Identification of plasma protein markers of allergic disease risk: a mendelian randomization approach to proteomic analysis.

BACKGROUND: While numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework. METHODS: Large-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications. RESULTS: Eleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR. CONCLUSION: Eleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets.

Inflammatory bowel disease and allergic diseases: A Mendelian randomization study.

BACKGROUND: Inflammatory bowel disease (IBD) and allergic diseases possess similar genetic backgrounds and pathogenesis. Observational studies have shown a correlation, but the exact direction of cause and effect remains unclear. The aim of this Mendelian randomization (MR) study is to assess bidirectional causality between inflammatory bowel disease and allergic diseases. METHOD: We comprehensively analyzed the causal relationship between inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC) and allergic disease (asthma, Hay fever, and eczema) as a whole, allergic conjunctivitis (AC), atopic dermatitis (AD), allergic asthma (AAS), and allergic rhinitis (AR) by performing a bidirectional Mendelian randomization study using summary-level data from genome-wide association studies. The analysis results mainly came from the random-effects model of inverse variance weighted (IVW-RE). In addition, multivariate Mendelian randomization (MVMR) analysis was conducted to adjust the effect of body mass index (BMI) on the instrumental variables. RESULTS: The IVW-RE method revealed that IBD genetically increased the risk of allergic disease as a whole (OR = 1.03, 95% CI = 1.01-1.04, fdr.p = .015), AC (OR = 1.04, 95% CI = 1.01-1.06, fdr.p = .011), and AD (OR = 1.06, 95% CI = 1.02-1.09, fdr.p = .004). Subgroup analysis further confirmed that CD increased the risk of allergic disease as a whole (OR = 1.02, 95% CI = 1.00-1.03, fdr.p = .031), AC (OR = 1.03, 95% CI = 1.01-1.05, fdr.p = .012), AD (OR = 1.06, 95% CI = 1.02-1.09, fdr.p = 2E-05), AAS (OR = 1.05, 95% CI = 1.02-1.08, fdr.p = .002) and AR (OR = 1.03, 95% CI = 1.00-1.07, fdr.p = .025), UC increased the risk of AAS (OR = 1.02, 95% CI = 0.98-1.07, fdr.p = .038). MVMR results showed that after taking BMI as secondary exposure, the causal effects of IBD on AC, IBD on AD, CD on allergic disease as a whole, CD on AC, CD on AD, CD on AAS, and CD on AR were still statistically significant. No significant association was observed in the reverse MR analysis. CONCLUSION: This Mendelian randomized study demonstrated that IBD is a risk factor for allergic diseases, which is largely attributed to its subtype CD increasing the risk of AC, AD, ASS, and AR. Further investigations are needed to explore the causal relationship between allergic diseases and IBD.

Gonadal sex and chromosome complement influence the gut microbiome in a mouse model of allergic airway inflammation.

Evidence abounds that gut microbiome components are associated with sex disparities in the immune system. However, it remains unclear whether the observed sex disparity in asthma incidence is associated with sex-dependent differences in immune-modulating gut microbiota, and/or its influence on allergic airway inflammatory processes. Using a mouse model of house dust mite (HDM)-induced allergic inflammation and the four core genotypes (FCGs) model, we have previously reported sex differences in lung inflammatory phenotypes. Here, we investigated associations of gut microbiomes with these phenotypes by challenging FCG mice [mouse with female sex chromosome and male gonad (XXM), mouse with female sex chromosome and female gonad (XXF), mouse with male sex chromosome and male gonad (XYM), and mouse with male sex chromosome and female gonad (XYF); n = 7/group] with HDM (25 µg) or PBS intranasally for 5 wk and collecting fecal samples. We extracted fecal DNA and analyzed the 16S microbiome via Targeted Metagenomic Sequencing. We compared α and ß diversity across genotypes and assessed the Firmicutes/Bacteroidetes (F/B) ratio. When comparing baseline and after exposure for the FCG, we found that the gut F/B ratio was only increased in the XXM genotype. We also found that α diversity was significantly increased in all FCG mice upon HDM challenge, with the highest increase in the XXF, and the lowest in the XXM genotypes. Similarly, ß diversity of the microbial community was also affected by challenge in a gonad- and chromosome-dependent manner. In summary, our results indicated that HDM treatment, gonads, and sex chromosomes significantly influence the gut microbial community composition. We concluded that allergic lung inflammation may be affected by the gut microbiome in a sex-dependent manner involving both hormonal and genetic influences.NEW & NOTEWORTHY Recently, the gut microbiome and its role in chronic respiratory disease have been the subject of extensive research and the establishment of its involvement in immune functions. Using the FCG mouse model, our findings revealed the influence of gonads and sex chromosomes on the microbial community structure before and after exposure to HDM. Our data provide a potential new avenue to better understand mediators of sex disparities associated with allergic airway inflammation.

Granulysin-mediated reduction of PDZRN3 induces Cx43 gap junctions activity exacerbating skin damage in trichloroethylene hypersensitivity syndrome.

Trichloroethylene (TCE)-induced hypersensitivity syndrome (THS) has been a concern for many researchers in the field of environmental and occupational health. Currently, there is no specific treatment for THS, leaving patients to contend with severe infections arising from extensive skin lesions, consequently leading to serious adverse effects. However, the pathogenesis of severe skin damage in THS remains unclear. This study aims to investigate the specific danger signals and mechanisms underlying skin damage in THS through in vivo and in vitro experiments. We identified that cell supernatant containing 15 kDa granulysin (GNLY), released from activated CD3-CD56+NK cells or CD3+CD56+NKT cells in PBMC induced by TCE or its metabolite, promoted apoptosis in HaCaT cells. The apoptosis level decreased upon neutralization of GNLY in the supernatant by a GNLY-neutralizing antibody in HaCaT cells. Subcutaneous injection of recombinant 15 kDa GNLY exacerbated skin damage in the THS mouse model and better mimicked patients' disease states. Recombinant 15 kDa GNLY could directly induce cellular communication disorders, inflammation, and apoptosis in HaCaT cells. In addition to its cytotoxic effects, GNLY released from TCE-activated NK cells and NKT cells or synthesized GNLY alone could induce aberrant expression of the E3 ubiquitin ligase PDZRN3, causing dysregulation of the ubiquitination of the cell itself. Consequently, this resulted in the persistent opening of gap junctions composed of connexin43, thereby intensifying cellular inflammation and apoptosis through the "bystander effect". This study provides experimental evidence elucidating the mechanisms of THS skin damage and offers a novel theoretical foundation for the development of effective therapies targeting severe dermatitis induced by chemicals or drugs.

The genome-wide association study of serum IgE levels demonstrated a shared genetic background in allergic diseases.

Immunoglobulin E (IgE) synthessis is highly related to a variety of atopic diseases, and several genome-wide association studies (GWASs) have demonstrated the association between genes and IgE level. In this study, we conducted the largest genome-wide association study of IgE involving a Taiwanese Han population. Eight independent variants exhibited genome-wide significance. Among them, an intronic SNP of CD28, rs1181388, and an intergenic SNP, rs1002957030, on 11q23.2 were identified as novel signals for IgE. Seven of the loci were replicated successfully in a meta-analysis using data on Japanese population. Among all the human leukocyte antigen (HLA) regions, HLA-DQA1*03:02 - HLA-DQB1*03:03 was the most significant haplotype (OR = 1.25, SE = 0.02, FDR = 1.6 × 10-14), corresponding to HLA-DQA1 Asp160 and HLA-DQB1 Leu87 amino acid residues. The genetic correlation showed significance between IgE and allergic diseases including asthma, atopic dermatitis, and pollinosis. IgE PRS was significantly correlated with total IgE levels. Furthermore, the top decile IgE polygenic risk score (PRS) group had the highest risk of asthma for the Taiwan Biobank and Biobank Japan cohorts. IgE PRS may be used to aid in predicting the occurrence of allergic reactions before symptoms occur and biomarkers are detectable. Our study provided a more comprehensive understanding of the impact of genomic variants, including complex HLA alleles, on serum IgE levels.

Analytical challenges in omics research on asthma and allergy: A National Institute of Allergy and Infectious Diseases workshop.

Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes the major points and conclusions from this NIAID workshop. As a group, the investigators underscored the imperatives for rigorous analytic frameworks, integration of different omics data types, cross-disciplinary interaction, strategies for overcoming current limitations, and the overarching goal to improve scientific understanding and care of asthma and allergic diseases.

A common NFKB1 variant detected through antibody analysis in UK Biobank predicts risk of infection and allergy.

Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses to multiple pathogens, including those from the herpes, retro-, and polyoma-virus families. An insertion-deletion variant thought to affect NFKB1 expression (rs28362491), was mapped as the likely causal variant and could play a key role in regulation of the immune response. Using 121 infection- and inflammation-related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression of NFKB1, as a result of the deletion, modulates hematopoietic pathways and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation.

Allergic Diseases and Chronic Adenotonsillar Diseases: A Mendelian Randomization Study.

OBJECTIVE: The existing epidemiological evidence regarding the intricate relationship between allergic diseases and chronic adenotonsillar diseases (CATD) remains inconclusive. Herein, the objective of our study is to explore the causal association using Mendelian randomization (MR). METHODS: Employing data from large genome-wide association studies, a comprehensive two-sample bidirectional MR study was conducted. The studied traits encompassed allergic rhinitis (cases n = 9707, controls n = 331173), allergic asthma (cases n = 8525, controls n = 193857), allergic conjunctivitis (cases n = 18321, controls n = 324178), atopic dermatitis (cases n = 11964, controls n = 306909), and CATD (cases n = 38983, controls n = 258553). All the patients were of European descent and participants in cohort studies. The primary analysis was executed using inverse-variance-weighted MR. Furthermore, six additional MR methods (MR-Egger, weighted median, simple mode, weighted mode, MR pleiotropy residual sum and outlier, MR robust adjusted profile score) were employed to ensure the reliability and detect potential horizontal pleiotropy within the results. The estimates obtained from the MR analysis were factored into the overall effect calculation. RESULTS: Genetically anticipated outcomes demonstrated a significant association between CATD risk and allergic rhinitis (OR = 1.141, p = 6.30E-06), allergic asthma (OR = 1.115, p = 8.31E-05), allergic conjunctivitis (OR = 1.197, p = 8.69E-07), and a suggestive association with atopic dermatitis (OR = 1.053, p = 0.040). However, no substantial correlation was observed in the reverse direction. CONCLUSIONS: Findings of our study provide evidence supporting a causal role of allergic diseases in the development of CATD, whereas the converse relationship does not appear to hold true. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2653-2658, 2024.

The Effects of Environmental Exposure on Epigenetic Modifications in Allergic Diseases.

Allergic diseases are one of the most common chronic conditions and their prevalence is on the rise. Environmental exposure, primarily prenatal and early life influences, affect the risk for the development and specific phenotypes of allergic diseases via epigenetic mechanisms. Exposure to pollutants, microorganisms and parasites, tobacco smoke and certain aspects of diet are known to drive epigenetic changes that are essential for immune regulation (e.g., the shift toward T helper 2-Th2 cell polarization and decrease in regulatory T-cell (Treg) differentiation). DNA methylation and histone modifications can modify immune programming related to either pro-allergic interleukin 4 (IL-4), interleukin 13 (IL-13) or counter-regulatory interferon γ (IFN-γ) production. Differential expression of small non-coding RNAs has also been linked to the risk for allergic diseases and associated with air pollution. Certain exposures and associated epigenetic mechanisms play a role in the susceptibility to allergic conditions and specific clinical manifestations of the disease, while others are thought to have a protective role against the development of allergic diseases, such as maternal and early postnatal microbial diversity, maternal helminth infections and dietary supplementation with polyunsaturated fatty acids and vitamin D. Epigenetic mechanisms are also known to be involved in mediating the response to common treatment in allergic diseases, for example, changes in histone acetylation of proinflammatory genes and in the expression of certain microRNAs are associated with the response to inhaled corticosteroids in asthma. Gaining better insight into the epigenetic regulation of allergic diseases may ultimately lead to significant improvements in the management of these conditions, earlier and more precise diagnostics, optimization of current treatment regimes, and the implementation of novel therapeutic options and prevention strategies in the near future.

Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond.

Signal transducer and activator of transcription (STAT)-6 is a transcription factor central to pro-allergic immune responses, although the function of human STAT6 at the whole-organism level has long remained unknown. Germline heterozygous gain-of-function (GOF) rare variants in STAT6 have been recently recognized to cause a broad and severe clinical phenotype of early-onset, multi-system allergic disease. Here, we provide an overview of the clinical presentation of STAT6-GOF disease, discussing how dysregulation of the STAT6 pathway causes severe allergic disease, and identifying possible targeted treatment approaches. Finally, we explore the mechanistic overlap between STAT6-GOF disease and other monogenic atopic disorders, and how this group of inborn errors of immunity (IEIs) powerfully inform our fundamental understanding of common human allergic disease.

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.

The Mas-related G protein-coupled receptor d (Mrgprd) mediates pain hypersensitivity in painful diabetic neuropathy.

ABSTRACT: Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. Painful diabetic neuropathy is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, axonal degeneration, and changes in cutaneous innervation. However, the complete molecular profile underlying the hyperexcitable cellular phenotype of DRG nociceptors in PDN has not been elucidated. This gap in our knowledge is a critical barrier to developing effective, mechanism-based, and disease-modifying therapeutic approaches that are urgently needed to relieve the symptoms of PDN. Using single-cell RNA sequencing of DRGs, we demonstrated an increased expression of the Mas-related G protein-coupled receptor d (Mrgprd) in a subpopulation of DRG neurons in the well-established high-fat diet (HFD) mouse model of PDN. Importantly, limiting Mrgprd signaling reversed mechanical allodynia in the HFD mouse model of PDN. Furthermore, in vivo calcium imaging allowed us to demonstrate that activation of Mrgprd-positive cutaneous afferents that persist in diabetic mice skin resulted in an increased intracellular calcium influx into DRG nociceptors that we assess in vivo as a readout of nociceptors hyperexcitability. Taken together, our data highlight a key role of Mrgprd-mediated DRG neuron excitability in the generation and maintenance of neuropathic pain in a mouse model of PDN. Hence, we propose Mrgprd as a promising and accessible target for developing effective therapeutics currently unavailable for treating neuropathic pain in PDN.

Epigenetics, hypersensibility and asthma: what do we know so far?

In this review, we describe recent advances in understanding the relationship between epigenetic changes, especially DNA methylation (DNAm), with hypersensitivity and respiratory disorders such as asthma in childhood. It is clearly described that epigenetic mechanisms can induce short to long-term changes in cells, tissues, and organs. Through the growing number of studies on the Origins of Health Development and Diseases, more and more data exist on how environmental and genomic aspects in early life can induce allergies and asthma. The lack of biomarkers, standardized assays, and access to more accessible tools for data collection and analysis are still a challenge for future studies. Through this review, the authors draw a panorama with the available information that can assist in the establishment of an epigenetic approach for the risk analysis of these pathologies.

A Review of the Epigenetic Clock: Emerging Biomarkers for Asthma and Allergic Disease.

DNA methylation (DNAm) is a dynamic, age-dependent epigenetic modification that can be used to study interactions between genetic and environmental factors. Environmental exposures during critical periods of growth and development may alter DNAm patterns, leading to increased susceptibility to diseases such as asthma and allergies. One method to study the role of DNAm is the epigenetic clock-an algorithm that uses DNAm levels at select age-informative Cytosine-phosphate-Guanine (CpG) dinucleotides to predict epigenetic age (EA). The difference between EA and calendar age (CA) is termed epigenetic age acceleration (EAA) and reveals information about the biological capacity of an individual. Associations between EAA and disease susceptibility have been demonstrated for a variety of age-related conditions and, more recently, phenotypes such as asthma and allergic diseases, which often begin in childhood and progress throughout the lifespan. In this review, we explore different epigenetic clocks and how they have been applied, particularly as related to childhood asthma. We delve into how in utero and early life exposures (e.g., smoking, air pollution, maternal BMI) result in methylation changes. Furthermore, we explore the potential for EAA to be used as a biomarker for asthma and allergic diseases and identify areas for further study.

Climate change and epigenetic biomarkers in allergic and airway diseases.

Human epigenetic variation is associated with both environmental exposures and allergic diseases and can potentially serve as a biomarker connecting climate change with allergy and airway diseases. In this narrative review, we summarize recent human epigenetic studies examining exposure to temperature, precipitation, extreme weather events, and malnutrition to discuss findings as they relate to allergic and airway diseases. Temperature has been the most widely studied exposure, with the studies implicating both short-term and long-term exposures with epigenetic alterations and epigenetic aging. Few studies have examined natural disasters or extreme weather events. The studies available have reported differential DNA methylation of multiple genes and pathways, some of which were previously associated with asthma or allergy. Few studies have integrated climate-related events, epigenetic biomarkers, and allergic disease together. Prospective longitudinal studies are needed along with the collection of target tissues beyond blood samples, such as nasal and skin cells. Finally, global collaboration to increase diverse representation of study participants, particularly those most affected by climate injustice, as well as strengthen replication, validation, and harmonization of measurements will be needed to elucidate the impacts of climate change on the human epigenome.

The role of DNA methylation in personalized medicine for immune-related diseases.

Epigenetics functions as a bridge between host genetic & environmental factors, aiding in human health and diseases. Many immune-related diseases, including infectious and allergic diseases, have been linked to epigenetic mechanisms, particularly DNA methylation. In this review, we summarized an updated overview of DNA methylation and its importance in personalized medicine, and demonstrated that DNA methylation has excellent potential for disease prevention, diagnosis, and treatment in a personalized manner. The future implications and limitations of the DNA methylation study have also been well-discussed.

Molecular detection of Imbrasia belina proteins associated with allergic reactions on harvesters and consumers from selected districts in Matabeleland: a comparative study.

BACKGROUND: Harvesting and consuming insects (entomophagy), particularly Imbrasia belina is widespread in developing countries like Zimbabwe. Due to their extraordinary nutritional content, tastiness, ease of processing and storage, Imbrasia belina has become a delicacy, reachable nutritious complement, and money source for some people in Zimbabwean communities. However, some harvesters and consumers have become allergic to the Imbrasia belina, popularly known as Mopani worms. This has been attributed or associated with the changes in the genetic structure of Imbrasia belina. Therefore, this research sought to compare the presence of the genes associated with allergic reactions to mopane worms from Gwanda and Umguza districts in Zimbabwe. METHODS: A lab-based observational study was conducted on collected Imbrasia belina samples from both districts. Fifteen samples of mopane worms were collected from each district, and DNA extraction was performed using DNeasy blood and tissue kit. The DNA extraction products were then amplified using a Polymerase chain reaction. The polymerase chain reaction products were run on agarose gel electrophoresis to determine the presence of the target genes. RESULTS: Three of the five samples from Gwanda district were positive for the tropomyosin gene, whereas two samples from Umguza district were positive. All the samples from the two districts were negative for arginine kinase genes. CONCLUSION: The study results highlighted that allergic reactions to Imbrasia belina reported in Gwanda district are associated with the presence of the tropomyosin gene, which has undergone polymorphism. Responsible authorities such as Gwanda local authority should develop bylaws that govern Imbrasia belina harvesting in the district.

PDE4D gene variants and haplotypes are associated with asthma and atopy in Brazilian children.

PDE4D (Phosphodiesterase 4D) gene encodes a hydrolase of cyclic AMP. PDE4D genetic variants have been associated with asthma susceptibility. Therefore, this study aimed to investigate the association between PDE4D variants (and haplotypes) with asthma and atopy in a Brazilian population. The study comprised 1,246 unrelated participants from the SCAALA (Social Changes Asthma and Allergy in Latin America) program. Genotyping was performed using the Illumina 2.5 Human Omni bead chip. Multivariate logistic regression was used to investigate the association between PDE4D variants and asthma/atopy phenotypes in PLINK 1.09 software. Twenty-four SNVs in PDE4D were associated with atopy or asthma. The rs6898082 (A) variant increased asthma susceptibility (OR 2.76; CI 99% 1.26-6.03) and was also related to a greater PDE4D expression in the GTEx database. Also, the variant rs6870632 was further associated with asthma in meta-analysis with a replication cohort. In addition, the variants rs75699812 (C), rs8007656 (G), and rs958851 (T) were positively associated with atopy. Moreover, these variants formed an atopy risk haplotype (OR 1.82; CI 99% 1.15-2.88). Also, these variants were related to lower levels of IL-10. Functional in silico assessment showed that some PDE4D SNVs may have an impact on gene regulation and expression. Variants in the PDE4D are positively associated with asthma and allergy markers. It is possible that these variants lead to alteration in PDE4D expression and therefore impact immunity and pulmonary function.