The prevalence of platelet activating factor acetylhydrolase single nucleotide polymorphisms in relationship to necrotizing enterocolitis in Northwest Louisiana infants (original) (raw)
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Scientific Reports, 2016
The p.Thr1406Asn (rs1047891) polymorphism of the carbamoyl-phosphate synthetase 1 (CPS1) gene has been linked to functional consequences affecting the downstream availability of the nitric oxide precursor L-arginine. L-arginine concentrations are decreased in preterm infants with necrotizing enterocolitis (NEC). In this multicenter prospective study, we investigated the association of the p.Thr1406Asn polymorphism with NEC in 477 preterm infants (36 cases of NEC) from 4 European neonatal intensive care units (Maastricht, Las Palmas de Gran Canaria, Mantova, and Milan). Allele and genotype frequencies of the p.Thr1406Asn polymorphism did not significantly differ between the infants with and without NEC. In contrast, the minor A-allele was significantly less frequent in the group of 64 infants with the combined outcome NEC or death before 34 weeks of corrected gestational age than in the infants without the outcome (0.20 vs. 0.31, P = 0.03). In addition, a significant negative associa...
ABCD Arq Bras Cir Dig, 2022
BACKGROUND: Abnormalities in the different stages of the intestinal maturation process cause metabolic and molecular changes. Among the genetic alterations associated with necrotizing enterocolitis, the-94ins/delATTG polymorphism in NFKB1 gene leads to unregulated activation of the NFKB protein due to an increase in the inherent pro-inflammatory state of the premature intestine. AIMS: To determine the prevalence of the-94ins/delATTG polymorphism in NFKB1 gene in neonates with and without necrotizing enterocolitis. METHODS: This is a case-control study, in which 25 neonates were evaluated as the case group and 50 neonates as the control group, of both genders. DNA was extracted from peripheral blood leukocytes, and the site encompassing the polymorphism was amplified by molecular techniques (polymerase chain reaction/polymorphism in restriction fragment length). RESULTS: Necrotizing enterocolitis was diagnosed in 25 (33%) neonates and, of these, 3 (12%) died. Male gender was more prevalent in both groups (p=0.1613): cases (52%) and controls (62%). Moderate and extreme preterm newborns were predominant in both groups: cases (80%) and controls (88%) (p=0.3036). Low birth weight and extremely low birth weight newborns were the most prevalent in cases (78%), and very low birth weight and extremely low birth weight were the most prevalent in controls (81%) (p=0.1073). Clinical treatment was successful in 72%, and hospital discharge was achieved in 88% of newborns with NEC. The-94ins/delATTG polymorphism in NFKB1 gene was not identified in all the 150 alleles analyzed (100%). CONCLUSIONS: The absence of the-94ins/delATTG polymorphism in NFKB1 gene in newborns with and without necrotizing enterocolitis does not rule out the possibility of alterations in this and/or in other genes in newborns with this condition, which reinforces the need for further research.
Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis?
Scientific Reports, 2015
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56-32.52). Neonates with TGFβ-1 (rs2241712) had a decreased incidence of NEC-related perforation (p = 0.044; OR = 0.28, 95% CI: 0.08-0.97) and an increased incidence of mortality (p = 0.049; OR = 2.99, 95% CI: 1.01-8.86). TRIM21 (rs660) was associated with NEC-related intestinal perforation (p = 0.038; OR = 4.65, 95% CI 1.09-19.78). In premature Caucasian neonates, the functional SNP IL-6 (rs1800795) is associated with both the development and increased severity of NEC. TRIM21 (rs660) and TGFβ-1 (rs2241712) were associated with NEC-related perforation in all neonates in the cohort. These findings suggest a possible genetic role in the development of NEC. Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among preterm neonates 1,2. Its prevalence has increased over the last 30 years as advances in neonatal critical care have led to improved survival of more preterm neonates. In fact, a recent study looking at mortality among extremely premature neonates between 2000-2011, noted that although overall mortality among this population has declined, deaths related to NEC have increased 3. There is an overall mortality rate of 20-30% in infants with NEC and approaches 100% in neonates with pan-intestinal disease (NEC totalis) 4. The onset of NEC is variable, and is inversely proportional to gestational age 5. Signs and symptoms of the disease are often non-specific and require a high index of suspicion. The diagnosis of NEC is made using specific criteria as classified by the Modified Bell Staging (Table 1) 6,7 .
Journal of Pediatrics & Neonatal Care, 2018
Background: Arginine deficiency contributes a significant metabolic problem in preterm babies especially those with necrotizing enterocolitis (NEC). A [C-to A-] nucleotide transverse in the gene encodes Carbamyol-Phosphate Synthetase 1 (CPS1) enzyme has been associated with low arginine level among term neonates but not in adult. Aim of the study: We aimed at investigating the association between CPS1 gene (4217 C>A) polymorphism and plasma L-arginine level among Egyptian preterm infants with NEC. Material & methods: A case-control study was conducted on 30 preterm infant (26-34 weeks of gestation) with NEC. Thirty sex and gestational age harmonized preterm babies without NEC were eligible as controls. Both cases and controls were subjected to plasma L-arginine level measurement using ELISA and genotyped for CPS1 gene (4217 C>A) using PCR-based RFLP-assay. Results: There were significant decrease in plasma L-arginine concentration in preterm with NEC when compared to controls (P=0.002).The frequency distribution of CPS1 gene (4217 C>A) genotypes were in agreement with Hardy Weinberg (HW) equilibrium. The distribution of CPS1 gene (4217 C>A) C/C , C/A, A/A genotypes and A allele were 20(66.6%),8(26.7%), 2(6.7%) and12(20%) among cases and 22(7.3%),6(20%),2(6.7%) and 10(16.7%) among controls with estimated odds ratio of 1.46 ,1.1 and 1.25 respectively. There was no significant relation between low L-arginine level and CPS1 gene (4217 C>A) genotypes. A significantly lower L-arginine levels were observed among NEC non-survivors when compared to survivors (P=0.004), however, there was no significant difference between 2 groups regarding CPS1 gene (4217 C>A) genotype distribution. (P=0.570). Conclusion: A significantly lower L-arginine level was detected among preterm with NEC and significantly related to poor outcome. However, no significant relation was observed between low L-arginine level and CPS1 gene (4107 C>A) polymorphism.
Frontiers in Pediatrics, 2020
The etiology of necrotizing enterocolitis (NEC) is multifactorial and an underlying genetic predisposition to NEC is increasingly being recognized. A growing number of studies identified single nucleotide polymorphisms (SNPs) of selected genes with potential biological relevance in the development of NEC. However, few of these genetic studies have been replicated in validation cohorts. We aimed to confirm in a cohort of 358 preterm newborns (gestational age <30 weeks, 26 cases of NEC ≥ Bell stage II) the association with NEC of three candidate SNPs: the vascular endothelium growth factor (VEGF) C-2578A polymorphism (rs699947), the interleukin (IL)-18 C-607A polymorphism (rs1946518), and the IL-4 receptor α-chain (IL-4Rα) A-1902G polymorphism (rs1801275). We observed that allele and genotype frequencies of the three SNPs did not significantly differ between the infants with and without NEC. In contrast, the minor G-allele of the IL-4Rα A-1902G polymorphism was significantly less frequent in the group of 51 infants with the combined outcome NEC or death before 34 weeks postmenstrual age than in the infants without the outcome (0.206 vs. 0.331, P = 0.01). In addition, a significant negative association of the G-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.44, 95% CI 0.21-0.92), recessive (aOR 0.15, 95% CI 0.03-0.74), and additive (aOR 0.46, 95% CI 0.26-0.80) genetic models. In conclusion our study provides further evidence that a genetic variant of the IL-4Rα gene may contribute to NEC.
Transfusion, 2003
Background: The study of the immunogenetics of the human platelet antigens is important to the improvement of diagnosis and genetic counseling and to the develo ment of eening programs for women at risk of having babies with neonatal arl,mmunq rombocytopenia. Description of the immunogenetics of the human platelet ant ens in some racial groups has been incomplete. Study Design and Methods: A reverse dot blot technique employing polymerase chain reaction-amplified genomic DNA was applied in genotyping the five major human platelet antigens in the following populations: 100 African American and 100 white .women admitted to the obstetric unit at Johns Hopkins Hospital (Baltimore, MD) and 100 inpatients at Yonsei Universi (Seoul, Korea). Results: The gene frequencies of HPA-2b?kF) and HPA-5b (SP) in African Americans were twice those in whites (African Americans: 0.18 and 0.21, respectively; whites: 0.09 and 0.11, respectively). There is a very low gene frequency of the HPA-Ib (PP') allele in Koreans (0.005). No significant differences were found in the gene frequencies of the human platelet antigens in whites in this series and those in published European studies. Conclusion: These studies indicate a higher potential risk for alloimmunization to HPA-2 (KO) and HPA-5 (Br) antigens in African Americans than in whites. In addition, the low gene frequency of HPA-Ib (P P) in African Americans and Koreans suggests that alloimmunization to HPA-1 a (PIA1) would be very unusual in these populations. These data may provide the basis for planning neonatal alloimmune thrombocytopenia screening programs in certain ethnic populations. Abbreviations: HPA = human platelet antigen; PCR = polymerasechain mctlon; SDS =sodium dodecyl sulfate; SSC = salinesodium cltrate.
Critical Care Medicine, 2003
Objective-Studies of genetic associations with common diseases, such as between cytokine gene polymorphisms and severe bacterial sepsis, have reached conflicting conclusions. Failure to follow methodologic standards may have contributed to discordant findings. The −308 G→A transition in the tumor necrosis factor-− promoter has been genotyped by a variety of methods. Based on our observation of genotyping inaccuracies, we sought to determine whether published studies followed a series of acceptable methodologic standards and whether failure to follow the standard of genotyping reproducibility could lead to erroneous conclusions about gene-disease associations. Design-Systematic review and reanalysis of banked genetic material. We applied a published series of seven methodologic standards to five reports of the association between this variant and bacterial sepsis. We then studied the accuracy of restriction fragment length polymorphism for the −308 site using DNA from a cohort of injury victims. Setting-Surgery research laboratory. Measurements and Main Results-We observed that methodologic quality was not uniform and that reproducibility of genotyping was infrequently met. In our subjects, we found that 4 of 46 heterozygotes analyzed by restriction fragment length polymorphism were actually GGhomozygotes (9% misclassified) according to alternative genotyping methods. Conclusions-Failure to confirm genotype may have led to conclusions that this polymorphism is not associated with sepsis or outcome. Our observations have implications for the conduct and evaluation of studies of complex genetic disease.
Gut and Liver, 2014
Background/Aims: Tumor necrosis factor α (TNF-α) encoded by TNFA is a key mediator in inflammation, a precursor condition for peptic ulceration. Promoter polymorphisms of TNFA that influence its transcriptional activity and TNF-α production are known. TNFA-308G>A (rs1800629) and TNFA-1031T>C (rs1799964), which are responsible for increased TNFA transcription, could influence the risk of peptic ulceration. This study aimed to investigate these polymorphisms and to evaluate their association with peptic ulcer disease and Helicobacter pylori infection in the Polish population. Methods: Gastric mucosa specimens obtained from 177 Polish peptic ulcer patients were used to conduct rapid urease tests and to assess the investigated polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data were compared with the results obtained from healthy individuals of Polish origin. Results: There were no significant differences in genotype and allele frequency of the investigated polymorphisms between peptic ulcer patients and healthy individuals. No associations between the frequencies of particular genotypes and alleles for both single-nucleotide polymorphisms (SNPs) and the presence of H. pylori infection in peptic ulcer patients and in subgroups of men and women with peptic ulcer disease were found. Conclusions: The investigated SNPs are not risk factors for either peptic ulcer or H. pylori infection development in the Polish population. The results require verification in a larger cohort. (Gut Liver 2014;8:632-636)
Molecular Human Reproduction, 2002
Infection is believed to be a leading cause of preterm premature rupture of membranes (PPROM). The bacterial cell wall component, lipopolysaccharide (LPS), is thought to initiate tissue responses leading to PPROM in the setting of Gram negative infection. LPS is recognized by the innate immune system, including the proteins encoded by the CARD15 and TLR4 genes. A recently described mutation (2936insC) in CARD15 and a polymorphism in TLR4 896 A>G impair responses to LPS. The objective of this study was to determine if African Americans, who have a higher incidence of PPROM than Caucasians, have different frequencies of the mutant CARD15 allele and the TLR4 hyporesponsive variant, and if risk of PPROM is influenced by fetal carriage of these alleles. The allele frequencies for the CARD15 mutation and the TLR4 896G variant in African Americans were similar to those reported for Caucasians. There was no association between the TLR4 alleles examined and PPROM. However, the CARD15 mutation was only detected in controls and not in PPROM cases. We conclude that the CARD15 mutation and hyporesponsive TLR4 allele do not contribute to ethnic variation in the incidence of PPROM.
Pediatric research, 2018
Twin studies suggest that genetic factors may account for up to 50% increased risk for necrotizing enterocolitis (NEC), but genome-wide association studies (GWAS) for NEC are lacking. Genotyping was done on Illumina BeadChip, followed by analysis using PLINK with logistic regression under an additive model. Among 751 extremely low birth weight (<1000 g, >401 g) neonates, 30 had surgical NEC. 261 single nucleotide polymorphisms (SNPs) showed association with NEC at P<0.05, of which 35 were significant at P<10. Minor allele(s) in a a cluster of SNPs spanning a 43 Kb region of chromosome 8 (8q23.3) conferred an odds ratio of 4.72 (95% CI 2.51-8.88) for elevated risk of NEC. Two smaller clusters on chromosome 14 and chromosome 11 exhibited P values 10-10. The chromosome 8 cluster is in an intergenic region between CUB And Sushi Multiple Domains 3 (-1.43 Mb) and Trichorhinophalangeal Syndrome I (+542 kb). RNA sequencing in this region identified a potential novel open reading...