BACKGROUND: Improved nutrition early in life is associated with better pulmonary function for patients with cystic fibrosis (CF). However, nutritional status is poorly correlated with the CFTR genotype. OBJECTIVE: We investigated the extent to which modifier genes influence nutrition in children with CF. DESIGN: BMI data were longitudinally collected from the CF Twin-Sibling Study and Cystic Fibrosis Foundation Patient Registry for twins and siblings from 2000 to 2010. A nutritional phenotype was derived for 1124 subjects by calculating the average BMI z score from 5-10 y of age (BMI-z(5to10)). The genetic contribution to the variation in BMI-z(5to10) (ie, heritability) was estimated by comparing the similarity of the phenotype in monozygous twins to that in dizygous twins and siblings. Linkage analysis identified potential modifier-gene loci. RESULTS: The median BMI-z(5to10) was -0.07 (range: -3.89 to 2.30), which corresponded to the 47th CDC percentile. BMI-z(5to10) was negatively correlated with pancreatic insufficiency, history of meconium ileus, and female sex but positively correlated with later birth cohorts and lung function. Monozygous twins showed greater concordance for BMI-z(5to10) than did dizygous twins and siblings; heritability estimates from same-sex twin-only analyses ranged from 0.54 to 0.82. For 1010 subjects with pancreatic insufficiency, genome-wide significant linkage was identified on chromosomes 1p36.1 [log of odds (LOD): 5.3] and 5q14 (LOD: 5.1). These loci explained ≥16% and ≥15%, respectively, of the BMI variance. CONCLUSIONS: The analysis of twins and siblings with CF indicates a prominent role for genes other than CFTR to BMI variation. Specifically, regions on chromosomes 1 and 5 appear to harbor genetic modifiers of substantial effect.
"In another approach, body mass index data collected from the CF Twin-Sibling Study (ClinicalTrials.Gov identifier NCT00037778)41 were analyzed to define the contribution of genetic modifiers to the nutritional status of young CF patients aged 5–10 years.59 For 1,010 individuals with pancreatic insufficiency, significant linkage of body mass index and the two chromosomal regions 1p36.1 and 5q14 was found, the latter including the arrestin domain-containing 3 (ARRDC3) gene, a regulator of body mass and energy expenditure in males.60 "
[Show abstract][Hide abstract] ABSTRACT: The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.
The Application of Clinical Genetics 07/2014; 7:133-46. DOI:10.2147/TACG.S18675
[Show abstract][Hide abstract] ABSTRACT: Objectives:
To test the hypothesis that pubertal peak height velocity (PHV) in cystic fibrosis (CF) has improved and is influenced by prepubertal growth and genetic potential.
PHV from 1862 children born in 1984-87 and documented in the 1986-2008 US CF Foundation Registry was determined by statistical modeling and classified into normal, delayed (2-SD > average age), attenuated (magnitude <5th percentile), or both delayed and attenuated (D&A). Genetic potential for height was estimated by parental stature.
PHV averaged 8.4 cm/year at age 14.0 years in boys and 7.0 cm/year at age 12.1 years in girls, ∼6-month delay and ∼15% reduction compared with healthy children. PHV was normal in 60%, delayed in 9%, attenuated in 21%, and D&A in 5%. Patients with delayed PHV reached similar adult height percentile (boys: 34th, girls: 46th) to those with normal PHV (boys: 33rd, girls: 34th); both were significantly taller than the attenuated (boys: 11th, girls: 19th) and D&A PHV subgroups (boys: 8th, girls: 14th). Pancreatic-sufficient patients had taller prepubertal and adult heights but similar PHV compared with pancreatic-insufficient or meconium ileus patients. Adjusting for genetic potential reduced adult height percentiles more in boys (from 25th to 16th) than girls (from 28th to 24th). Height at age 7 years, PHV age and magnitude, and parental stature significantly predicted adult height.
Pubertal PHV has improved in children with CF born after mid-1980s compared with older cohorts but remains below normal. Suboptimal prepubertal and pubertal growth led to adult height below genetic potential in CF.
The Journal of pediatrics 03/2013; 163(2). DOI:10.1016/j.jpeds.2013.02.026 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Three major clinical subgroups are usually distinguished in Mucopolysaccharidosis type I: Hurler (MPS IH, severe presentation), Hurler-Scheie (MPS IH/S, intermediate) and Scheie (MPS IS, mild). To facilitate treatment with hematopoietic stem-cell transplantation, early diagnosis is important for MPS IH patients. Although screening for MPS I in newborns would allow detection at an early age, it may be difficult to predict the phenotype on the basis of the genotype in these infants. Extra diagnostic tools are thus required. Based on the hypothesis that distinct MPS I phenotypes may result from differences in residual α-l-iduronidase (IDUA) activity, we modified the common IDUA assay using the substrate 4-methylumbelliferyl-α-l-iduronide to allow quantification of low IDUA activity in MPS I fibroblasts. Enzyme incubation was performed with high protein concentrations at different time points up to 8h. Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5). These results suggest that residual IDUA activity and severity of the MPS I phenotype are correlated. Two MPS IS patients with rare (E276K/E276K) or indefinite (A327P/unknown) IDUA genotypes had residual IDUA activity in the MPS IS range, illustrating the usefulness of our approach. IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability. We conclude that this procedure for determining residual IDUA activity in fibroblasts of MPS I patients may be helpful to predict MPS I phenotype.
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