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Abstract Background Despite the success of genome-wide association studies for asthma, few, if any, definitively causal variants have been identified and there is still a substantial portion of the heritability of the disease yet to be discovered. Some of this “missing heritability” may be accounted for by family-specific coding variants found to be segregating with asthma. Methods To identify family-specific variants segregating with asthma, we recruited one family from a previous study of asthma as reporting multiple asthmatic and non-asthmatic children. We performed whole-exome sequencing on all four children and both parents and identified coding variants segregating with asthma that were not found in other variant databases. Results Ten novel variants were identified that were found in the two affected offspring and affected mother, but absent in the unaffected father and two unaffected offspring. Of these ten, variants in three genes (PDE4DIP, CBLB, and KALRN) were deemed of particular interest based on their functional prediction scores and previously reported function or asthma association. We did not identify any common risk variants segregating with asthma, however, we did observe an increase in the number of novel, nonsynonymous variants in asthma candidate genes in the asthmatic children compared to the non-asthmatic children. Conclusions This is the first report applying exome sequencing to identify asthma susceptibility variants. Despite having sequenced only one family segregating asthma, we have identified several potentially functional variants in interesting asthma candidate genes. This will provide the basis for future work in which more families will be sequenced to identify variants across families that cluster within genes.

AbstractBackgroundSpecific genetic contributions for preeclampsia (PE) are currently unknown. This genome-wide association study (GWAS) aims to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) involved in the etiology of PE.MethodsA genome-wide scan was performed on 177 PE cases (diagnosed according to National Heart, Lung and Blood Institute guidelines) and 116 normotensive controls. White female study subjects from Iowa were genotyped on Affymetrix SNP 6.0 microarrays. CNV calls made using a combination of four detection algorithms (Birdseye, Canary, PennCNV, and QuantiSNP) were merged using CNVision and screened with stringent prioritization criteria. Due to limited DNA quantities and the deleterious nature of copy-number deletions, it was decided a priori that only deletions would be selected for assay on the entire case-control dataset using quantitative real-time PCR.ResultsThe top four SNP candidates had an allelic or genotypic p-value between 10-5 and 10-6, however, none surpassed the Bonferroni-corrected significance threshold. Three recurrent rare deletions meeting prioritization criteria detected in multiple cases were selected for targeted genotyping. A locus of particular interest was found showing an enrichment of case deletions in 19q13.31 (5/169 cases and 1/114 controls), which encompasses the PSG11 gene contiguous to a highly plastic genomic region. All algorithm calls for these regions were assay confirmed.ConclusionsCNVs may confer risk for PE and represent interesting regions that warrant further investigation. Top SNP candidates identified from the GWAS, although not genome-wide significant, may be useful to inform future studies in PE genetics.

Triple-crossover randomized controlled intervention trial to test whether reduced exposure to household NO2 or fine particles results in reduced symptoms among children with persistent asthma. Children (n = 126) aged 5–11 years with persistent asthma living in homes with gas stoves and levels of NO2 15 ppb or greater recruited in Connecticut and Massachusetts (2015–2019) participated in an intervention involving three air cleaners configured for: (1) NO2 reduction: sham particle filtration and real NO2 scrubbing; (2) particle filtration: HEPA filter and sham NO2 scrubbing; (3) control: sham particle filtration and sham NO2 scrubbing. Air cleaners were randomly assigned for 5-week treatment periods using a three-arm crossover design. Outcome was number of asthma symptom-days during final 14 days of treatment. Treatment effects were assessed using repeated measures, linear mixed models. Measured NO2 was lower (by 4 ppb, p <.0001) for NO2-reducing compared to control or particle-reducing treatments. NO2-reducing treatment did not reduce asthma morbidity compared to control. In analysis controlling for measured NO2, there were 1.8 (95% CI −0.3 to 3.9, p =.10) fewer symptom days out of 14 in the particle-reducing treatment compared to control. It remains unknown if using an air cleaner alone can achieve levels of NO2 reduction large enough to observe reductions in asthma symptoms. We observed that in small, urban homes with gas stoves, modest reductions in asthma symptoms occurred using air cleaners that remove fine particles. An intervention targeting exposures to both NO2 and fine particles is complicated and further research is warranted. NCT02258893. [ABSTRACT FROM AUTHOR]

This study estimates the effect of maternal infections during pregnancy on childhood asthma. One-thousand four-hundred and twenty-eight pregnant women were prospectively followed using structured interviews and chart review until their child's 6th year of life. Infections were identified from outpatient and hospital visits. Childhood asthma was defined as physician diagnosis with symptoms at age six. Adjusted odds ratios were calculated from multivariable logistic regression models. Six-hundred and thirty-five women experienced an infection during pregnancy. Among antepartum infections, maternal urinary tract infections were significantly associated with childhood asthma (aOR 1.60, 95% CI 1.12-2.29). Chorioamnionitis and maternal group beta streptococcus colonization were not significantly associated with an increased risk in childhood asthma. This study found an increased risk of asthma in children of women diagnosed with urinary tract infections during pregnancy, while other maternal infections did not increase the risk. Keywords Childhood asthma * Prenatal exposures * Maternal infection, Introduction Asthma is one of the most common chronic illnesses worldwide with an increasing prevalence and medical burden among children. Growing evidence suggests that an asthmatic phenotype may be programmed [...]