Semira Gonseth

Seasonal Variation of Overall and Cardiovascular Mortality: A Study in 19 Countries from Different Geographic Locations

Background Cardiovascular diseases (CVD) mortality has been shown to follow a seasonal pattern. Several studies suggested several possible determinants of this pattern, including misclassification of causes of deaths. We aimed at assessing seasonality in overall, CVD, cancer and non-CVD/non-cancer mortality using data from 19 countries from different latitudes. Methods and Findings Monthly mortality data were compiled from 19 countries, amounting to over 54 million deaths. We calculated ratios of the observed to the expected numbers of deaths in the absence of a seasonal pattern. Seasonal variation (peak to nadir difference) for overall and cause-specific (CVD, cancer or non-CVD/non-cancer) mortality was analyzed using the cosinor function model. Mortality from overall, CVD and non-CVD/non-cancer showed a consistent seasonal pattern. In both hemispheres, the number of deaths was higher than expected in winter. In countries close to the Equator the seasonal pattern was considerably lower for mortality from any cause. For CVD mortality, the peak to nadir differences ranged from 0.185 to 0.466 in the Northern Hemisphere, from 0.087 to 0.108 near the Equator, and from 0.219 to 0.409 in the Southern Hemisphere. For cancer mortality, the seasonal variation was nonexistent in most countries. Conclusions In countries with seasonal variation, mortality from overall, CVD and non-CVD/non-cancer show a seasonal pattern with mortality being higher in winter than in summer. Conversely, cancer mortality shows no substantial seasonality.

Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes

Folate deficiency during early embryonic development constitutes a risk factor for neural tube defects and potentially for childhood leukemia via unknown mechanisms. We tested whether folate consumption during the 12 months prior to conception induced DNA methylation modifications at birth in healthy neonates with a genome-wide and agnostic approach. We hypothesized that DNA methylation in genes involved in neural tube development and/or cancer susceptibility would be affected by folate exposure. We retrospectively assessed folate exposure at the time of conception by food-frequency questionnaires administered to the mothers of 343 healthy newborns. We measured genome-wide DNA methylation from neonatal blood spots. We implemented a method based on bootstrap resampling to decrease false-positive findings. Folate was inversely associated with DNA methylation throughout the genome. Among the top folate-associated genes that were replicated in an independent Gambian study were TFAP2A, a gene critical for neural crest development, STX11, a gene implicated in acute myeloid leukemia, and CYS1, a candidate gene for cystic kidney disease. Reduced periconceptional folate intake was associated with increased methylation and, in turn, decreased gene expression at these 3 loci. The top folate-sensitive genes defined by their associated CpG sites were enriched for numerous transcription factors by Gene Set Enrichment Analysis, including those implicated in cancer development (e.g., MYC-associated zinc finger protein). The influence of estimated periconceptional folate intake on neonatal DNA methylation levels provides potential mechanistic insights into the role of this vitamin in the development of neural tube defects and childhood cancers.

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

&NA; Pre‐pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta‐analysed the association between pre‐pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother‐newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother‐child pairs), we meta‐analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10‐7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well‐powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large‐scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Genetic contribution to variation in DNA methylation at maternal smoking-sensitive loci in exposed neonates

ABSTRACT Epigenome-wide DNA methylation association studies have identified highly replicable genomic loci sensitive to maternal smoking during gestation. The role of inter-individual genetic variation in influencing DNA methylation, leading to the possibility of confounding or bias of such associations, has not been assessed. We investigated whether the DNA methylation levels at the top 10 CpG sites previously associated with exposure to maternal smoking during gestation were associated with individual genetic variation at the genome-wide level. Genome-wide association tests between DNA methylation at the top 10 candidate CpG and genome-wide SNPs were performed in 736 case and control participants of the California Childhood Leukemia Study. Three of the strongest maternal-smoking sensitive CpG sites in newborns were significantly associated with SNPs located proximal to each gene: cg18146737 in the GFI1 gene with rs141819830 (P = 8.2×10−44), cg05575921 in the AHRR gene with rs148405299 (P = 5.3×10−10), and cg12803068 in the MYO1G gene with rs61087368 (P = 1.3×10−18). For the GFI1 CpG cg18146737, the underlying genetic variation at rs141819830 confounded the association between maternal smoking and DNA methylation in our data (the regression coefficient changed from −0.02 [P = 0.139] to −0.03 [P = 0.015] after including the genotype). Our results suggest that further studies using DNA methylation at cg18146737, cg05575921, or cg12803068 that aim to assess exposure to maternal smoking during gestation should include genotype at the corresponding SNP. New methods are required for adequate and routine inclusion of genotypic influence on DNA methylation in epigenome-wide association studies to control for potential confounding.

GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21

Childhood acute lymphoblastic leukemia (ALL) (age 0–14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children’s Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near IKZF3/ZPBP2/GSDMB/ORMDL3, a locus encompassing a transcription factor important for lymphocyte development (IKZF3), and at an 8q24 region known for structural contacts with the MYC oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways.Childhood acute lymphoblastic leukemia is common in Latino Americans. Here, the authors conduct a genome-wide association study in a Californian cohort containing children of Latino heritage, and identify loci on 17q12 and 8q24 which may affect hematopoietic and growth-regulation pathways.

Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia

Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and childs passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction = 0.04). The total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL. Cancer Res; 77(7); 1674-83. ©2017 AACR.

Excess winter deaths caused by cardiovascular diseases are associated with both mild winter temperature and socio-economic inequalities in the U.S.

a University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, CA 94158, USA b University of California, Berkeley, Department of Environmental Science, Policy, and Management, Berkeley, CA 94720, USA c University of Lausanne, Institute of Social and Preventive Medicine, 1010 Lausanne, Switzerland d University of Lausanne, Institute of History of Medicine and Public Health, 1007 Lausanne, Switzerland

Abstract 831: In utero polycyclic aromatic hydrocarbons exposure and genome-wide DNA methylation modifications at birth in children who develop acute lymphoblastic leukemia

Introduction Previously, residential dust content of polycyclic aromatic hydrocarbons (PAHs) was associated with an increased risk of acute lymphoblastic childhood leukemia (ALL), and PAHs exposure levels have been associated with differentially methylated regions (DMRs) in candidate genes studies. Thus, we hypothesized that in utero exposure to residential PAHs may be associated with genome-wide DMRs in genes that may influence ALL development. Methods PAHs were measured in dust samples collected using a high-volume surface sampler or household vacuum cleaners from homes of California Childhood Leukemia Study participants who have lived in the same home since diagnosis. The different PAHs were summed according to their toxic equivalency. DNA was extracted from archived neonatal blood spots of participants, then treated with bisulfite and assayed on Illumina Infinium 450K genome-wide DNA methylation arrays. Following removal of cross-reacting probes, SNP-related and polymorphic CpGs, we analyzed the association of residential PAH levels with methylation intensity of 319,265 CpGs in two independent case-only datasets (model #1: set 1 cases n = 84, set 2 cases n = 51). We used a false discovery rate with random resampling to reduce the number of false-positive findings and cross-validated the results between sets. This first step of the analysis gave 11 significant and sign concordant CpGs. Then we assessed interactions between case/control status and PAHs levels with methylation intensities at those 11 CpGs in set 1 (model #2: total cases and controls n = 306). Models were adjusted for cell mixture, sex, gestational age, race and the first 2 principal components of the models’ residuals. Results In model #1, methylation levels at 11 CpGs were significantly associated with residential PAH levels and sign concordant in both sets with a corresponding q-value Conclusions For the first time, our genome-wide methylation investigation found that residential PAH levels were associated with 11 CpGs at birth among children who later developed ALL. Moreover, the future cases had significantly different DNA methylation responses to PAH exposures than the unaffected controls for 7 CpGs. This may suggest a case/control difference present at birth in the sensitivity to PAHs in particular cell-cycle and tumor-suppressor genes. These CpGs may be good candidates to further investigate with respect to leukemogenesis. Citation Format: Semira Gonseth, Todd P. Whitehead, Ritu Roy, E. Andres Houseman, Adam J. de Smith, Mi Zhou, Seung-Tae Lee, Margaret R. Wrensch, Stephen M. Rappaport, Catherine Metayer, Joseph L. Wiemels. In utero polycyclic aromatic hydrocarbons exposure and genome-wide DNA methylation modifications at birth in children who develop acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 831. doi:10.1158/1538-7445.AM2015-831