Association between NKX2-5 rs29784 and infantile hypertrophic pyloric stenosis in Chinese Han population.
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ABSTRACT:
SUBMITTER: Feng Z
PROVIDER: S-EPMC4402900 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Project description:Infantile hypertrophic pyloric stenosis (IHPS) is a severe condition characterized by hypertrophy of the pyloric sphincter muscle. We conducted a genome-wide association study (GWAS) on 1,001 surgery-confirmed cases and 2,401 controls from Denmark. The six most strongly associated loci were tested in a replication set of 796 cases and 876 controls. Three SNPs reached genome-wide significance. One of these SNPs, rs11712066 (odds ratio (OR) = 1.61; P = 1.5 × 10(-17)) at 3p25.1, is located 150 kb upstream of MBNL1, which encodes a factor that regulates splicing transitions occurring shortly after birth. The second SNP, rs573872 (OR = 1.41; P = 4.3 × 10(-12)), maps to an intergenic region at 3p25.2 approximately 1.3 Mb downstream of MBNL1. The third SNP, rs29784 (OR = 1.42; P = 1.5 × 10(-15)) at 5q35.2, is 64 kb downstream of NKX2-5, which is involved in development of cardiac muscle tissue and embryonic gut development.
| S-EPMC3693399 | biostudies-literature
Project description:IntroductionInfantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter muscle.ObjectivesSince previous reports have implicated lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-related metabolites in newborns, and (2) address whether detected differences in metabolite levels were likely to be driven by genetic differences between IHPS cases and controls or by differences in early life feeding patterns.MethodsWe used population-based random selection of IHPS cases and controls born in Denmark between 1997 and 2014. We randomly took dried blood spots of newborns from 267 pairs of IHPS cases and controls matched by sex and day of birth. We used a mixed-effects linear regression model to evaluate associations between 148 metabolites and IHPS in a matched case-control design.ResultsThe phosphatidylcholine PC(38:4) showed significantly lower levels in IHPS cases (P = 4.68 × 10-8) as did six other correlated metabolites (four phosphatidylcholines, acylcarnitine AC(2:0), and histidine). Associations were driven by 98 case-control pairs born before 2009, when median age at sampling was 6 days. No association was seen in 169 pairs born in 2009 or later, when median age at sampling was 2 days. More IHPS cases than controls had a diagnosis for neonatal difficulty in feeding at breast (P = 6.15 × 10-3). Genetic variants known to be associated with PC(38:4) levels did not associate with IHPS.ConclusionsWe detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.
| S-EPMC7794101 | biostudies-literature
Project description:IntroductionLaparoscopic pyloromyotomy (LP) for the treatment of infantile hypertrophic pyloric has advantage of smaller incisions, faster recovery, reduction in wound-related complications and better cosmesis. Various laparoscopic knives and spreaders have been used for LP, but they do not provide the depth and tissue perception as in open surgery. We describe the laparoscopic hybrid pyloromyotomy (LHP) which makes procedure simple and safe without the requirement of any special instrument.Materials and methodsThis retrospective and prospective comparative study was conducted over a period of 4.5 years in a tertiary teaching hospital in central India. All patients with infantile hypertrophic pyloric stenosis diagnosed on the basis of clinical history, examination and ultrasonography were included in the study. Retrospective data of three-port conventional LP (CLP) using monopolar diathermy hook for incision was used as control group against prospective data of 25 patients undergoing LHP. After a proper layout, LHP was done using one umbilical optical port, right paraumbilical grasper of holding the pyloric olive and an epigastric incision for hybrid pyloromyotomy using 11 no blade and blunt-tipped mosquito artery forceps.ResultsProspective group of LHP included 25 patients which were compared with a retrospective group of CLP consisting of 25 patients. On comparison of two groups, it was found that LHP reduces operative duration significantly. The outcome in terms of complications and recovery was comparable in two groups. None of the patients developed recurrence and required any redo surgery.ConclusionLHP is a simplified approach which is easy to learn and teach, improves safety and accuracy of the procedure.
| S-EPMC7597870 | biostudies-literature
Project description:ImportanceInfantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited.ObjectivesTo search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets.Design, setting, and participantsDuring stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease-free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998-2005), with a total of 1663 cases and 2315 controls.Main outcomes and measuresAssociation of genetic variation with the presence of infantile hypertrophic pyloric stenosis.ResultsWe found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 × 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS.Conclusions and relevanceThis study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation.
| S-EPMC4031654 | biostudies-literature
Project description:Infantile hypertrophic pyloric stenosis (IHPS) is the most common form of bowel obstruction in infancy. The disease affects males four times more often than females and is considered a paradigm for the sex-modified model of multifactorial inheritance. However, pedigrees consistent with autosomal dominant inheritance have also been documented. We analyzed a 3-generation family with IHPS including 10 affected individuals (5 males and 5 females) and mapped the underlying disease locus to chromosome 16p12-p13 (LOD score 3.23) by using a single-nucleotide polymorphism-based genomewide scan. The analysis of 10 additional multiplex pedigrees yielded negative or nonsignificant LOD scores, indicating the presence of locus heterogeneity. Sequence analysis of candidate genes from the chromosome 16 disease interval excluded the presence of pathogenic mutations in the GRIN2A and MYH11 genes.
| S-EPMC1559485 | biostudies-literature
Project description:ObjectiveTo assess the association between use of macrolide antibiotics in mothers and infants from pregnancy onset until 120 days after birth and infantile hypertrophic pyloric stenosis (IHPS).DesignNationwide register based cohort study.SettingDenmark, 1996-2011.Participants999,378 liveborn singletons and linked individual level information on macrolide prescriptions (maternal use during pregnancy, n=30,091; maternal use after birth, n=21,557; use in infants, n=6591), surgery for IHPS, and potential confounders.Main outcome measuresSurgery for IHPS by three categories of macrolide use: in mothers during pregnancy, in mothers after birth, and in infants after birth.Results880 infants developed IHPS (0.9 cases per 1000 births). Compared with infants with no use of macrolides, the adjusted rate ratio for IHPS in infants with use of macrolides during days 0 to 13 after birth was 29.8 (95% confidence interval 16.4 to 54.1) and during days 14 to 120 was 3.24 (1.20 to 8.74); the corresponding absolute risk differences were 24.4 (95% confidence interval 13.0 to 44.1) and 0.65 (0.06 to 2.21) cases per 1000 infants exposed to macrolides, respectively. The rate ratio for maternal use of macrolides for days 0 to 13 after birth was 3.49 (1.92 to 6.34) and for days 14 to 120 was 0.70 (0.26 to 1.90); the corresponding absolute risk differences were 2.15 (0.82 to 4.64) and -0.11 (-0.26 to 0.31). The rate ratios for maternal use of macrolides during pregnancy were 1.02 (0.65 to 1.59) for weeks 0 to 27 and 1.77 (0.95 to 3.31) for weeks 28 to birth; the corresponding absolute risk differences were 0.01 (-0.31 to 0.50) and 0.67 (-0.06 to 2.02).ConclusionsTreatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.
| S-EPMC3949411 | biostudies-literature
Project description:Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ?2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.
| S-EPMC6322072 | biostudies-literature
Project description:Infantile hypertrophic pyloric stenosis (IHPS) is one of the hallmark pediatric surgical diseases. However, its etiology remains incompletely understood. By systematically reviewing the literature, we aim to clarify the effect of the effect of occupational and environmental factors and role of nitric oxide (NO) metabolism in the etiopathogenesis of IHPS. The systematic review is drafted with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE). Systematic literature search will be performed for the period 2000 (Jan) to 2020 (Dec) in the databases: MEDLINE, EMBASE, PubMed. The systematic search will cover the literature in English and Turkish language and will be limited to studies on human subjects. Four investigators will independently search the databases (MEDLINE, EMBASE, PubMed) according to the defined search strategy. The full-text of the selected articles will be screened independently by four reviewers, against the inclusion criteria. Descriptive data will be extracted from each study regarding: study details, methods, participants, outcomes and calculations of association for potential further statistical analysis. If meta-analysis could not be undertaken, systematic approach to analyzing the findings of included multiple studies will be described. Heterogeneity will be assessed by quantifying the inconsistency across studies using I2 statistic. Statistical analysis will be performed using Comprehensive Meta-Analysis Version 3.0 software. The p values lower than 0.05 will be considered statistically significant for all analyses.
| S-EPMC7886114 | biostudies-literature
Project description:Infantile hypertrophic pyloric stenosis (IHPS), characterized by enlarged pyloric musculature and gastric-outlet obstruction, is associated with altered expression of neuronal nitric oxide synthase (nNOS). Here we have studied molecular mechanisms by which nNOS gene expression is altered in pyloric tissues of 16 infants with IHPS and 9 controls. A significant decreased expression of total nNOS mRNA was found by quantitative RT-PCR in IHPS after normalization against GAPDH, which predominantly affected exon 1c with a reduction of 88% compared with controls (P < 0.001). After normalization against the neuronal-specific gene PGP9.5, expression of exon 1c was still decreased (P < 0.001), whereas expression of exon 1f was increased significantly (P = 0.001), indicating a compensatory up-regulation of this nNOS mRNA variant. DNA samples of 16 IHPS patients and 81 controls were analyzed for nNOS exon 1c promoter mutations and single-nucleotide polymorphism (SNP). Sequencing of the 5'-flanking region of exon 1c revealed mutations in 3 of 16 IHPS tissues, whereas 81 controls showed the wild-type sequence exclusively. Carriers of the A allele of a previously uncharacterized nNOS exon 1c promoter SNP (-84G --> A) had increased risk for development of IHPS (odds ratio, 8.0; 95% confidence interval, 2.5-25.6). Reporter gene assays revealed an unchanged promoter activity for mutations but a approximately 30% decrease for the -84A SNP (P < 0.001). In summary, our findings indicate that genetic alterations in the nNOS exon 1c regulatory region influence expression of the nNOS gene and may contribute to the pathogenesis of IHPS.
| S-EPMC341814 | biostudies-other
Project description:Infantile hypertrophic pyloric stenosis (IHPS) has an incidence of 1-8 per 1000 live births and is inherited as a complex sex-modified multifactorial trait with a striking male preponderance. Syndromic and monogenic forms exist, and two loci have been identified. Infants present with vomiting due to gastric-outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. A genome-wide SNP-based high-density linkage scan was carried out on 81 IHPS pedigrees. Nonparametric and parametric linkage analysis identified loci on chromosomes 11q14-q22 (Z(max) = 3.9, p < 0.0001; HLOD(max) = 3.4, alpha = 0.34) and Xq23 (Z(max) = 4.3, p < 0.00001; HLOD(max) = 4.8, alpha = 0.56). The two linked chromosomal regions each harbor functional candidate genes that are members of the canonical transient receptor potential (TRPC) family of ion channels and have a potential role in smooth-muscle control and hypertrophy.
| S-EPMC2427303 | biostudies-literature