Association of grandmaternal smoking during pregnancy with DNA methylation of grandchildren: the Isle of Wight study.

Background: To investigate the intergenerational effects of grandmaternal smoking during pregnancy (GMSDP) on the DNA methylation of grandchildren. Methods: Data from the Isle of Wight birth cohort with information regarding GMSDP and DNA methylation profiling at the birth of grandchildren (n = 161) were used. Differentially methylated CpG sites related to GMSDP were identified using testing-training screening, analysis of variance and multivariate analysis of covariance. The association between identified CpG sites and expression levels of neighboring genes was tested by linear regression. Results: Twenty-three CpG sites were differentially methylated in grandchildren because of GMSDP, and eight of these were associated with expression levels of 13 neighboring genes. Conclusion: GMSDP has an intergenerational effect on the DNA methylation profile of grandchildren independent of maternal smoking during pregnancy.

Lay abstract This study aimed to assess how grandmaternal smoking during pregnancy can affect the health of grandchildren. Underlying mechanisms may include epigenetic modifications. To address this topic, the authors investigated the intergenerational effects of grandmaternal smoking during pregnancy on the DNA methylation of grandchildren at birth based on the Isle of Wight birth Cohort. Twenty-three CpG sites were differentially methylated in grandchildren because of grandmaternal smoking during pregnancy, and eight of these were associated with changes in expression levels of 13 neighboring genes. Thus, grandmaternal smoking during pregnancy has an intergenerational effect on the DNA methylation profile of grandchildren independent of maternal smoking during pregnancy.

Cricket ball in the right heart: A case report of right atrial myxoma.

INTRODUCTION: Myxomas are the most common type of cardiac benign tumors and most of them are located in the left atrium, followed by the right atrium. The majority of Myxomas is located in the left atrium and has a variable clinical presentation. Myxomas affect patients within a wide age range (15-80 years), and the average age is approximately 50 years. There is a female predominance in the sporadic form. Myxomas are usually pedunculated, solitary, and sporadic but may be associated with familial autosomal dominant syndromes. CASE PRESENTATION: We report a 38-year-old female presented with large myxoma in the right atrium and atypical presentation and successfully underwent surgical excision of right atrial myxoma. The patient was asymptomatic on 6 months follow up. CONCLUSION: Cardiac myxomas are the most frequent finding among primary cardiac tumors. Clinical manifestations depend on the involvement in valvular obstruction, distant arterial embolisms, or nonspecific, constitutional symptoms. Transoesophageal Echocardiography is the cornerstone for diagnosis of atrial myxoma. Cardiac myxomas should be managed with surgical resection.

Rare case of aortic aneurysm with type A dissection (extending to right coronary artery) and severe AR in a nonhypertensive and non pregnant female.

INTRODUCTION: Typically a patient with acute aortic dissection presents with severe chest pain radiating to the back, tearing in nature. Rarely it can present as painless acute aortic dissection this is seen in iatrogenic cases or when associated with atherosclerosis, diabetes, or aortic aneurysm. CASE PRESENTATION: We hereby present a case of a 32-year aged female who presented with dyspnoea & palpitations (NYHA III) from last 6 months, diagnosed to have Aortic Aneurysm with Type A dissection & Severe AR. She eventually underwent BENTALL'S procedure with CABG and had an uneventful recovery. DISCUSSION: Clinical manifestation of Aortic dissection can be variable, therefore its diagnosis is challenging. 25% of cases, may have associated ECG changes suggestive of acute coronary syndrome leading to a possible misdiagnosis especially if associated ST elevation in ECG. Aorto arteritis is a non-atherosclerotic chronic inflammatory vascular disease of unknown etiology that affects the aorta, proximal parts of its major branches. In this case, there is a possibility that there was underlying spontaneous coronary artery dissection which in turn could be cause for silent ischemia in young women. CONCLUSION: Acute aortic dissection is a life-threatening disease with a high rate of cardiovascular morbidity and mortality. The most important and common risk factor is systemic hypertension which has been reported in the 70% of the patients with aortic dissection. Most of the aortic dissection observed in young women has been reported to be related to pregnancy. Dissection should be suspected during any acute coronary syndrome, particularly Inferior wall MI.

Epigenome-wide association study of asthma and wheeze characterizes loci within HK1.

BACKGROUND: To identify novel epigenetic markers of adolescent asthma and replicate findings in an independent cohort, then explore whether such markers are detectable at birth, predictive of early-life wheeze, and associated with gene expression in cord blood. METHODS: We performed epigenome-wide screening with recursive random forest feature selection and internal validation in the IOW birth cohort. We then tested whether we could replicate these findings in the independent cohort ALSPAC and followed-up our top finding with children of the IOW cohort. RESULTS: We identified 10 CpG sites associated with adolescent asthma at a 5% false discovery rate (IOW, n = 370), five of which exhibited evidence of associations in the replication study (ALSPAC, n = 720). One site, cg16658191, within HK1 displayed particularly strong associations after cellular heterogeneity adjustments in both cohorts (ORIOW = 0.17, 95% CI 0.04-0.57) (ORALSPAC = 0.57, 95% CI 0.38-0.87). Additionally, higher expression of HK1 (OR = 3.81, 95% CI 1.41-11.77) in cord blood was predictive of wheezing in infancy (n = 82). CONCLUSION: We identified novel associations between asthma and wheeze with methylation at cg16658191 and the expression of HK1, which may serve as markers of, predictors of, and potentially etiologic factors involved in asthma and early life wheeze.

Effect of gestational oily fish intake on the risk of allergy in children may be influenced by FADS1/2, ELOVL5 expression and DNA methylation.

BACKGROUND: Evidence suggests that prenatal exposure to n-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces the incidence of allergic disease in children. LCPUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by the FADS1/2 and ELOVL5 genes. DNA methylation regulates gene activity and fatty acid supplementation could alter DNA methylation (DNA-M) at these genes. We investigated whether DNA-M and expression of the FADS1/2 and ELOVL5 genes were associated with allergy in children and gestational fish intake. We studied 170 participants from the Isle of Wight 3rd Generation Cohort, UK. Phenotype data and exposure was assessed by questionnaires. Genome-wide DNA-M in cord blood samples was quantified using the Illumina Infinium HumanMethylation450 and EPIC Beadchips. Five SNPs (single-nucleotide polymorphisms) in the FADS gene cluster and one SNP in ELOVL5 were genotyped in offspring. FADS gene expression in offspring cord blood was determined. RESULTS: Gestational fish intake was significantly associated with increased methylation of cg12517394 (P = 0.049), which positively correlated with FADS1 mRNA levels (P = 0.021). ELOVL5 rs2397142 was significantly associated with eczema (P = 0.011) and methylation at cg11748354 and cg24524396 (P < 0.001 and P = 0.036, respectively). Gestational fish intake was strongly associated with elevated DNA-M at cg11748354 and cg24524396 (P = 0.029 and P = 0.002, respectively) and reduced ELOVL5 mRNA expression (P = 0.028). CONCLUSION: The association between induced FADS1/2 and ELOVL5 DNA-M and reduced gene expression due to gestational fish intake provide a mechanistic explanation of the previously observed association between maternal LCPUFA intake and allergy development in early childhood.

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.

BACKGROUND: 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. METHODS: The FAIR birth cohort was established on the Isle of Wight (UK) between 2001 and 2002 (n = 969). Children were followed up prospectively, skin prick tested (SPT) to peanut allergens at 1, 2, 3 and 10 years and food challenges performed. The Isle of Wight (IOW) birth cohort was established in 1989 (n = 1456). SPTs were performed at 1, 2, 4 and 10 years. Peanut allergy was based on positive SPT and a good clinical history. RESULTS: In the FAIR cohort, the prevalence of sensitization to peanut was 0.4%, 2.0%, 2.0% and 2.4% at 1, 2, 3 and 10 years, respectively. At 10 years of age, 12 of 828 (1.5%) children were diagnosed with peanut allergy. One child (8%) outgrew her peanut allergy between 3 and 10 years and two children (15%) presented with new onset peanut allergy. Over the first 10 years of life, 13 of 934 (1.4%) children were diagnosed with peanut allergy. In the IOW cohort, 6 of 1034 (0.58%) were diagnosed with peanut allergy at 10 years. We found no significant differences between the FAIR and the IOW birth cohort for any of the time points studied. CONCLUSION: Peanut allergy appears to be stable over the first 10 years of life in our cohorts. There was no significant difference in peanut sensitization or clinical peanut allergy between 1989 and 2001.

Very low prevalence of IgE mediated wheat allergy and high levels of cross-sensitisation between grass and wheat in a UK birth cohort.

BACKGROUND: Patients often report adverse reactions to wheat. Interpretation of sensitization to wheat pollen and flour with/without sensitization to grass pollen is a clinical problem. AIM: We set out to determine the prevalence of wheat allergy in a birth cohort (10/11 year olds) and investigate the usefulness of performing skin prick tests (SPT), specific IgE tests and component resolved diagnostics to wheat pollen and flour. METHODS: The Food Allergy and Intolerance Research (FAIR) birth cohort included babies born on the Isle of Wight (UK) between September 2001-August 2002 (n = 969). Children were followed up at 1, 2, 3 and 10/11 years. 588 children had SPTs to wheat pollen and grass during the 10 year follow-up. 294 children underwent further SPT to wheat flour and 246 had specific IgE testing to wheat and grass. RESULTS: Eight children underwent oral food challenges (OFC). We diagnosed 0.48 % (4/827; 95 % CI 0-1 %) children with wheat allergy based on OFC. 16.3 % (96/588) were sensitized to grass pollen, 13.4 % (79/588) to wheat pollen; 78 % (75/96) sensitized to both. Only one child was sensitized to wheat flour and wheat pollen, but not grass pollen. For specific IgE, 15.0 % (37/246) and 36.2 % (89/246) were sensitized to wheat and grass pollen, with 40.5 % (36/89) sensitized to both. Of the 37 children sensitized to wheat, 3 (8.1 %) were sensitized to omega 5 gliadin, 1 (2.7 %) to wheat lipid transfer protein and 1 to wheat gliadin. CONCLUSION: Clinicians should be aware of the high level of cross-sensitization when performing tests to wheat and grass pollen i.e. sensitisation to wheat specific IgE and wheat pollen SPT should be assessed in the presence of grass pollen SPT and/or specific IgE.

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

BACKGROUND: Prevalence, incidence and natural history of food hypersensitivity (FHS) and its trends in an unselected cohort of older children are unclear. METHODS: A birth cohort born on the Isle of Wight (UK) between 2001 and 2002 was followed up prospectively. Children were clinically examined and skin prick tested at set times and invited for food challenges when indicated. At 10 years of age, children were also invited for a blood test. RESULTS: A total of 969 children were recruited at 12 weeks of pregnancy, and 92.9%, 88.5%, 91.6% and 85.3% were assessed at 1, 2, 3 and 10 years. Prevalence of sensitization to any allergen over 10 years was 186 of 969 (19.2%; 95% CI: 16.84-21.8) and 108 of 969 (11.2%; 95% CI: 9.31-13.29) children were sensitized to at least one predefined food allergen. Excluding wheat (due to cross-reactivity with pollen), 40 of 969 (4.1%; 95% CI: 3.19-5.32) children were sensitized to a predefined food allergen. Using food challenges and/or a good clinical history, the cumulative incidence of food hypersensitivity (FHS) in the first decade of life was 64 of 947 (6.8%, 95% CI: 5.2-8.4), while the prevalence of FHS at 10 years was 30 of 827 (3.6%, 95% CI: 2.54-5.15). The vast majority, 25 of 827 (3.0%, 95% CI: 1.8-4.2), suffered from IgE-mediated food allergy, while 5 of 827 (0.6%, 95% CI: 0.07-1.3) had non-IgE-mediated food allergy/food intolerance. CONCLUSIONS: By the age of 10 years, 6.8% of children suffered from FHS based on food challenges and a good clinical history. There was a large discrepancy between reported and diagnosed FHS.

Use of CT Angiogram in Interventions Involving Coronary Artery Anomalies: A Case Series.

BACKGROUND: Coronary artery anomalies are rare, accounting for about 0.3-1.3% of patients undergoing diagnostic coronary angiography. Interventions in these cases are still rare, and therefore pose technical challenges during intervention. CT Angiography provides a non-invasive means of assessment of coronary artery disease and also shows the anatomy of the coronary tree. This helps in knowing the origin of the coronaries and also to plan selection of hardware. There are no specific guidelines for use of guiding catheters and guide wires in anomalous coronary artery intervention. CASE REPORT: We report a series of 5 patients presenting with effort angina who had anomalous coronary arteries with coronary stenosis diagnosed by CT angiography. Three patients received percutaneous intervention, 1 patient underwent CABG, and 1 patient received medical management. CONCLUSIONS: CT Angiography provides a useful tool for showing the coronary anatomy and for selecting the guiding catheter and the guide wire that remain the mainstay of interventions in coronary artery anomalies.

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

BACKGROUND: The 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. METHODS: Atopy 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). RESULTS: In 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. CONCLUSIONS: We 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).

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

BACKGROUND: 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. METHODS: We have utilized the 10-yr old follow-up cohort of the Food Allergy and Intolerance Research (FAIR) study from the Isle of Wight and assessed the child's HRQL with the Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) which measures HRQL using four domains: food anxiety, emotional impact, social and dietary limitation. RESULTS: When comparing the two groups of children (proven FHS vs. perceived FHS), no difference in HRQL was found, although food anxiety showed a p-value of (p = 0.062). This was also the case when correcting for all confounding factors identified. CONCLUSION: We have found that having a clear diagnosis of FHS is not an independent predictor of HRQL. Future studies are required comparing two more similar groups. We also need to focus more on the effect of continuous input from the multidisciplinary team on HRQL and which particular factors of FHS management affect HRQL.

Identifying the heterogeneity of young adult rhinitis through cluster analysis in the Isle of Wight birth cohort.

BACKGROUND: Rhinitis affects many young adults and often shows comorbidity with asthma. OBJECTIVE: We hypothesized that young adult rhinitis, like asthma, exhibits clinical heterogeneity identifiable by means of cluster analysis. METHODS: Participants in the Isle of Wight birth cohort (n = 1456) were assessed at 1, 2, 4, 10, and 18 years of age. Cluster analysis was performed on those with rhinitis at age 18 years (n = 468) by using 13 variables defining clinical characteristics. RESULTS: Four clusters were identified. Patients in cluster 1 (n = 128 [27.4%]; ie, moderate childhood-onset rhinitis) had high atopy and eczema prevalence and high total IgE levels but low asthma prevalence. They showed the best lung function at 18 years of age, with normal fraction of exhaled nitric oxide (Feno), low bronchial hyperresponsiveness (BHR), and low bronchodilator reversibility (BDR) but high rhinitis symptoms and treatment. Patients in cluster 2 (n = 199 [42.5%]; ie, mild-adolescence-onset female rhinitis) had the lowest prevalence of comorbid atopy, asthma, and eczema. They had normal lung function and low BHR, BDR, Feno values, and total IgE levels plus low rhinitis symptoms, severity, and treatment. Patients in cluster 3 (n = 59 [12.6%]; ie, severe earliest-onset rhinitis with asthma) had the youngest rhinitis onset plus the highest comorbid asthma (of simultaneous onset) and atopy. They showed the most obstructed lung function with high BHR, BDR, and Feno values plus high rhinitis symptoms, severity, and treatment. Patient 4 in cluster 4 (n = 82 [17.5%]; ie, moderate childhood-onset male rhinitis with asthma) had high atopy, intermediate asthma, and low eczema. They had impaired lung function with high Feno values and total IgE levels but intermediate BHR and BDR. They had moderate rhinitis symptoms. CONCLUSION: Clinically distinctive adolescent rhinitis clusters are apparent with varying sex and asthma associations plus differing rhinitis severity and treatment needs.

Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation.

BACKGROUND: The prevalence of asthma in girls increases after puberty. Previous studies have detected associations between sex hormones and asthma, as well as between sex hormones and T helper 2 (Th2) asthma-typical immune responses. Therefore, we hypothesized that exogenous or endogenous sex hormone exposure (represented by oral contraceptive pill (OCP) use and early menarche, respectively) are associated with DNA methylation (DNA-M) of the Th2 transcription factor gene, GATA3, in turn affecting the risk of asthma in girls, possibly in interaction with genetic variants. Blood samples were collected from 245 female participants aged 18 years randomly selected for methylation analysis from the Isle of Wight birth cohort, UK. Information on use of OCPs, age at menarche, and concurrent asthma were assessed by questionnaire. Genome-wide DNA-M was determined using the Illumina Infinium HumanMethylation450 beadchip. In a first stage, we tested the interaction between sex hormone exposure and genetic variants on DNA-M of specific cytosine-phosphate-guanine (CpG) sites. In a second stage, we determined whether these CpG sites interact with genetic variants in GATA3 to explain the risk of asthma. RESULTS: Interactions between OCP use and seven single nucleotide polymorphisms (SNPs) of GATA3 were analyzed for 14 CpG sites (stage 1). The interaction between OCP use and SNP rs1269486 was found to be associated with the methylation level of cg17124583 (P = 0.002, false discovery rate (FDR) adjusted P = 0.04). DNA-M of this same CpG site was also influenced by the interaction between age at menarche and rs1269486 (P = 0.0017). In stage 2, we found that cg17124583 modified the association of SNP rs422628 with asthma risk at the age of 18 years (P = 0.006, FDR adjusted P = 0.04). Subjects with genotype AG showed an increase in average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when methylation level increased from 0.02 to 0.12, relative to genotype AA. CONCLUSION: A two-stage model consisting of genetic variants in the GATA3 gene, OCP use, age at menarche, and DNA-M may explain how sex hormones in women can increase the asthma prevalence after puberty.

The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition.

BACKGROUND: Genetic effects on asthma of genes in the T-helper 2 (Th2) pathway may interact with epigenetic factors including DNA methylation. We hypothesized that interactions between genetic variants and methylation in genes in this pathway (IL4, IL4R, IL13, GATA3, and STAT6) influence asthma risk, that such influences are age-dependent, and that methylation of some CpG sites changes over time in accordance with asthma transition. We tested these hypotheses in subsamples of girls from a population-based birth cohort established on the Isle of Wight, UK, in 1989. RESULTS: Logistic regression models were applied to test the interaction effect of DNA methylation and SNP on asthma within each of the five genes. Bootstrapping was used to assess the models identified. From 1,361 models fitted at each age of 10 and 18 years, 8 models, including 4 CpGs and 8 SNPs, showed potential associations with asthma risk. Of the 4 CpGs, methylation of cg26937798 (IL4R) and cg23943829 (IL4) changes between ages 10 and 18 (both higher at 10; P = 9.14 × 10(-6) and 1.07 × 10(-5), respectively). At age 10, the odds of asthma tended to decrease as cg12405139 (GATA3) methylation increased (log-OR = -12.15; P = 0.049); this effect disappeared by age 18. At age 18, methylation of cg09791102 (IL4R) was associated with higher risk of asthma among subjects with genotype GG compared to AG (P = 0.003), increased cg26937798 methylation among subjects with rs3024685 (IL4R) genotype AA (P = 0.003) or rs8832 (IL4R) genotype GG (P = 0.01) was associated with a lower asthma risk; these CpGs had no effect at age 10. Increasing cg26937798 methylation over time possibly reduced the risk of positive asthma transition (asthma-free at age 10 → asthma at age 18; log-OR = -3.11; P = 0.069) and increased the likelihood of negative transition (asthma at age 10 → asthma-free at age 18; log-OR = 3.97; P = 0.074). CONCLUSIONS: The interaction of DNA methylation and SNPs in Th2 pathway genes is likely to contribute to asthma risk. This effect may vary with age. Methylation of some CpGs changed over time, which may influence asthma transition.