Association of PHACTR1 with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10-14) and among males (p = 1.0 × 10-9), but the signal was not genome-wide significant among females (p = 6.4 × 10-6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10-8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10-7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10-7) than former smokers (p = 7.5 × 10-3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10-8) and current smokers (p = 1.7 × 10-7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Examining the Effect of Genes on Depression as Mediated by Smoking and Modified by Sex.

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components). In secondary analyses, we adjusted for age, sex, current smoking status, genetic ancestry (via principal components), income, education, and living status (urban vs. rural). In addition, we examined sex-stratified mediation models and sex-moderated mediation models. For both analyses, we adjusted for age, current smoking status, and genetic ancestry (via principal components). In the UK Biobank, rs6424532 [LOC105378800] had a statistically significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 4.0 × 10-4) among all participants and a marginally significant indirect effect among females (p = 0.02) and males (p = 4.0 × 10-3). Moreover, rs10501696 [GRM5] had a marginally significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 0.01) among all participants and a significant indirect effect among females (p = 2.2 × 10-3). In the secondary analyses, the sex-moderated indirect effect was marginally significant for rs10501696 [GRM5] on broad depression through the log of pack-years of cigarette smoking (p = 0.01). In the COPDGene study, the effect of an SNP (rs10501696) in GRM5 on depressive symptoms and medication was mediated by log of pack-years (p = 0.02); however, no SNPs had a sex-moderated mediated effect on depressive symptoms. In the UK Biobank, we found SNPs in two genes [LOC105378800, GRM5] with an indirect effect on broad depression through the log of pack-years of cigarette smoking. In addition, the indirect effect for GRM5 on broad depression through smoking may be moderated by sex. These results suggest that genetic regions associated with broad depression may be mediated by cigarette smoking and this relationship may be moderated by sex.

GSDMB/ORMDL3 Rare/Common Variants Are Associated with Inhaled Corticosteroid Response among Children with Asthma.

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (DPP10, FBXL7, NDFIP1, TBXT, GLCCI1, HDAC9, TBXAS1, STAT6, GSDMB/ORMDL3, CRHR1, GNGT2, FCER2), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants (p-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (p-value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.

Asthma exacerbations and eosinophilia in the UK Biobank: a genome-wide association study.

Background: Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. Methods: UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10-6) in the GERA cohort. Results: In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10-8) in the primary analysis, 116 signals were suggestively significant (p<5×10-6). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes. Conclusions: Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.

Supportive interventions for childhood cancer: An umbrella review of randomized evidence.

Therapeutic advancements have improved pediatric cancer prognosis, shifting the interest towards the management of psychosocial burden and treatment-related morbidity. To critically appraise the available evidence, we conducted an umbrella review of meta-analyses of randomized controlled trials on supportive interventions for childhood cancer. Thirty-four publications (92 meta-analyses, 1 network, 14,521 participants) were included. The most concrete data showed a reduction in procedure-related pain and distress through hypnosis. Moreover, exercise improved the functional mobility of the patients. Regarding pharmacological interventions, most of the meta-analyses pertained to the treatment of nausea/vomiting (ondansetron was effective) and infections/febrile neutropenia [granulocyte-(macrophage) colony-stimulating factors showed benefits]. Substantial heterogeneity was detected in 31 associations. Conclusively, supportive interventions for pediatric cancer are being thoroughly evaluated. However, most of the studies are small and of moderate quality, highlighting the need for more randomized evidence in order to increase precision in improving the quality of life of patients, survivors and their families.

Covariate adjustment of spirometric and smoking phenotypes: The potential of neural network models.

To increase power and minimize bias in statistical analyses, quantitative outcomes are often adjusted for precision and confounding variables using standard regression approaches. The outcome is modeled as a linear function of the precision variables and confounders; however, for many complex phenotypes, the assumptions of the linear regression models are not always met. As an alternative, we used neural networks for the modeling of complex phenotypes and covariate adjustments. We compared the prediction accuracy of the neural network models to that of classical approaches based on linear regression. Using data from the UK Biobank, COPDGene study, and Childhood Asthma Management Program (CAMP), we examined the features of neural networks in this context and compared them with traditional regression approaches for prediction of three outcomes: forced expiratory volume in one second (FEV1), age at smoking cessation, and log transformation of age at smoking cessation (due to age at smoking cessation being right-skewed). We used mean squared error to compare neural network and regression models, and found the models performed similarly unless the observed distribution of the phenotype was skewed, in which case the neural network had smaller mean squared error. Our results suggest neural network models have an advantage over standard regression approaches when the phenotypic distribution is skewed. However, when the distribution is not skewed, the approaches performed similarly. Our findings are relevant to studies that analyze phenotypes that are skewed by nature or where the phenotype of interest is skewed as a result of the ascertainment condition.

Therapeutic interventions for childhood cancer: An umbrella review of randomized evidence.

Treatment advancements in pediatric cancer have improved prognosis, but the strength of supporting evidence has not been thoroughly evaluated. To critically appraise it, we performed an umbrella review of meta-analyses of randomized controlled trials examining the efficacy and safety of therapeutic interventions for pediatric malignancies. Fourteen publications (68 meta-analyses, 31,496 participants) were eligible. Acute lymphoblastic leukemia (ALL) was investigated at most. Substantial heterogeneity was detected in 10 associations, with limited indications for small-study effects and excess-significance bias. The most concrete evidence pertained to the use of methotrexate and vincristine-prednisone pulses for ALL, improving event-free survival. Evidence regarding other cancers was relatively weak. Conclusively, we found few small meta-analyses focusing mainly on ALL. Randomized evidence stemming from adult populations still seems to serve as valuable indirect evidence backup. More randomized evidence and individual patient data meta-analyses are needed to increase certainty and precision in the care of pediatric cancer patients.