Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

BackgroundThe prevalence of allergic diseases such as asthma has significantly increased worldwide, making it a public health concern. There is an urgent need for new anti-inflammatory agents with selective pharmacology and lower toxicity. Plant extracts have been used for centuries in traditional medicine to alleviate inflammatory diseases. In this work, we evaluated the anti-allergic activity of Cymbopogon citratus (Cy), a medicinal herb used by folk medicine to treat asthma.MethodsWe used a murine model of respiratory allergy to the mite Blomia tropicalis (Bt) and evaluated certain parameters known to be altered in this model. A/J mice were sensitized (100 μg/animal s.c.) and challenged (10 μg/animal i.n.) with Bt mite extract and treated with 60, 120 or 180 mg/kg of Cy standardized hexane extract. The parameters evaluated included: cellular infiltrate in bronchoalveolar lavage (BAL); eosinophil peroxidase activity (EPO); histopathological examination of the lung; serum levels of specific IgE, IgG1 and IgG2a; Th2 cytokine concentrations in BAL and expression of NF-κB.ResultsOur results showed that oral administration of a Cy hexane extract (especially 180 mg/Kg) reduced the numbers of leukocytes/eosinophils in BAL; the eosinophil peroxidase activity in BAL; the infiltration of leukocytes in lung tissue; the production of mucus in the respiratory tract; the level of IL-4 in BAL and the nuclear expression of NF-κB.ConclusionsThe results presented demonstrate the potential of the Cy hexane extract to modulate allergic asthma; this extract may be an alternative future approach to treat this pathology.

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).

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Background Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi‐ancestry meta‐analysis of genome‐wide association studies (meta‐GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods A meta‐GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10−5) were assessed for replication in 36,477 European and 1078 non‐European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results One hundred and twenty‐six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule‐1/exostosin like glycosyltransferase‐2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 × 10−6 and replication: ORT allele = 0.89, p = 5.35 × 10−3) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10−5 and replication: ORC allele = 0.89, p = 1.30 × 10−2). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions This multi‐ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Accumulated evidence supports the contribution of genetic factors in modulating airway function, especially ancestry. We investigated whether genetic polymorphisms can affect lung function in a mixed Brazilian child population using the admixture mapping strategy through RFMix software version 1.5.4 (Stanford University, Stanford, CA, USA), followed by fine mapping, to identify regions whereby local African or European ancestry is associated with lung function measured by the forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio, an indicator of airway obstruction. The research cohort included 958 individuals aged 4 to 11 years enrolled in the SCAALA (Social Change, Asthma, Allergy in Latin America) Program. We identified that African ancestry at 17q21.31, 10q22.2, and 2p23.1 regions was associated with lower lung function measured by FEV1/FVC p < 1.9 × 10−4. In contrast, European ancestry at 17q21.31 showed an opposite effect. Fine mapping pointed out 5 single nucleotide polymorphisms (SNPs) also associated in our replication cohort (rs10999948, rs373831475, rs8068257, rs6744555, and rs1520322). Our results suggest that genomic regions associated with ancestry may contribute to differences in lung function measurements in African American children in Brazil replicated in a cohort of Brazilian adults. The analysis strategy used in this work is especially important for phenotypes, such as lung function, which has considerable disparities in terms of measurements across different populations.

RATIONALE: Aryl hydrocarbon receptor (AhR), a receptor for common environmental contaminants, is an important regulator of immune responses. Our previous studies have suggested a role of AhR in protecting against cockroach allergen-induced lung inflammation by using AhR-/mice. Autophagy plays a major role in controlling immune responses and inflammation. We sought to determine whether the activated AhR signaling specifically in airway epithelium by cockroach allergen modulates cockroach allergen-induced lung inflammation through autophagy METHODS: The role of AhR expressed in epithelium in cockroach allergen (CRE) induced allergic inflammation was investigated in a mouse model of asthma with AhR epithelial conditional knock out mice (ftpc-Cre;AhR flox/flox). Cockroach allergen induced the activation of AhR and autophagy signaling in epithelium was determined. The role of autophagy in CRE-induced asthma was also investigated. RESULTS: CRE-challenged Sftpc-Cre; AhR flox/flox mice displayed decreased lung infiltrates, mucus production, and airway hyper-responsiveness. These mice also showed reduced levels of IL-4, IL-5, IL-13, IL-17, but increased IL-10 and IL-22 in the BAL fluids. Decreased IC3B II in airways was also observed. Moreover, CRE can activate AhR (CYP1A1 and CYP1B1) and autophagy (Beclin-1, Atg5, and p62) signaling in epithelial cells in vitro, and AhR agonist TCDD can potentiate CRE-induced autophagy. Furthermore, CRE-induced lung inflammation was significantly suppressed when autophagy inhibitor was used in the mouse model with decreased lung infiltrates and Th2/T17 cytokines in BAL fluids. CONCLUSIONS: Contrast to the protective role previously observed in AhR-/mice, AhR in airway epithelial may exacerbate CRE-induced inflammation, which may through activating autophagy signaling.

Asthma is an important health concern in Latin America (LA) where it is associated with variable prevalence and disease burden between countries. High prevalence and morbidity have been observed in some regions, particularly marginalized urban populations. Research over the past 10 years from LA has shown that childhood disease is primarily non‐atopic. The attenuation of atopy may be explained by enhanced immune regulation induced by intense exposures to environmental factors such as childhood infections and poor environmental conditions of the urban poor. Non‐atopic symptoms are associated with environmental and lifestyle factors including poor living conditions, respiratory infections, psychosocial stress, obesity, and a diet of highly processed foods. Ancestry (particularly African) and genetic factors increase asthma risk, and some of these factors may be specific to LA settings. Asthma in LA tends to be poorly controlled and depends on access to health care and medications. There is a need to improve management and access to medication through primary health care. Future research should consider the heterogeneity of asthma to identify relevant endotypes and underlying causes. The outcome of such research will need to focus on implementable strategies relevant to populations living in resource‐poor settings where the disease burden is greatest.