title: 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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gia M
authors.initials: GM
authors.lastname: Bradley
authors.forename: Scott M
authors.initials: SM
authors.lastname: Blackman
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Watson
authors.forename: Vishal K
authors.initials: VK
authors.lastname: Doshi
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
mesh_terms: D015992:Body Mass Index; D002657:Child Development; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009752:Nutritional Status; D010179:Pancreas / Q000503:physiopathology; D012042:Registries; D035781:Siblings; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator