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1.
Am J Clin Nutr ; 96(6): 1299-308, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23134884

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.


Subject(s)
Child Development , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 5/genetics , Cystic Fibrosis/genetics , Genetic Variation , Nutritional Status , Body Mass Index , Child, Preschool , Cystic Fibrosis/metabolism , Cystic Fibrosis/physiopathology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Female , Genetic Loci , Genome-Wide Association Study , Humans , Longitudinal Studies , Male , Pancreas/physiopathology , Registries , Siblings , Twins, Dizygotic , Twins, Monozygotic
2.
Nat Genet ; 44(5): 562-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22466613

ABSTRACT

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.


Subject(s)
Cell Membrane/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/genetics , Genetic Predisposition to Disease , Ileus/genetics , Meconium , Polymorphism, Single Nucleotide/genetics , Amino Acid Transport Systems , Amino Acid Transport Systems, Neutral/genetics , Antiporters/genetics , Genome-Wide Association Study , Genotype , Humans , Intestinal Obstruction/etiology , Sodium-Hydrogen Exchanger 3 , Sodium-Hydrogen Exchangers/genetics , Sulfate Transporters
3.
PLoS Genet ; 8(3): e1002580, 2012.
Article in English | MEDLINE | ID: mdl-22438829

ABSTRACT

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5' to and within the MSRA gene were associated with MI (P = 1.99 × 10(-5) to 1.08 × 10(-6); Bonferroni P = 0.057 to 3.1 × 10(-3)). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53-0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2 × 10(-4)). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr(-/-) and Cftr(-/-)Msra(-/-) mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Intestinal Obstruction , Methionine Sulfoxide Reductases , Animals , Cystic Fibrosis/complications , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Genetic Association Studies , Goblet Cells/pathology , Haplotypes , Humans , Intestinal Obstruction/complications , Intestinal Obstruction/genetics , Intestinal Obstruction/metabolism , Methionine Sulfoxide Reductases/genetics , Methionine Sulfoxide Reductases/metabolism , Mice , Mice, Inbred CFTR , Polymorphism, Single Nucleotide
4.
Nat Genet ; 43(6): 539-46, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21602797

ABSTRACT

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.


Subject(s)
Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 20 , Cystic Fibrosis/genetics , Genetic Linkage , Lung Diseases/genetics , Adolescent , Adult , Child , Female , Genome-Wide Association Study , Humans , Male , Phenotype , Quantitative Trait Loci
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