TY - JOUR
T1 - Relative Contribution of Genetic and Nongenetic Modifiers to Intestinal Obstruction in Cystic Fibrosis
AU - Blackman, Scott M.
AU - Deering-Brose, Rebecca
AU - McWilliams, Rita
AU - Naughton, Kathleen
AU - Coleman, Barbara
AU - Lai, Teresa
AU - Algire, Marilyn
AU - Beck, Suzanne
AU - Hoover-Fong, Julie
AU - Hamosh, Ada
AU - Fallin, M. Daniele
AU - West, Kristen
AU - Arking, Dan E.
AU - Chakravarti, Aravinda
AU - Cutler, David J.
AU - Cutting, Garry R.
N1 - Funding Information:
Supported by grant HL 68927 from the National Institute of Heart, Lung and Blood, by grant CUTTIN00A0 from the US Cystic Fibrosis Foundation, by T32 DK07751 from the National Institute of Digestive and Diabetes and Kidney Disease (S.B.), and by T32 GM007814 from the National Institute of General Medical Sciences (R.D.-B.).
PY - 2006/10
Y1 - 2006/10
N2 - Background & Aims: Neonatal intestinal obstruction (meconium ileus [MI]) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and nongenetic modifiers to the development of this major complication of CF. Methods: A total of 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage. Results: Specific mutations in the CF transmembrane conductance regulator (CFTR), the gene responsible for CF, correlated with MI, indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (P = 1 × 10-5), showing that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (P = 8 × 10-4). Unlike MI, concordance analysis indicated that the risk for development of distal intestinal obstruction syndrome in CF patients is caused primarily by nongenetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene on chromosome 19 in a region previously linked to MI. Conclusions: The CFTR gene along with 2 or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, whereas intestinal obstruction in older CF patients is caused primarily by nongenetic factors.
AB - Background & Aims: Neonatal intestinal obstruction (meconium ileus [MI]) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and nongenetic modifiers to the development of this major complication of CF. Methods: A total of 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage. Results: Specific mutations in the CF transmembrane conductance regulator (CFTR), the gene responsible for CF, correlated with MI, indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (P = 1 × 10-5), showing that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (P = 8 × 10-4). Unlike MI, concordance analysis indicated that the risk for development of distal intestinal obstruction syndrome in CF patients is caused primarily by nongenetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene on chromosome 19 in a region previously linked to MI. Conclusions: The CFTR gene along with 2 or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, whereas intestinal obstruction in older CF patients is caused primarily by nongenetic factors.
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U2 - 10.1053/j.gastro.2006.07.016
DO - 10.1053/j.gastro.2006.07.016
M3 - Article
C2 - 17030173
AN - SCOPUS:33749328098
SN - 0016-5085
VL - 131
SP - 1030
EP - 1039
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -