不平衡区域的常见变异会增加非综合征型TOF的风险。已知PTPN11中的罕见突变会通过上调Ras/丝裂原活化蛋白激酶（MAPK）信号传导导致常染色体显性疾病努南综合征，该疾病包括先天性心脏病。我们的结果表明，PTPN11功能的轻度扰动在散发性非综合征型先天性心脏病中起作用。
