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Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results.

ABSTRACT: Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case-control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy-Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.

SUBMITTER: Dorfman R

PROVIDER: S-EPMC2888886 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results.

Dorfman Ruslan R Li Weili W Sun Lei L Lin Fan F Wang Yongqian Y Sandford Andrew A Paré Peter D PD McKay Karen K Kayserova Hana H Piskackova Tereza T Macek Milan M Czerska Kamila K Sands Dorota D Tiddens Harm H Margarit Sonia S Repetto Gabriela G Sontag Marci K MK Accurso Frank J FJ Blackman Scott S Cutting Garry R GR Tsui Lap-Chee LC Corey Mary M Durie Peter P Zielenski Julian J Strug Lisa J LJ

Human genetics 20091201 6

Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than l ...[more]

PMID: 19662435

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Project description:IntroductionMeconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is suspected if a baby fails to pass meconium shortly after birth and develops symptoms of bowel obstruction, such as distention of the abdomen or vomiting. MI can lead to bowel perforation, a twisting of the bowel, or inflammation and infection of the abdominal cavity.ObjectivesTo find the incidence and prevalence of meconium ileus in cystic fibrosis patients and to report on the most common gene mutation of MI in CF patients.MethodologyRetrospective review of the medical documentations of all MI patients during the period of 1989-2018.ResultsA total of 40 CF confirmed patients were presented with MI. Twenty-nine patients (71%) are alive and 11 patients (29%) died or lost to follow-up. The following CFTR mutations were found: Eight patients (20%) with c.2988+1G>A; Intron 18. Seven patients (17.5%) with c.1418delG; Exon 11. Five patients (12.5%) with c.579+1G>T; Intron 5. Four patients (10%) with c.1911delG; Exon 14. Four patients (10%) with c.1521_1523delCTT; Exon 11. Four patients (10%) with c.416A>T; Exon 13. Three patients (7.5%) with c.2421A>G; Exon 14. Two patients (5%) with c.3908A>C; Exon 21. One patient (2.5%) with c.3889dupT; Exon 24. One patient (2.5%) with c.1657C>T; Exon 12. One patient (2.5%) with c.2547C>A; Exon 14a. Eighteen patients (45%) were presented with vomiting, 38 patients (95%) had postnatal radiological findings, 7 patients (17.5%) had electrolytes imbalance. Five patients (12.5%) had cholestasis and 4 patients (10%) developed chronic liver disease. Thirty-five patients (79.5%) underwent surgical repair and 9 patients (20.5%) were treated medically. Mean age of operation was 2.25 (2) days. Of 9 patients, 6 (66.6%) were treated with gastrograffin enema, 2 patients (22.2%) with oral N-acetylcysteine and 1 patient (11.1%) with saline rectal wash. Thirteen patients (31.5%) required TPN. Five patients had recurrent operation.ConclusionCF and meconium ileus are commonly present in CF patients in Saudi Arabia. Prognosis is similar to other CFs without MI, if treated early. Thirty percent of our CF/MI patients have intronic mutations.

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Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results.

Publications

Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results.

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