Veeresh Patil

The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years

BackgroundThe occurrence of asthma is weakly explained by known genetic variants. Epigenetic marks, DNA methylation (DNA-M) in particular, are considered to add to the explanation of asthma. However, no etiological model has yet been developed that integrates genetic variants and DNA-M. To explore a new model, we focused on one asthma candidate gene, the IL-4 receptor (IL4R). We hypothesized that genetic variants of IL4R in interaction with DNA-M at cytosine-phosphate-guanine (CpG) sites jointly alter the risk of asthma during adolescence. Blood samples were collected at age 18 years from 245 female cohort participants randomly selected for methylation analysis from a birth cohort (n = 1,456, Isle of Wight, UK). Genome-wide DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip.ResultsThirteen single nucleotide polymorphisms (SNPs) and twelve CpG sites of IL4R gene were analyzed. Based on linkage disequilibrium and association with asthma, eight SNPs and one CpG site were selected for further analyses. Of the twelve CpG sites in the IL4R gene, only methylation levels of cg09791102 showed an association with asthma at age 18 years (Wilcoxon test: P = 0.01). Log-linear models were used to estimate risk ratios (RRs) for asthma adjusting for uncorrelated SNPs within the IL4R gene and covariates. Testing for interaction between the eight SNPs and the methylation levels of cg09791102 on the risk for asthma at age 18 years, we identified the statistically significant interaction term of SNP rs3024685 × methylation levels of cg09791102 (P = 0.002; after adjusting for false discovery rate). A total of 84 participants had methylation levels ≤0.88, 112 participants between 0.89 and 0.90, and 35 between 0.91 and 0.92. For the SNP rs3024685 (‘CC’ vs. ‘TT’) at methylation levels of ≤0.85, 0.86, 0.90, 0.91, and 0.92, the RRs were 0.01, 0.04, 4.65, 14.76, 14.90, respectively (interaction effect, P = 0.0003).ConclusionsAdjusting for multiple testing, our results suggest that DNA-M modulates the risk of asthma related to genetic variants in the IL4R gene. The strong interaction of one SNP and DNA-M is encouraging and provides a novel model of how a joint effect of genetic variants and DNA-M can explain occurrence of asthma.

Interaction of prenatal maternal smoking, interleukin 13 genetic variants and DNA methylation influencing airflow and airway reactivity.

BackgroundAsthma is characterized by airflow limitation and airway reactivity (AR). Interleukin-13 (IL-13) is involved in the pathogenesis of asthma. Two functional SNPs, rs20541 and rs1800925, of the IL-13 gene (IL13) have been frequently associated with asthma-related lung functions. However, genetic variation alone does not fully explain asthma risk. DNA-methylation (DNA-M) is an epigenetic mechanism that regulates gene expression and can be influenced by both environment and genetic variants. To explore the interplay of prenatal maternal smoking, genetic variants and DNA-M, we used a two-stage model: (1) identifying cytosine phosphate guanine (CpG) sites where DNA-M is influenced by the interaction between genetic variants and maternal smoking during pregnancy (conditional methQTL (methylation quantitative trait loci)); and (2) determining the effect of the interaction between DNA-M of CpG (from stage 1) and SNPs (modifying genetic variants; modGV) on airflow limitation and AR in 245 female participants of the Isle of Wight birth cohort. DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip.FindingsSix CpG sites were analyzed in stage 1. DNA-M at cg13566430 was influenced by interaction of maternal smoking during pregnancy and rs20541. In stage 2, genotype at rs1800925 interacted with DNA-M at cg13566430 significantly affecting airflow limitation (P = 0.042) and AR (P = 0.01).ConclusionBoth genetic variants and environment affect DNA-M. This study supports the proposed two-stage model (methQTL and modGV) to study genetic variants, environment and DNA-M interactions in asthma-related lung function.

Changing prevalence of wheeze, rhinitis and allergic sensitisation in late childhood: findings from 2 Isle of Wight birth cohorts 12 years apart

While the prevalence of asthma in children is decreasing or remaining the same, time trends in the prevalence of rhinitis in children are not known. Understanding sensitisation trends may help inform about trends in asthma and rhinitis prevalence.

Health-related quality of life in children with perceived and diagnosed food hypersensitivity

The few studies measuring health‐related quality of life (HRQL) in food hypersensitivity (FHS) have found significantly reduced HRQL in patients and their families, particularly in the areas of family and social activities, emotional issues and family economy. One aspect that has not been studied is the effect of suspected FHS (food allergy/intolerance) vs. diagnosed FHS [based on a food challenge or a positive skin prick test (SPT) and good clinical history] on HRQL. Therefore, the aim of this study was to investigate the HRQL in children with a proven diagnosis of FHS vs. those with reported FHS.

The prevalence, natural history and time trends of peanut allergy over the first 10 years of life in two cohorts born in the same geographical location 12 years apart

The aim of this study was to explore the natural history of peanut allergy in childhood in two birth cohorts from the same geographical region in the South of England.

Association of season of birth with DNA methylation and allergic disease

Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long‐lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy.

DNA methylation loci associated with atopy and high serum IgE: a genome-wide application of recursive Random Forest feature selection

BackgroundThe prevalence of allergic diseases are increasing worldwide, emphasizing the need to elucidate their pathogeneses. The aims of this study were to use a two-stage design to identify DNA methylation levels at cytosine–phosphate–guanine (CpG) sites across the genome associated with atopy and high serum immunoglobulin E (IgE), then to replicate our findings in an independent cohort.MethodsAtopy was assessed via skin prick tests and high serum IgE. Methylation levels were measured from whole blood using the Illumina Infinium HumanMethylation450 BeadChip from 18-year-old women (n = 245) and men (n = 122) in the Isle of Wight birth cohort. After data cleaning and processing, and removing probes with possible single nucleotide polymorphisms, DNA methylation levels from 254,460 CpG sites from the 245 women were subjected to recursive Random Forest feature selection for stage 1. The sites selected from stage 1 were tested in stage 2 for associations with atopy and high IgE levels (>200 kU/L) via logistic regression adjusted for predicted cell-type proportions and sex. Sites significantly associated with atopy in stage 2 underwent replication tests in the independent Swedish birth cohort BAMSE (n = 464).ResultsIn stage 1, 62 sites were selected, of which 22 were associated with atopy in stage 2 (P-value range 6.5E−9 to 1.4E−5) and 12 associated with high IgE levels (P-value range 1.1E−5 to 7.1E−4) at the Bonferroni adjusted alpha (0.05/62 = 0.0008). Of the 19 available sites, 13 were replicated.ConclusionsWe identified 13 novel epigenetic loci associated with atopy and high IgE that could serve as candidate loci for future studies; four were within genes with known roles in the immune response (cg04983687 in the body of ZFPM1, cg18219873 in the 5′UTR of PRG2, cg27469152 in the 3′UTR of EPX, and cg09332506 in the body of COPA).

Epigenomics and allergic disease.

Allergic disease development is affected by both genes and the environment, and epigenetic mechanisms are hypothesized to mediate these environmental effects. In this article, we discuss the link between the environment, DNA methylation and allergic disease, as well as questions of causality inherent to analyses of DNA methylation. From the practical side, we describe characteristics of allergic phenotypes and contrast different epidemiologic study designs used in epigenetic research. We examine methodological considerations, how best to conduct preprocessing and analysis of DNA methylation data sets, and the latest methods, technologies and discoveries in this rapidly advancing field. DNA methylation and other epigenetic marks are firmly entwined with allergic disease, a link that may hold the basis for future allergic disease diagnosis and treatment.

Prevalence and cumulative incidence of food hyper‐sensitivity in the first 10 years of life

Prevalence, incidence and natural history of food hypersensitivity (FHS) and its trends in an unselected cohort of older children are unclear.

The diversity of young adult wheeze: a cluster analysis in a longitudinal birth cohort

Cluster analyses have enhanced understanding of the heterogeneity of both paediatric and adult wheezing. However, while adolescence represents an important transitional phase, the nature of young adult wheeze has yet to be clearly characterised.