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

Effect of Segmental Bronchoalveolar Lavage on Quantitative Computed Tomography of the Lung

Rationale and Objectives: With employment of both multidetector computed tomography (MDCT) and endobronchial procedures in multicenter studies, effects of timing of endobronchial procedures on quantitative imaging (Q-MDCT) metrics is a question of increasing importance.Materials and Methods: Six subjects were studied via MDCT at baseline, immediately following and at 4 hours and 24 hours post-bronchoalveolar lavage (SAL) (right middle lobe and lingula). Through quantitative image analysis, non-air, or "tissue" volume (TV) in each lung and lobe was recorded. Change in TV from baseline was used to infer retention and redistribution of lavage fluid.Results: Bronchoscopist reported unrecovered BAL volume correlated well with Q-MDCT for whole lung measures, but less well with individual lobes indicating redistribution. TV in all lobes except the right lower lobe differed significantly (P &lt;.05) from baseline immediately post lavage. At 24 hours, all lobes except the left lower lobe (small 1% mean difference at 24 hours) returned to baseline.Conclusions: These findings suggest fluid movement affecting Q-MDCT metrics between lobes and between lungs before eventual resolution, and preclude protocols involving the lavage of one lung and imaging of the other to avoid interactions. We demonstrate that Q-MDCT is sensitive to lavage fluid retention and redistribution, and endobronchial procedures should not precede Q-MDCT imaging by less than 24 hours.</p

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

Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation

Background: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. Methods and Findings: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. Conclusions: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients. Please see later in the article for the Editors' Summar

The CD4+ T-cell transcriptome and serum IgE in asthma: IL17RB and the role of sex

<p>Abstract</p> <p>Background</p> <p>The relationships between total serum IgE levels and gene expression patterns in peripheral blood CD4+ T cells (in all subjects and within each sex specifically) are not known.</p> <p>Methods</p> <p>Peripheral blood CD4+ T cells from 223 participants from the Childhood Asthma Management Program (CAMP) with simultaneous measurement of IgE. Total RNA was isolated, and expression profiles were generated with Illumina HumanRef8 v2 BeadChip arrays. Modeling of the relationship between genome-wide gene transcript levels and IgE levels was performed in all subjects, and stratified by sex.</p> <p>Results</p> <p>Among all subjects, significant evidence for association between gene transcript abundance and IgE was identified for a single gene, the interleukin 17 receptor B (IL17RB), explaining 12% of the variance (r²) in IgE measurement (p value = 7 × 10^-7, 9 × 10^-3after adjustment for multiple testing). Sex stratified analyses revealed that the correlation between IL17RB and IgE was restricted to males only (r²= 0.19, p value = 8 × 10^-8; test for sex-interaction p < 0.05). Significant correlation between gene transcript abundance and IgE level was not found in females. Additionally we demonstrated substantial sex-specific differences in IgE when considering multi-gene models, and in canonical pathway analyses of IgE level.</p> <p>Conclusions</p> <p>Our results indicate that IL17RB may be the only gene expressed in CD4+ T cells whose transcript measurement is correlated with the variation in IgE level in asthmatics. These results provide further evidence sex may play a role in the genomic regulation of IgE.</p

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

Cardiac Sarcoidosis: When and How to Treat Inflammation

Sarcoidosis is a complex, multisystem inflammatory disease with a heterogeneous clinical spectrum. Approximately 25% of patients with systemic sarcoidosis will have cardiac involvement that portends a poorer outcome. The diagnosis, particularly of isolated cardiac sarcoidosis, can be challenging. A paucity of randomised data exist on who, when and how to treat myocardial inflammation in cardiac sarcoidosis. Despite this, corticosteroids continue to be the mainstay of therapy for the inflammatory phase, with an evolving role for steroid-sparing and biological agents. This review explores the immunopathogenesis of inflammation in sarcoidosis, current evidence-based treatment indications and commonly used immunosuppression agents. It explores a multidisciplinary treatment and monitoring approach to myocardial inflammation and outlines current gaps in our understanding of this condition, emerging research and future directions in this field

Genes to Diseases (G2D) Computational Method to Identify Asthma Candidate Genes

Asthma is a complex trait for which different strategies have been used to identify its environmental and genetic predisposing factors. Here, we describe a novel methodological approach to select candidate genes for asthma genetic association studies. In this regard, the Genes to Diseases (G2D) computational tool has been used in combination with a genome-wide scan performed in a sub-sample of the Saguenay−Lac-St-Jean (SLSJ) asthmatic familial collection (n = 609) to identify candidate genes located in two suggestive loci shown to be linked with asthma (6q26) and atopy (10q26.3), and presenting differential parent-of-origin effects. This approach combined gene selection based on the G2D data mining analysis of the bibliographic and protein public databases, or according to the genes already known to be associated with the same or a similar phenotype. Ten genes (LPA, NOX3, SNX9, VIL2, VIP, ADAM8, DOCK1, FANK1, GPR123 and PTPRE) were selected for a subsequent association study performed in a large SLSJ sample (n = 1167) of individuals tested for asthma and atopy related phenotypes. Single nucleotide polymorphisms (n = 91) within the candidate genes were genotyped and analysed using a family-based association test. The results suggest a protective association to allergic asthma for PTPRE rs7081735 in the SLSJ sample (p = 0.000463; corrected p = 0.0478). This association has not been replicated in the Childhood Asthma Management Program (CAMP) cohort. Sequencing of the regions around rs7081735 revealed additional polymorphisms, but additional genotyping did not yield new associations. These results demonstrate that the G2D tool can be useful in the selection of candidate genes located in chromosomal regions linked to a complex trait

Association Between Interstitial Lung Abnormalities and All-Cause Mortality.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.To investigate whether interstitial lung abnormalities are associated with increased mortality.Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).Interstitial lung abnormality status as determined by chest CT evaluation.All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.National Institutes of Health (NIH) T32 HL007633 Icelandic Research Fund 141513-051 Landspitali Scientific Fund A-2015-030 National Cancer Institute grant 1K23CA157631 NIH K08 HL097029 R01 HL113264 R21 HL119902 K25 HL104085 R01 HL116931 R01 HL116473 K01 HL118714 R01 HL089897 R01 HL089856 N01-AG-1-2100 HHSN27120120022C P01 HL105339 P01 HL114501 R01 HL107246 R01 HL122464 R01 HL111024 National Heart, Lung, and Blood Institute's Framingham Heart Study contract N01-HC-2519.5 GlaxoSmithKline NCT00292552 5C0104960 National Institute on Aging (NIA) grant 27120120022C NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament) NIA 27120120022

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements: We conducted genome-wide analyses across three independent studies and meta-analysed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results: We identified and replicated three new genome-wide significant (P<5×10−8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1 and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF, supports recent studies demonstrating the importance of mTOR signalling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility