Genetic modifiers of nutritional status in cystic fibrosis
ABSTRACT 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.
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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
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ABSTRACT: Rationale Diabetes is associated with increased mortality in cystic fibrosis. Aggressive screening and early institution of insulin treatment significantly reduced this risk over the period of 1992-2008. Objective To determine if progressive improvement in CFRD mortality has continued since 2008, and examine associations with CFTR genotypes linked to pancreatic insufficiency and with gender. Methods Chart review was performed on 664 patients followed 2008-2012. Measurements and Main Results Overall mortality for patients with CFRD was 1.8 per 100 person years, compared to 0.5 in CF patients without diabetes (p=0.0002); neither rate changed significantly from mortality reported for 2003-2008. Genotype impacted both mortality and diabetes risk: adults with severe CFTR genotypes experienced greater mortality at every age over 32 years than those with mild genotypes (p=0.002), and the risk of developing CFRD was also greatly increased in those with severe genotypes (prevalence 60% in adult patients with severe vs 14% in adults with mild mutations). CFRD had a direct influence on mortality since it was associated with increased risk of death within each genotype category (20 vs 2%, p=0.007 for mild; 12 vs 4%, p=0.012 for severe). There was also a gender difference in adults with severe CFTR genotypes; both mortality and CFRD prevalence were higher at every age in females than males. Conclusions Despite substantial improvement over time, mortality for CFRD patients >30 years remains higher than for CF patients without diabetes.American Journal of Respiratory and Critical Care Medicine 12/2014; 191(2). DOI:10.1164/rccm.201403-0576OC · 11.99 Impact Factor
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ABSTRACT: The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.Nature Reviews Genetics 11/2014; DOI:10.1038/nrg3849 · 39.79 Impact Factor