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A survey of epigenetic associations between serum immunoglobulin E concentrations indicating allergy and methylation at CpG islands in families and a population sample has revealed associations at 36 loci that harbour genes encoding proteins including eosinophil products and phospholipid inflammatory mediators. IgE blocker targets identified Drugs that block immunoglobulin E (IgE) are widely used to treat asthma, hay fever and allergic asthma, but genetic association studies have failed to identify the pathways underlying the pathways that regulate IgE's role in mediating the allergic state. Using DNA from peripheral blood leukocytes, William Cookson and colleagues surveyed families for epigenetic associations between serum IgE concentrations and methylation at CpG islands genome-wide. They identified associations between IgE and low methylation at 36 loci that harbour genes encoding proteins including eosinophil products and phospholipid inflammatory mediators. The three most-associated loci accounted for 13% of IgE variation in the primary subject panel. The study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases. Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever 1 and allergic asthma 1 , 2 . Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation 3 , 4 , 5 , 6 . We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations—with a meta-analysis false discovery rate less than 10 −4 —between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies 3 , 4 . This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.

Childhood asthma genes Rates of childhood asthma diagnosis are rising: 6% of children in the United States are sufferers. Both genetic and environmental factors are clearly important. To discover more about the genetic element, Moffatt et al . looked for genes linked to asthma in a genome-wide association scan. More than a third of children with asthma of onset below the age of seven showed variations in expression of the ORMDL3 gene on chromosome 17. Similar genes are found in yeast and other primitive organisms, suggesting that they may be components of an ancient and conserved immune mechanism. Variations in expression of the gene ORMDL3 were found to be associated with development of childhood asthma, suggesting this gene should be examined in more patient groups. Asthma is caused by a combination of poorly understood genetic and environmental factors 1 , 2 . We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P  value of P  < 10 -12 . In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children ( P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort ( P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated ( P  < 10 -22 ) in cis with transcript levels of ORMDL3 , a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum 3 . The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.

Chronic hyperglycemia is a major risk factor for glomerular or retinal microangiopathy and cardiovascular complications of type 1 diabetes (T1D). At the interface of genetics and environment, dynamic epigenetic changes associated with hyperglycemia may unravel some of the mechanisms contributing to these T1D complications. In this study, blood samples were collected from 112 young patients at T1D diagnosis and 3 years later in average. Whole genome-wide bisulfite sequencing was used to measure blood DNA methylation changes of about 28 million CpGs at single base resolution over this time. Chronic hyperglycemia was estimated every 3–4 months by HbA1c measurement. Linear regressions with adjustment to age, sex, treatment duration, blood proportions and batch effects were employed to characterize the relationships between the dynamic changes of DNA methylation and average HbA1c levels. We identified that longitudinal DNA methylation changes at 815 CpGs (with suggestive p-value threshold of 1e-4) were associated with average HbA1c. Most of them (> 98%) were located outside of the promoter regions and were enriched in CpG island shores and multiple immune cell type specific accessible chromatin regions. Among the 36 more strongly associated loci (p-value < 5e-6), 16 were harbouring genes or non-coding sequences involved in angiogenesis regulation, glomerular and retinal vascularization or development, or coronary disease. Our findings support the identification of new genomic sites where CpG methylation associated with hyperglycemia may contribute to long-term complications of T1D, shedding light on potential mechanisms for further exploration.

Background: Aristolochic acid (AA) is a nephrotoxicant associated with AA nephropathy (AAN) and upper urothelial tract cancer (UUTC). Whole-genome sequences of 14 Romanian cases of renal cell carcinoma (RCC) recently exhibited mutational signatures consistent with AA exposure, although RCC had not been previously linked with AAN and AA exposure was previously reported only in localised rural areas. Methods: We performed mass spectrometric measurements of the aristolactam (AL) DNA adduct 7-(deoxyadenosin- N 6 -yl) aristolactam I (dA-AL-I) in nontumour renal tissues of the 14 Romanian RCC cases and 15 cases from 3 other countries. Results: We detected dA-AL-I in the 14 Romanian cases at levels ranging from 0.7 to 27 adducts per 10 8 DNA bases, in line with levels reported in Asian and Balkan populations exposed through herbal remedies or food contamination. The 15 cases from other countries were negative. Interpretation: Although the source of exposure is uncertain and likely different in AAN regions than elsewhere, our results demonstrate that AA exposure in Romania exists outside localised AAN regions and provide further evidence implicating AA in RCC.

Perilipin, the most abundant adipocyte-specific lipid-droplet coat protein, is required for optimal lipid incorporation and release from the droplet. The authors identified mutations in the perilipin gene in families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Although the adverse consequences of an excessive fat mass (obesity) are widely appreciated, adipose tissue also has key metabolic functions, including storage of surplus energy and buffering of the postprandial influx of free fatty acids and their release in the fasting state or during exercise for oxidation by other tissues — all of which are essential for health. 1 Small intracytoplasmic lipid droplets are found in most cell types, whereas white fat cells (adipocytes) store triglycerides within a large, single lipid droplet, which occupies up to 90% of the cell volume. The unilocular droplet of white adipocytes allows optimal energy storage . . .

PurposeThe Canadian Longitudinal Study on Aging (CLSA) Comprehensive cohort was established to provide unique opportunities to study the genetic and environmental contributions to human disease as well as ageing process. The aim of this report was to describe the genomic data included in CLSA.ParticipantsA total of 26 622 individuals from the CLSA Comprehensive cohort of men and women aged 45–85 recruited between 2010 and 2015 underwent genome-wide genotyping of DNA samples collected from blood. Comprehensive quality control metrics were measured for genetic markers and samples, respectively. The genotypes were imputed to the TOPMed reference panel. Sex chromosome abnormalities were identified by copy number profiling. Classical human leukocyte antigen gene haplotypes were imputed at two-field (four-digit).Findings to dateOf the 26 622 genotyped participants, 24 655 (92.6%) were identified as having European ancestry. These genomic data were linked to physical, lifestyle, medical, economic, environmental and psychosocial factors collected longitudinally in CLSA. The combined analysis, including CLSA genomic data, uncovered over 100 novel loci associated with key parameters to define glaucoma. The CLSA genomic dataset validated the contribution of a polygenic risk score to screen individuals with high fracture risk. It is also a valuable resource to directly identify common genetic variations associated with conditions related to complex traits. Taking advantage of the comprehensive interview and physical information collected in CLSA, this genomic dataset has been linked to psychosocial factors to investigate both the independent and interactive effects on cardiovascular disease.Future plansThe CLSA overall is ongoing. Follow-up data will continue to be collected from participants in the current genomic subcohort, including the DNA methylation and metabolomic data. Ongoing studies focus on elucidating the role of genetic factors in cognitive decline and cardiovascular diseases. This genomic data resource is available on request through the CLSA data access application process.

Background CpG methylation variation is involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions through the application of targeted arrays. We generate whole-genome bisulfite sequencing data for approximately 30 adipose and blood samples from monozygotic and dizygotic twins for the characterization of non-genetic and genetic effects at single-site resolution. Results Purely invariable CpGs display a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs account for approximately 15–20 % of total CpGs per tissue, are enriched in enhancer-associated regions and depleted in promoters, and single nucleotide polymorphisms at CpGs are a frequent confounder of extreme methylation variation. Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific. Tobacco smoking is associated with differential methylation in blood with no evidence of this exposure impacting cell counts. Opposite to non-genetic effects, genetic effects of CpG methylation are shared across tissues and thus limit inter-tissue epigenetic drift. CpH methylation is rare, and shows similar characteristics of variation patterns as CpGs. Conclusions Our study highlights the utility of low pass whole-genome bisulfite sequencing in identifying methylome variation beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues requires assessment of understudied intergenic CpGs distal to gene promoters to reveal the full extent of inter-individual variation.

Sickle cell trait is the quintessential example of the human evolutionary response to malaria, providing protection against severe disease, but leading to sickle cell disease (SCD) in the homozygous state. Fetal Hemoglobin (HbF) reduces the pathology of SCD and several mutations lead to the prolonged production of HbF into childhood and adult life. HbF has been suggested to contribute to protection against malaria. Two long-term cohorts were genotyped for three quantitative trait loci associated with HbF production and analyzed for HbF titers, malaria clinical episodes and the production of parasite stages infectious to mosquitoes, gametocytes, in asymptomatic infections. Plasmodium falciparum parasites were also grown in vitro in HbSS cells with measured levels of HbF. The genetic determinants of prolonged HbF production were associated with increased HbF titers and that increased HbF afforded protection from malaria disease but increased the production of gametocytes. The presence of HbF in sickled red cells was also shown in in vitro culture to enable parasite persistence in conditions otherwise deleterious for the parasite and enabled complete maturation of gametocytes. The beneficial personal effect of HbF, whether through protection against malaria or alleviating effects of SCD, is seemingly offset by increased parasite transmissibility and potential disease burden for the community. These individuals represent a potentially important reservoir of infection and could be targeted in elimination strategies.