Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation.
Hirschsprung's disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, homeobox B5 (HOXB5), L1 cell adhesion molecule (L1CAM), paired-like homeobox 2b (PHOX2B), PROK1 and PROKR1) chosen because they are involved in ENCC proliferation, migration and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P-values between 10(-3) and 10(-31)) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration and differentiation could be risk factors for HSCR.
Department of Health and Human Services, Division of Epidemiology, Statistics, and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Tonia C
TC
Carter
Denise M
DM
Kay
Marilyn L
ML
Browne
Aiyi
A
Liu
Paul A
PA
Romitti
Devon
D
Kuehn
Mary R
MR
Conley
Michele
M
Caggana
Charlotte M
CM
Druschel
Lawrence C
LC
Brody
James L
JL
Mills
D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D017615:Enteric Nervous System / Q000473:pathology; D005006:Ethnicity / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009432:Neural Crest / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
C489126:HOXB5 protein, human; D018398:Homeodomain Proteins; C000715470:MAS1 protein, human; C109220:NBPhox protein; D000090063:Proto-Oncogene Mas; D022821:RNA Splice Sites; D014157:Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human