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Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the Ϫ159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannosebinding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture-proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n ϭ15) and the IL6-174G allele (n ϭ121) had a significantly higher rate of blood culture-proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p ϭ 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; p Ͻ 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0 -3.9; p ϭ 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0 -10.4; p ϭ 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5% versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p ϭ 0.033). Although advances in neonatal intensive care have led to improved survival, sepsis continues to be an important cause of death among VLBW infants (1, 2). Recent advances in our understanding of the innate immune system triggered the identification of specific point mutations that are associated with an altered response of the innate immune system. CD14 is the main receptor for bacterial LPS and is expressed on the surface of phagocytes. In adults, the homozygotic Ϫ159T mutation of the CD14 gene (CD14-159T) is associated with a high mortality rate in sepsis (3). The TLR4 is a coreceptor for LPS, harboring a transmembrane domain, which is important for intracellular signaling. The 896G mutation of the TLR4 (TLR4-896G) leads in vitro to a reduced NF-B activation after LPS stimulation, and in vivo to a reduced systemic inflammatory response after LPS inhalation (4). This mutation was found frequently in adults who developed septic shock (5), suggesting an association of this mutation with sepsis. NOD2 is a gene that also confers responsiveness to bacterial LPS. The NOD2-3020insC mutation is associated in vitro with reduced NF-B response after stimulation with several Gram-negative bacteria (6) and is associated with Crohns' disease (6 -8). IL-6 is an important proinf...

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