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NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants

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NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants. / Härtel, Christoph; Hartz, Annika; Pagel, Julia; Rupp, Jan; Stein, Anja; Kribs, Angela; Müller, Andreas; Haase, Roland; Gille, Christian; Böttger, Ralf; Kittel, Jochen; Jensen, Reinhard; Wieg, Christian; Herting, Egbert; Göpel, Wolfgang; German Neonatal Network (GNN).

In: INFLAMM BOWEL DIS, Vol. 22, No. 2, 02.2016, p. 249-56.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Härtel, C, Hartz, A, Pagel, J, Rupp, J, Stein, A, Kribs, A, Müller, A, Haase, R, Gille, C, Böttger, R, Kittel, J, Jensen, R, Wieg, C, Herting, E, Göpel, W & German Neonatal Network (GNN) 2016, 'NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants', INFLAMM BOWEL DIS, vol. 22, no. 2, pp. 249-56. https://doi.org/10.1097/MIB.0000000000000658

APA

Härtel, C., Hartz, A., Pagel, J., Rupp, J., Stein, A., Kribs, A., Müller, A., Haase, R., Gille, C., Böttger, R., Kittel, J., Jensen, R., Wieg, C., Herting, E., Göpel, W., & German Neonatal Network (GNN) (2016). NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants. INFLAMM BOWEL DIS, 22(2), 249-56. https://doi.org/10.1097/MIB.0000000000000658

Vancouver

Härtel C, Hartz A, Pagel J, Rupp J, Stein A, Kribs A et al. NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants. INFLAMM BOWEL DIS. 2016 Feb;22(2):249-56. https://doi.org/10.1097/MIB.0000000000000658

Bibtex

@article{2de5a765a33744638d5b0c1d314fb38f,
title = "NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants",
abstract = "BACKGROUND: NOD2 loss-of-function mutations, that is, R702W [rs2066844], G908R [rs2066845], and Leu1007fsinsC [rs5743293], have been linked to inflammatory bowel diseases. It is yet unknown whether these variants are also associated with necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) in infants of very low birth weight (VLBW).METHODS: To test this hypothesis, we genotyped 9082 VLBW infants with European ancestry enrolled in a prospective, population-based cohort study of the German Neonatal Network. We assessed the effect of the NOD2 gene variants on the risk for major morbidities of the gastrointestinal tract, that is, NEC/FIP requiring surgery in multivariable logistic regression analyses.RESULTS: In the whole cohort of VLBW infants, carriers of ≥ 2 NOD2 variant alleles had an increased risk for NEC requiring surgery (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.27-10.04; P = 0.03) and NEC or FIP requiring surgery (OR, 3.81; 95% CI, 1.70-8.51; P = 0.004) as compared with wild-type genotypes. In a multivariable logistic regression analysis including gestational age, birth weight, gender, multiple birth, and inborn delivery, the association between ≥ 2 NOD2 variant alleles and NEC surgery (OR, 4.14; 95% CI, 1.41-12.12; P = 0.009), FIP surgery (OR, 3.50; 95% CI, 1.02-12.04; P = 0.047), and NEC or FIP surgery (OR, 4.10; 95% CI, 1.74-9.73; P = 0.001) proved to be independent. We also performed a regression analysis in the subgroup of infants with available information on Lactobacillus acidophilus/Bifidobacterium infantis probiotic supplementation (n = 3638). Although probiotics had a protective effect on NEC and NEC or FIP requiring surgery, the NOD2 variants had no significant impact in this subgroup.CONCLUSIONS: VLBW infants carrying ≥ 2 NOD2 genetic risk factors of inflammatory bowel disease in adults have an increased risk for severe gastrointestinal complications, such as NEC requiring surgery. Therefore, infants might benefit from NOD2 genotyping followed by supplementation with probiotics. Replication studies are needed along with genome-wide arrays to allow risk-adapted prevention and therapeutic strategies.",
keywords = "Adult, Enterocolitis, Necrotizing/drug therapy, Follow-Up Studies, Germany/epidemiology, Humans, Infant, Infant, Very Low Birth Weight, Intestinal Perforation/drug therapy, Mutation/genetics, Nod2 Signaling Adaptor Protein/genetics, Probiotics/therapeutic use, Prognosis, Prospective Studies",
author = "Christoph H{\"a}rtel and Annika Hartz and Julia Pagel and Jan Rupp and Anja Stein and Angela Kribs and Andreas M{\"u}ller and Roland Haase and Christian Gille and Ralf B{\"o}ttger and Jochen Kittel and Reinhard Jensen and Christian Wieg and Egbert Herting and Wolfgang G{\"o}pel and {German Neonatal Network (GNN)}",
year = "2016",
month = feb,
doi = "10.1097/MIB.0000000000000658",
language = "English",
volume = "22",
pages = "249--56",
journal = "INFLAMM BOWEL DIS",
issn = "1078-0998",
publisher = "John Wiley and Sons Inc.",
number = "2",

}

RIS

TY - JOUR

T1 - NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants

AU - Härtel, Christoph

AU - Hartz, Annika

AU - Pagel, Julia

AU - Rupp, Jan

AU - Stein, Anja

AU - Kribs, Angela

AU - Müller, Andreas

AU - Haase, Roland

AU - Gille, Christian

AU - Böttger, Ralf

AU - Kittel, Jochen

AU - Jensen, Reinhard

AU - Wieg, Christian

AU - Herting, Egbert

AU - Göpel, Wolfgang

AU - German Neonatal Network (GNN)

PY - 2016/2

Y1 - 2016/2

N2 - BACKGROUND: NOD2 loss-of-function mutations, that is, R702W [rs2066844], G908R [rs2066845], and Leu1007fsinsC [rs5743293], have been linked to inflammatory bowel diseases. It is yet unknown whether these variants are also associated with necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) in infants of very low birth weight (VLBW).METHODS: To test this hypothesis, we genotyped 9082 VLBW infants with European ancestry enrolled in a prospective, population-based cohort study of the German Neonatal Network. We assessed the effect of the NOD2 gene variants on the risk for major morbidities of the gastrointestinal tract, that is, NEC/FIP requiring surgery in multivariable logistic regression analyses.RESULTS: In the whole cohort of VLBW infants, carriers of ≥ 2 NOD2 variant alleles had an increased risk for NEC requiring surgery (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.27-10.04; P = 0.03) and NEC or FIP requiring surgery (OR, 3.81; 95% CI, 1.70-8.51; P = 0.004) as compared with wild-type genotypes. In a multivariable logistic regression analysis including gestational age, birth weight, gender, multiple birth, and inborn delivery, the association between ≥ 2 NOD2 variant alleles and NEC surgery (OR, 4.14; 95% CI, 1.41-12.12; P = 0.009), FIP surgery (OR, 3.50; 95% CI, 1.02-12.04; P = 0.047), and NEC or FIP surgery (OR, 4.10; 95% CI, 1.74-9.73; P = 0.001) proved to be independent. We also performed a regression analysis in the subgroup of infants with available information on Lactobacillus acidophilus/Bifidobacterium infantis probiotic supplementation (n = 3638). Although probiotics had a protective effect on NEC and NEC or FIP requiring surgery, the NOD2 variants had no significant impact in this subgroup.CONCLUSIONS: VLBW infants carrying ≥ 2 NOD2 genetic risk factors of inflammatory bowel disease in adults have an increased risk for severe gastrointestinal complications, such as NEC requiring surgery. Therefore, infants might benefit from NOD2 genotyping followed by supplementation with probiotics. Replication studies are needed along with genome-wide arrays to allow risk-adapted prevention and therapeutic strategies.

AB - BACKGROUND: NOD2 loss-of-function mutations, that is, R702W [rs2066844], G908R [rs2066845], and Leu1007fsinsC [rs5743293], have been linked to inflammatory bowel diseases. It is yet unknown whether these variants are also associated with necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) in infants of very low birth weight (VLBW).METHODS: To test this hypothesis, we genotyped 9082 VLBW infants with European ancestry enrolled in a prospective, population-based cohort study of the German Neonatal Network. We assessed the effect of the NOD2 gene variants on the risk for major morbidities of the gastrointestinal tract, that is, NEC/FIP requiring surgery in multivariable logistic regression analyses.RESULTS: In the whole cohort of VLBW infants, carriers of ≥ 2 NOD2 variant alleles had an increased risk for NEC requiring surgery (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.27-10.04; P = 0.03) and NEC or FIP requiring surgery (OR, 3.81; 95% CI, 1.70-8.51; P = 0.004) as compared with wild-type genotypes. In a multivariable logistic regression analysis including gestational age, birth weight, gender, multiple birth, and inborn delivery, the association between ≥ 2 NOD2 variant alleles and NEC surgery (OR, 4.14; 95% CI, 1.41-12.12; P = 0.009), FIP surgery (OR, 3.50; 95% CI, 1.02-12.04; P = 0.047), and NEC or FIP surgery (OR, 4.10; 95% CI, 1.74-9.73; P = 0.001) proved to be independent. We also performed a regression analysis in the subgroup of infants with available information on Lactobacillus acidophilus/Bifidobacterium infantis probiotic supplementation (n = 3638). Although probiotics had a protective effect on NEC and NEC or FIP requiring surgery, the NOD2 variants had no significant impact in this subgroup.CONCLUSIONS: VLBW infants carrying ≥ 2 NOD2 genetic risk factors of inflammatory bowel disease in adults have an increased risk for severe gastrointestinal complications, such as NEC requiring surgery. Therefore, infants might benefit from NOD2 genotyping followed by supplementation with probiotics. Replication studies are needed along with genome-wide arrays to allow risk-adapted prevention and therapeutic strategies.

KW - Adult

KW - Enterocolitis, Necrotizing/drug therapy

KW - Follow-Up Studies

KW - Germany/epidemiology

KW - Humans

KW - Infant

KW - Infant, Very Low Birth Weight

KW - Intestinal Perforation/drug therapy

KW - Mutation/genetics

KW - Nod2 Signaling Adaptor Protein/genetics

KW - Probiotics/therapeutic use

KW - Prognosis

KW - Prospective Studies

U2 - 10.1097/MIB.0000000000000658

DO - 10.1097/MIB.0000000000000658

M3 - SCORING: Journal article

C2 - 26752461

VL - 22

SP - 249

EP - 256

JO - INFLAMM BOWEL DIS

JF - INFLAMM BOWEL DIS

SN - 1078-0998

IS - 2

ER -