Arnold Stacey, Pelet Anna, Amiel Jeanne, Borrego Salud, Hofstra Robert, Tam Paul, Ceccherini Isabella, Lyonnet Stanislas, Sherman Stephanie, Chakravarti Aravinda
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Hum Mutat. 2009 May;30(5):771-5. doi: 10.1002/humu.20944.
Individuals with Down syndrome (DS) display a 40-fold greater risk of Hirschsprung disease (HSCR) than the general population of newborns implicating chromosome 21 in HSCR etiology. Here we demonstrate that the RET enhancer polymorphism RET+9.7 (rs2435357:C>T) at chromosome 10q11.2 is associated with HSCR in DS individuals both by transmission disequilibrium (P=0.0015) and case-control (P=0.0115) analysis of matched cases. Interestingly, the RET+9.7 T allele frequency is significantly different between individuals with DS alone (0.26+/-0.04), HSCR alone (0.61+/-0.04), and those with HSCR and DS (0.41+/-0.04), demonstrating an association and interaction between RET and chromosome 21 gene dosage. This is the first report of a genetic interaction between a common functional variant (rs2435357) and a not infrequent copy number error (chromosome 21 dosage) in two human developmental disorders.
患有唐氏综合征（DS）的个体患先天性巨结肠症（HSCR）的风险比新生儿普通人群高40倍，这表明21号染色体与HSCR病因有关。在此，我们通过对匹配病例的传递不平衡分析（P=0.0015）和病例对照分析（P=0.0115）证明，位于10q11.2染色体上的RET增强子多态性RET+9.7（rs2435357:C>T）与DS个体的HSCR相关。有趣的是，仅患有DS的个体（0.26±0.04）、仅患有HSCR的个体（0.61±0.04）以及同时患有HSCR和DS的个体（0.41±0.04）之间的RET+9.7 T等位基因频率存在显著差异，这表明RET与21号染色体基因剂量之间存在关联和相互作用。这是首次报道在两种人类发育障碍中，常见功能变异（rs2435357）与不常见的拷贝数错误（21号染色体剂量）之间存在遗传相互作用。
