Polymorphisms in IL12A and cockroach allergy in children with asthma

<p>Abstract</p> <p>Background</p> <p>IL12A has been implicated in T-cell development and may thus influence the development of atopy and allergic diseases.</p> <p>Methods</p> <p>We tested for association between four linkage disequilibrium (LD)-tagging SNPs (rs2243123, rs2243151, rs668998, and rs17826053) in <it>IL12A </it>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.</p> <p>Results</p> <p>Among Costa Rican children with asthma, homozygosity for the minor allele of each of two SNPs in <it>IL12A </it>(rs2243123 and rs2243151) was associated with increased risks of STR to American cockroach (P ≤ 0.03 for both SNPs), STR to German cockroach (P ≤ 0.01 for both SNPs), and having a positive IgE to German cockroach (P < 0.05 for both SNPs). Among children in CAMP, homozygosity for the minor allele of SNP rs2243151 in <it>IL12A </it>was inversely associated with STR to German cockroach (P = 0.03) and homozygosity for the minor allele of SNP rs17826053 in <it>IL12A </it>was associated with increased risks of STR to American cockroach (P = 0.01) and STR to German cockroach (P = 0.007). There was no significant association between any SNP in <it>IL12A </it>and asthma, STR to dust mite, or total IgE in Costa Rica or CAMP.</p> <p>Conclusion</p> <p>Our findings suggest that variants in <it>IL12A </it>influence cockroach allergy among children with asthma.</p

Deadly diving? Physiological and behavioural management of decompression stress in diving mammals

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Proceedings of the Royal Society B Biological Sciences 279 (2012): 1041-1050, doi:10.1098/rspb.2011.2088.Decompression sickness (DCS; ‘the bends’) is a disease associated with gas uptake at pressure. The basic pathology and cause are relatively well known to human divers. Breath-hold diving marine mammals were thought to be relatively immune to DCS owing to multiple anatomical, physiological and behavioural adaptations that reduce nitrogen gas (N2) loading during dives. However, recent observations have shown that gas bubbles may form and tissue injury may occur in marine mammals under certain circumstances. Gas kinetic models based on measured time-depth profiles further suggest the potential occurrence of high blood and tissue N2 tensions. We review evidence for gas-bubble incidence in marine mammal tissues and discuss the theory behind gas loading and bubble formation. We suggest that diving mammals vary their physiological responses according to multiple stressors, and that the perspective on marine mammal diving physiology should change from simply minimizing N2 loading to management of the N2 load. This suggests several avenues for further study, ranging from the effects of gas bubbles at molecular, cellular and organ function levels, to comparative studies relating the presence/absence of gas bubbles to diving behaviour. Technological advances in imaging and remote instrumentation are likely to advance this field in coming years.This paper and the workshop it stemmed from were funded by the Woods Hole Oceanographic Institution Marine Mammal Centre

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 (mQTL), expression quantitative trait locus (eQTL), and expression quantitative trait methylation (eQTM) analyses to assess whether the top 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. In the meta-analysis of GWAS, a SNP in FLJ22447 (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbations (95% confidence interval=1.34 to 1.79, p=6.3×10-9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10-7). Thus, SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents (KCNJ2-AS1)

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma

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

<p>Abstract</p> <p>Background</p> <p>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 (<it>TSLP</it>) in the pathogenesis of AR has not been studied.</p> <p>Objective</p> <p>To test for associations between variants in <it>TSLP</it>, <it>TSLP</it>-related genes, and AR in children with asthma.</p> <p>Methods</p> <p>We genotyped 15 single nucleotide polymorphisms (SNPs) in <it>TSLP, OX40L, IL7R</it>, and <it>RXRα </it>in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for <it>TSLP</it>, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.</p> <p>Results</p> <p>Across the three cohorts, the T allele of <it>TSLP </it>SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10^-4). Our findings were significant after accounting for multiple comparisons. SNPs in <it>OX40L, IL7R</it>, and <it>RXRα </it>were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.</p> <p>Conclusions</p> <p><it>TSLP </it>SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for <it>TSLP </it>in the pathogenesis of AR in children with asthma.</p

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. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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. We followed a two-stage replication process utilizing three independent populations to validate our primary findings.</p> <p>Results</p> <p>We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung.</p> <p>Conclusions</p> <p>Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.</p

Essential Medicines at the National Level : The Global Asthma Network's Essential Asthma Medicines Survey 2014

Patients with asthma need uninterrupted supplies of affordable, quality-assured essential medicines. However, access in many low- and middle-income countries (LMICs) is limited. The World Health Organization (WHO) Non-Communicable Disease (NCD) Global Action Plan 2013-2020 sets an 80% target for essential NCD medicines' availability. Poor access is partly due to medicines not being included on the national Essential Medicines Lists (EML) and/or National Reimbursement Lists (NRL) which guide the provision of free/subsidised medicines. We aimed to determine how many countries have essential asthma medicines on their EML and NRL, which essential asthma medicines, and whether surveys might monitor progress. A cross-sectional survey in 2013-2015 of Global Asthma Network principal investigators generated 111/120 (93%) responses41 high-income countries and territories (HICs); 70 LMICs. Patients in HICs with NRL are best served (91% HICs included ICS (inhaled corticosteroids) and salbutamol). Patients in the 24 (34%) LMICs with no NRL and the 14 (30%) LMICs with an NRL, however no ICS are likely to have very poor access to affordable, quality-assured ICS. Many LMICs do not have essential asthma medicines on their EML or NRL. Technical guidance and advocacy for policy change is required. Improving access to these medicines will improve the health system's capacity to address NCDs.Peer reviewe