Genome-wide association study of polymorphisms predisposing to bronchiolitis

Bronchiolitis is a major cause of hospitalization among infants. Severe bronchiolitis is associated withlater asthma, suggesting a common genetic predisposition. Genetic background of bronchiolitis is notwell characterized. To identify polymorphisms associated with bronchiolitis, we conducted a genomewideassociation study (GWAS) in which 5,300,000 single nucleotide polymorphisms (SNPs) were testedfor association in a Finnish–Swedish population of 217 children hospitalized for bronchiolitis and 778controls. The most promising SNPs (n = 77) were genotyped in a Dutch replication population of 416cases and 432 controls. Finally, we used a set of 202 Finnish bronchiolitis cases to further investigatecandidate SNPs. We did not detect genome-wide significant associations, but several suggestiveassociation signals (p were nominally associated (p (eQTL) for KCND3, previously shown to be associated with occupational asthma. In the additionalset of Finnish cases, the association for another SNP (rs9591920) within a noncoding RNA locus wasfurther strengthened. Our results provide a first genome-wide examination of the genetics underlyingbronchiolitis. These preliminary findings require further validation in a larger sample size.</p

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Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis.

Bronchiolitis is a major cause of hospitalization among infants. Severe bronchiolitis is associated with later asthma, suggesting a common genetic predisposition. Genetic background of bronchiolitis is not well characterized. To identify polymorphisms associated with bronchiolitis, we conducted a genome-wide association study (GWAS) in which 5,300,000 single nucleotide polymorphisms (SNPs) were tested for association in a Finnish-Swedish population of 217 children hospitalized for bronchiolitis and 778 controls. The most promising SNPs (n = 77) were genotyped in a Dutch replication population of 416 cases and 432 controls. Finally, we used a set of 202 Finnish bronchiolitis cases to further investigate candidate SNPs. We did not detect genome-wide significant associations, but several suggestive association signals (p < 10-5) were observed in the GWAS. In the replication population, three SNPs were nominally associated (p < 0.05). Of them, rs269094 was an expression quantitative trait locus (eQTL) for KCND3, previously shown to be associated with occupational asthma. In the additional set of Finnish cases, the association for another SNP (rs9591920) within a noncoding RNA locus was further strengthened. Our results provide a first genome-wide examination of the genetics underlying bronchiolitis. These preliminary findings require further validation in a larger sample size

Genome-Wide Association Study of Polymorphisms Predisposing to Bronchiolitis OPEN

Bronchiolitis is a major cause of hospitalization among infants. Severe bronchiolitis is associated with later asthma, suggesting a common genetic predisposition. Genetic background of bronchiolitis is not well characterized. To identify polymorphisms associated with bronchiolitis, we conducted a genomewide association study (GWAS) in which 5,300,000 single nucleotide polymorphisms (SNPs) were tested for association in a Finnish-Swedish population of 217 children hospitalized for bronchiolitis and 778 controls. The most promising SNPs (n = 77) were genotyped in a Dutch replication population of 416 cases and 432 controls. Finally, we used a set of 202 Finnish bronchiolitis cases to further investigate candidate SNPs. We did not detect genome-wide significant associations, but several suggestive association signals (p &lt; 10 −5 ) were observed in the GWAS. In the replication population, three SNPs were nominally associated (p &lt; 0.05). Of them, rs269094 was an expression quantitative trait locus (eQTL) for KCND3, previously shown to be associated with occupational asthma. In the additional set of Finnish cases, the association for another SNP (rs9591920) within a noncoding RNA locus was further strengthened. Our results provide a first genome-wide examination of the genetics underlying bronchiolitis. These preliminary findings require further validation in a larger sample size. Bronchiolitis is a common lower respiratory infection (LRI) that primarily affects children under two years of age 1,2 . Respiratory syncytial virus (RSV) is recognized as the most important causative agent of bronchiolitis worldwide 3 . Typically, RSV epidemics occur in annual cycles and peak during the cold season in temperate climates and during the rainy season in warm climates 4 . During RSV epidemics, most infants become infected and develop mild disease. However, a fraction of children, between 2% and 3% of an age cohort, develop severe bronchiolitis that requires hospitalization 5 . RSV bronchiolitis is the most common infection-related cause of hospitalization among infants and young children in developed countrie

Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci.

BackgroundPreterm birth (MethodsWe conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively.ResultsThe meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action.ConclusionWe report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth

Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2

Abstract Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] &lt; 36 weeks) and 419 term controls (GA 38–41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10−6). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA &lt;32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10−7). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB