ABSTRACT
BACKGROUND: The genetic basis of dysfunctional immune responses in necrotizing enterocolitis (NEC) remains unknown. We hypothesized that variants in nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) and autophagy (ATG) genes modulate vulnerability to NEC. METHODS: We genotyped a multi-center cohort of premature infants with and without NEC for NOD1, NOD2, ATG16L1, CARD8, and NLRP3 variants. Chi-square tests and logistic regression were used for statistical analysis. RESULTS: In our primary cohort (n = 1,015), 86 (8.5%) infants developed NEC. The A allele of the ATG16L1 (Thr300Ala) variant was associated with increased NEC (AA vs. AG vs. GG; 11.3 vs. 8.4 vs. 4.8%, P = 0.009). In regression models for NEC that adjusted for epidemiological confounders, GA (P = 0.033) and the AA genotype (P = 0.038) of ATG16L1 variant were associated with NEC. The association between the A allele of the ATG16L1 variant and NEC remained significant among Caucasian infants (P = 0.02). In a replication cohort (n = 259), NEC rates were highest among infants with the AA genotype but did not reach statistical significance. CONCLUSION: We report a novel association between a hypomorphic variant in an autophagy gene (ATG16L1) and NEC in premature infants. Our data suggest that decreased autophagy arising from genetic variants may confer protection against NEC.
Subject(s)
Autophagy-Related Proteins/genetics , Autophagy , Enterocolitis, Necrotizing/genetics , Infant, Premature , Alleles , Carrier Proteins/genetics , Cohort Studies , Female , Genetic Predisposition to Disease , Genetic Variation , Genotype , Humans , Infant, Newborn , Polymorphism, Single Nucleotide , White PeopleABSTRACT
BACKGROUND: Previous work has demonstrated a strong association between lung injury in African American children with pneumonia and a polymorphic (TG)mTn region in cystic fibrosis transmembrane conductance (CFTR) involved in the generation of a nonfunctional CFTR protein lacking exon 9. A number of splicing factors that regulate the inclusion/exclusion of exon 9 have been identified. The objective of this study was to determine whether genetic variants in these splicing factors were associated with acute respiratory distress syndrome (ARDS) in children with pneumonia. METHODS: This is a prospective cohort genetic association study of lung injury in African American and non-Hispanic Caucasian children with community-acquired pneumonia evaluated in the emergency department or admitted to the hospital. Linkage-disequilibrium-tag single nucleotide polymorphisms (LD-tag SNPs) in genes of the following splicing factors (followed by gene name) involved in exon 9 skipping PTB1 (PTBP1), SRp40 (SFRS1), SR2/ASF (SFRS5), TDP-43 (TARDBP), TIA-1 (TIA1), and U2AF(65) (U2AF2) were genotyped. SNPs in the gene of the splicing factor CELF2 (CELF2) were selected by conservation score. Multivariable analysis was used to examine association between genotypes and ARDS. RESULTS: The African American cohort (n = 474) had 29 children with ARDS and the non-Hispanic Caucasian cohort (n = 304) had 32 children with ARDS. In the African American group multivariable analysis indicated that three variants in CELF2, rs7068124 (p = 0.004), rs3814634 (p = 0.032) and rs10905928 (p = 0.044), and two in TIA1, rs2592178 (p = 0.005) and rs13402990 (p = 0.018) were independently associated with ARDS. In the non-Hispanic Caucasian group, a single variant in CELF2, rs2277212 (p = 0.014), was associated with increased risk of developing ARDS. CONCLUSIONS: The data indicate that SNPs in CELF2 may be associated with the risk of developing ARDS in both African American and non-Hispanic Caucasian children with pneumonia and suggest that the potential role of the splicing factor CELF2 in ARDS should be explored further.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/physiology , Polymorphism, Single Nucleotide/physiology , RNA, Messenger/genetics , Respiratory Distress Syndrome/genetics , Adolescent , Black or African American/ethnology , Black or African American/genetics , CELF Proteins , Child , Child, Preschool , Cohort Studies , Cystic Fibrosis/genetics , Cystic Fibrosis/physiopathology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Female , Genetic Testing/methods , Genetic Variation , Humans , Infant , Infant, Newborn , Male , Multivariate Analysis , Nerve Tissue Proteins , Pneumonia/ethnology , Pneumonia/genetics , Pneumonia/physiopathology , Prospective Studies , Respiratory Distress Syndrome/ethnology , Respiratory Distress Syndrome/physiopathology , White People/ethnology , White People/geneticsABSTRACT
OBJECTIVES: The cystic fibrosis transmembrane conductance regulator regulates fluid balance in alveolar epithelial cells and appears to modulate the inflammatory response. To determine whether more severe lung injury in children who develop community-acquired pneumonia is associated with variations known to affect function in the gene coding for cystic fibrosis transmembrane conductance regulator. DESIGN: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia. SETTING: Three major tertiary care children's hospitals. SUBJECTS: Caucasian and African American children with community-acquired pneumonia either evaluated in the emergency department or admitted to the hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Caucasian and African American children with pneumonia were genotyped for the most common variants reported to affect cystic fibrosis transmembrane conductance regulator function, the p.508del mutation, the (TG)mTn variable repeat region, and the M470V polymorphism in the cystic fibrosis transmembrane conductance regulator gene. Genotypes and haplotypes were determined, and the association of high-risk alleles or high-risk haplotypes (defined as the presence of at least one variant known to decrease the level of functional cystic fibrosis transmembrane conductance regulator) with the need for mechanical ventilation or the development of acute lung injury was evaluated. Forty-two children in the Caucasian cohort (n = 304) required mechanical ventilation; 32 developed acute lung injury. Forty-three children in the African American cohort (n = 474) required mechanical ventilation; 29 developed acute lung injury. In African American children, high-risk (TG)mTn alleles known to result in decreased levels of functional cystic fibrosis transmembrane conductance regulator were associated with the need for mechanical ventilation (p = .0013) and the development of acute lung injury (p = .0061). Multivariable analysis demonstrated that high-risk (TG)mTn alleles were independently associated with mechanical ventilation (odds ratios = 3.19; 95% confidence interval, 1.63-6.26) and acute lung injury (odds ratios = 3.36; 95% confidence interval, 1.50-7.53) in African American children. CONCLUSION: Genetic variation in cystic fibrosis transmembrane conductance regulator is associated with acute lung injury in African American children with community-acquired pneumonia.
Subject(s)
Acute Lung Injury/genetics , Black or African American/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Pneumonia/genetics , Acute Lung Injury/ethnology , Adolescent , Alleles , Base Sequence , Child , Child, Preschool , Community-Acquired Infections/ethnology , Community-Acquired Infections/genetics , DNA Primers , Female , Humans , Infant , Infant, Newborn , Male , Pneumonia/ethnology , Polymorphism, Genetic/genetics , Prospective StudiesABSTRACT
The light-harvesting antenna (LH) proteins of Rhodospirillum rubrum are encoded by pufA and pufB with C-terminal extensions not present in the mature proteins. Point mutations were introduced into pufB, pufA, and both pufB and pufA so that proteins equivalent to the mature proteins were encoded. The mutants with these truncated proteins produced 3-30% of the wild-type level of LH. These findings suggest that the C-terminal extensions are required for wild-type levels of LH.
