Application and interpretation of transmission/disequilibrium tests: Transmission of HLA-DQ haplotypes to unaffected siblings in 526 families with type 1 diabetes
Application and interpretation of transmission/disequilibrium tests: Transmission of HLA-DQ haplotypes to unaffected siblings in 526 families with type 1 diabetes
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DOI：
10.1086/302780
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发表时间：
2000-02-01
影响因子：
9.8
通讯作者：
Undlien, DE
中科院分区：
文献类型：
--
作者：
Lie, BA;Ronningen, KS;Undlien, DE
人们普遍认为，如果一个遗传标记通过传递/不平衡检验（TDT）在患者中显示出传递失真，那么在健康同胞中的传递失真将以相反的方向出现。在复杂疾病中也是如此。此外，有人建议，用受影响和未受影响儿童之间传播的异质性检验取代TDT的McNemar统计，可以增加检测疾病相关性的能力。为了检验这两个假设的经验，我们分析了526个挪威家庭的1型糖尿病儿童和健康的兄弟姐妹的HLA-DQA 1-DQB 1单倍型的传输，因为一些DQA 1-DQB 1单倍型代表1型糖尿病的主要遗传危险因素。尽管与特定DQ单倍型有很强的阳性和阴性疾病相关性，但我们观察到向健康兄弟姐妹传播的50%没有显著偏离。这可能是由于易感性等位基因的低等位率，以及IDDM基因座也具有强保护性等位基因，可以覆盖其他基因座贡献的风险。我们的研究结果表明，在遗传复杂的疾病，可检测的失真传输到健康的兄弟姐妹不应该被期望。此外，原始的TDT似乎比异质性检验更强大。
It is widely believed that, if a genetic marker shows a transmission distortion in patients by the transmission/ disequilibrium test (TDT), then a transmission distortion in healthy siblings would be seen in the opposite direction. This is also the case in a complex disease. Furthermore, it has been suggested that replacing the McNemar statistics of the TDT with a test of heterogeneity between transmissions to affected and unaffected children could increase the power to detect disease association. To test these two hypotheses empirically, we analyzed the transmission of HLA-DQA1-DQB1 haplotypes in 526 Norwegian families with type 1 diabetic children and healthy siblings, since some DQA1-DQB1 haplotypes represent major genetic risk factors for type 1 diabetes. Despite the strong positive and negative disease associations with particular DQ haplotypes, we observed no significant deviation from 50% for transmission to healthy siblings. This could be explained by the low penetrance of susceptibility alleles, together with the fact that IDDM loci also harbor strongly protective alleles that can override the risk contributed by other loci. Our results suggest that, in genetically complex diseases, detectable distortion in transmission to healthy siblings should not be expected. Furthermore, the original TDT seems more powerful than a heterogeneity test.