FGF20 and PGM2 variants are associated with childhood asthma in family-based whole-genome sequencing studies.

Background: Asthma is a heterogeneous common respiratory disease that remains poorly understood. The established genetic associations fail to explain the high estimated heritability, and the prevalence of asthma differs between populations and geographic regions. Robust association analyses incorporating different genetic ancestries and whole-genome sequencing data may identify novel genetic associations.

Childhood Asthma: Low and Middle-Income Countries Perspective.

Our aim is to review current asthma epidemiology, achievements from the last 10 years, and persistent challenges of asthma management and control in low-middle income countries (LMICs). Despite global efforts, asthma continues to be an important public health problem worldwide, particularly in poorly resourced settings. Several epidemiological studies in the last decades have shown significant variability in the prevalence of asthma globally, but generally a marked increase in LMICs resulting in significant morbidity and mortality.

A genome-wide association study of severe asthma exacerbations in Latino children and adolescents.

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.

De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population.

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.

Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma.

Background: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma.

Methods: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study.

Trends in hospitalizations and mortality from asthma in Costa Rica over a 12- to 15-year period.

Background: Little is known about trends in morbidity and/or mortality due to asthma in Latin America.

Objective: To examine trends in hospitalizations and mortality due to asthma from 1997-2000 to 2011 in Costa Rica.

Methods: The rates of hospitalization due to asthma were calculated for each sex in 3 age groups from 1997 to 2011.

Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations.

Background: It has recently been shown that vitamin D deficiency can increase asthma development and severity and that variations in vitamin D receptor genes are associated with asthma susceptibility.

Objective: We sought to find genetic factors that might interact with vitamin D levels to affect the risk of asthma exacerbation.

Methods: We conducted a genome-wide study of gene-vitamin D interaction on asthma exacerbations using population-based and family-based approaches on 403 subjects and trios from the Childhood Asthma Management Program.

Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease.

Rationale: Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing.

Objectives: The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs).

Association of SERPINE2 with asthma.

Background: The "Dutch hypothesis" suggests that asthma and COPD have common genetic determinants. The serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2) gene previously has been associated with COPD. We sought to determine whether SERPINE2 is associated with asthma and asthma-related phenotypes.

Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma.

Background: Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied.

Asthma-susceptibility variants identified using probands in case-control and family-based analyses.

Background: Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs.

Methods: We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design.

Risk factors and predictive clinical scores for asthma exacerbations in childhood.

Background: Asthma is a major public health problem that affects millions of children worldwide, and exacerbations account for most of its morbidity and costs. Primary-care providers lack efficient tools to identify children at high risk for exacerbations. We aimed to construct a clinical score to help providers to identify such children.

MMP12, lung function, and COPD in high-risk populations.

Background: Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups.

Methods: We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV(1)]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV(1) and the time to the onset of COPD.

PRKCA: a positional candidate gene for body mass index and asthma.

Asthma incidence and prevalence are higher in obese individuals. A potential mechanistic basis for this relationship is pleiotropy. We hypothesized that significant linkage and candidate-gene association would be found for body mass index (BMI) in a population ascertained on asthma affection status.

Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica.

Rationale: Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood.

Objectives: To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood.

Polymorphisms in IL12A and cockroach allergy in children with asthma.

Background: IL12A has been implicated in T-cell development and may thus influence the development of atopy and allergic diseases.

Methods: We tested for association between four linkage disequilibrium (LD)-tagging SNPs (rs2243123, rs2243151, rs668998, and rs17826053) in IL12A and asthma and allergy-related (serum total and allergen-specific IgE, and skin test reactivity [STR] to two common allergens) phenotypes in two samples: 417 Costa Rican children with asthma and their parents, and 470 families of 503 white children in the Childhood Asthma Management Program (CAMP). The analysis was conducted using the family-based association test (FBAT) statistic implemented in the PBAT program.

Dust mite exposure modifies the effect of functional IL10 polymorphisms on allergy and asthma exacerbations.

Background: The allergenicity of dust mite exposure might be dependent on variants in the gene for IL-10 (IL10).

Objectives: To evaluate whether dust mite exposure modifies the effect of single nucleotide polymorphisms (SNPs) in IL10 on allergy and asthma exacerbations.

Methods: We genotyped 6 SNPs in IL10 in 417 Costa Rican children and 503 white children in the Childhood Asthma Management Program (CAMP) with asthma and their parents.

On the replication of genetic associations: timing can be everything!

The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations.

Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans.

Rationale: The basis for gender influences on allergen-specific IgEs is unclear.

Objectives: To perform regular and sex-stratified genomewide linkage analyses of IgE to each of three allergens (Ascaris lumbricoides, Blatella germanica [German cockroach]), and Dermatophagoides pteronyssinus [dust mite]) and to conduct an association study of a candidate gene in a linked genomic region.

Methods: Genomewide linkage analyses of allergen-specific IgEs were conducted in 653 members of eight large families of Costa Rican children with asthma.

Paternal asthma, mold exposure, and increased airway responsiveness among children with asthma in Costa Rica.

Background: Little is known about the determinants of airway hyperresponsiveness (AHR) among children with asthma in Hispanic America.

Methods: We examined the relations among selected familial and environmental factors, markers of allergy, spirometric measures of lung function, and AHR in a cross-sectional study of 403 Costa Rican children with asthma between the ages of 6 and 14 years. Study participants completed a protocol that included questionnaires, spirometry, measurements of serum total and allergen-specific IgE, peripheral blood eosinophil count, and body mass index, and the assessment of airway responsiveness to methacholine (ie, a methacholine challenge test [MCT]).

Comprehensive testing of positionally cloned asthma genes in two populations.

Rationale: Replication of gene-disease associations has become a requirement in complex trait genetics.

Objectives: In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.

Methods: We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica.

Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood.

Background: It is unclear whether single nucleotide polymorphisms (SNPs) in the gene for IL-13 (IL13) influence asthma severity and/or asthma morbidity.

Objectives: To examine the relation between IL13 SNPs and asthma-related phenotypes in 2 independent populations.

Methods: We used family-based methods to test for association between SNPs in IL13 and asthma-related phenotypes in Costa Rican children with asthma.

The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts.

A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort.

Sensitization to Ascaris lumbricoides and severity of childhood asthma in Costa Rica.

Background: Little is known about sensitization (defined as a positive IgE) to helminths and disease severity in patients with asthma.

Objectives: To examine the relationship between sensitization (defined as a positive IgE) to Ascaris lumbricoides and measures of asthma morbidity and severity in a Costa Rican population with low prevalence of parasitic infection but high prevalence of parasitic exposure.

Methods: Cross-sectional study of 439 children (ages 6 to 14 years) with asthma.