Genetic Variations in Toll-like Receptors and Susceptibility to Chronic Lung Disease in Very Low Birth Weight Babies (CLD)

• To determine if small variations in certain genes predispose infants to the development of chronic lung disease. [ Time Frame: through discharge from hospital ] [ Designated as safety issue: No ]
  

Chronic lung disease of prematurity (CLD) is diagnosed in >30% of Very low birth-weight infants (<1500gms) and is a major cause of mortality and long-term morbidity in this population. While multiple factors have been implicated in the pathogenesis of CLD, a body of evidence suggests that exposure to antenatal chorioamnionitis and postnatal infections substantially increase the risk of CLD. Environmental and genetic factors which increase susceptibility of the premature infant to infection mediated inflammation in the lung may result in CLD. Toll like receptors (TLRs) are pathogen recognition receptors which serve as the recognition and effector arm of the innate immune system. Since the premature infant is predominantly dependent on the innate immune system for host defense our hypothesis is that hypomorphic genetic variations in TLRs will increase susceptibility to CLD. Our hypothesis will be tested in VLBW infants in two specific aims: 1) To determine if the presence of previously described single nucleotide polymorphisms (SNPs) in TLR4 (Asp299Gly, Thr399Ile) TLR2 (Arg753Gln) and TLR5 (Arg392STOP) genes is associated with an increased risk of CLD and 2) To detect by DNA sequencing if novel genetic variations in TLR4, TLR2, TLR9 and MyD88 genes increases the risk of CLD. VLBW infants who develop CLD (oxygen requirement at 36 weeks postconceptional age) will serve as cases while VLBW infants who do not develop CLD will serve as controls. 1 ml of blood will be collected from enrolled infants via indwelling catheters or venipuncture for DNA analysis after consent is obtained. The detection of TLR4 (Asp299Gly, Thr399Ile) TLR2 (Arg753Gln) and TLR5 (Arg392STOP) SNPs will be done using a multiplex Single Base extension based technique. Novel genetic variations in the genes of interest will be detected using DNA sequencing. Benefits include the possibility of development of risk-based preventive and therapeutic strategies to prevent CLD, decreasing morbidity and mortality from the disease.