Association between Variants in Atopy-Related Immunologic Candidate Genes and Pancreatic Cancer Risk

<div><p>Background</p><p>Many epidemiology studies report that atopic conditions such as allergies are associated with reduced pancreas cancer risk. The reason for this relationship is not yet understood. This is the first study to comprehensively evaluate the association between variants in atopy-related candidate genes and pancreatic cancer risk.</p><p>Methods</p><p>A population-based case-control study of pancreas cancer cases diagnosed during 2011-2012 (via Ontario Cancer Registry), and controls recruited using random digit dialing utilized DNA from 179 cases and 566 controls. Following an exhaustive literature review, SNPs in 180 candidate genes were pre-screened using dbGaP pancreas cancer GWAS data; 147 SNPs in 56 allergy-related immunologic genes were retained and genotyped. Logistic regression was used to estimate age-adjusted odd ratio (AOR) for each variant and false discovery rate was used to adjust Wald p-values for multiple testing. Subsequently, a risk allele score was derived based on statistically significant variants.</p><p>Results</p><p>18 SNPs in 14 candidate genes (<i>CSF2</i>, <i>DENND1B</i>, <i>DPP10</i>, <i>FLG</i>, <i>IL13</i>, <i>IL13RA2</i>, <i>LRP1B</i>, <i>NOD1</i>, <i>NPSR1</i>, <i>ORMDL3</i>, <i>RORA</i>, <i>STAT4</i>, <i>TLR6</i>, <i>TRA</i>) were significantly associated with pancreas cancer risk. After adjustment for multiple comparisons, two <i>LRP1B</i> SNPs remained statistically significant; for example, <i>LRP1B</i> rs1449477 (AA vs. CC: AOR=0.37, 95% CI: 0.22-0.62; p (adjusted)=0.04). Furthermore, the risk allele score was associated with a significant reduction in pancreas cancer risk (p=0.0007).</p><p>Conclusions</p><p>Preliminary findings suggest certain atopy-related variants may be associated with pancreas cancer risk. Further studies are needed to replicate this, and to elucidate the biology behind the growing body of epidemiologic evidence suggesting allergies may reduce pancreatic cancer risk.</p></div

Additional file 1 of An evaluation of methods correcting for cell-type heterogeneity in DNA methylation studies

Contains plots showing simulated effect sizes among 500 CpGs in simulation scenario 1, and QQ plots for p values of several simulation scenarios. (PDF 771 kb

Additional file 2: of X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells

Table S1. Primers used in the study. (DOCX 12 kb

Additional file 8: of X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells

Table S5. Univariate analysis results, full model multivariate analysis results, as well as post hoc power calculations. (DOCX 14 kb

Boxplot of vitamin D binding protein levels by rs2282679 genotype.

<p>rs2282679 has three genotypes, i.e., AA, AC, and CC. Homozygous carriers of the major allele (AA) comprised 51.4% of the population, heterozygous carriers (AC) comprised 39.6%, and homozygous carriers of the minor allele (CC) comprised 9.0%. Individuals carrying the effect allele, C, had lower DBP levels than those with the more common allele (AA: 384.6 mg/l [SD 48.3], <i>n</i> = 1,159; CA: 360.7 mg/l [SD 45.9], <i>n</i> = 893; CC: 322.9 mg/l [SD 39.1], <i>n</i> = 202). The effect allele showed an inverse linear relationship with DBP levels.</p

Additional file 5: of X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells

Figure S2. Sodium bisulfite sequencing methylation analysis of 51 CGs across the ZPBP2 promoter region shows higher methylation levels in fibroblast cell lines with two and three copies of the Xq arm. A: location of the 51 CGs interrogated using the sodium bisulfite sequencing assay shown in the context of the UCSC browser (hg19). B: heatmap representing mean methylation levels for each of the 51 CGs in cell lines with one X chromosome (two fibroblast cell lines with karyotype 45,X and no SRY region) and two or three copies of Xq (data from four fibroblast cell lines with karyotype 46,XX and two fibroblast cell lines from Turner syndrome patients with karyotype 46,i(Xq)). The black box beneath the heatmap shows the location of the 10 CGs analyzed by the pyrosequencing assay. The color scale for percent methylation is shown on the right. (DOCX 292 kb

rs2282679 polymorphism association with diseases and traits that have been observationally related to vitamin D levels.

<p>Regression models were adjusted for age and sex. Analyses of disease-related traits were performed on both adult and youth CaMos cohorts; analyses of diseases were restricted to the CaMos adult cohort only. M-dashes indicate that summary data were not publically available.</p>∫<p>Measurement change for disease-related traits and OR for diseases. Change in measurement of disease-related trait is per each additional copy of the risk allele. All continuous variables were inspected for normality, and outliers (<1% of data points) were excluded. For diseases, ORs are reported per copy of risk allele. The null hypothesis is tested using α = 0.05. The Bonferroni method is used to maintain family-wise error rate when performing multiple testing through enforcing a more stringent α = 0.05/12 = 0.0042 (12 comparisons). Independence between outcomes was assumed in this correction.</p>∥<p>The natural logarithm was used.</p>¶<p>Effect estimates excluding participants with diabetes were similar for fasting glucose, −0.013 (95% CI −0.050, 0.023), <i>p</i> = 0.47, and for fasting insulin, −0.034 (95% CI −0.075, 0.007), <i>p</i> = 0.10.</p>*<p>ICBP had available GWAS data only on blood pressure measurements, not on hypertension; no association was found for systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure.</p>|<p>This effect estimate provided by METASTROKE is for overall ischemic stroke, which does not include TIA.</p><p>rs2282679 polymorphism association with diseases and traits that have been observationally related to vitamin D levels.</p

Additional file 1: of X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells

Figure S1. Experimental design. (DOCX 18 kb

Observational and instrumental variable analyses for the causal association of vitamin D binding protein with 25-hydroxy-vitamin D and common diseases and related traits in the CaMos cohort.

<p>Effect estimates are presented as absolute changes for continuous traits or ORs for disease per 1-SD increase in DBP. All observational regression and IV models were adjusted for age and sex only. Analyses of disease conditions were restricted to the adult cohort only. The null hypothesis is tested using α = 0.05. The Bonferroni method is used to maintain family-wise error rate when performing multiple testing through enforcing a more stringent α = 0.05/12 = 0.004 (12 comparisons).</p><p>*The Durbin-Wu-Hausman chi-square test (test for endogeneity) was computed for continuous outcomes.</p>∥<p>The outcome was transformed using the natural logarithm, and effect estimates are reported accordingly.</p>¶<p>Effect estimates with and without excluding participants with diabetes were similar for fasting glucose. Excluding participants with diabetes, effect estimate per 50 mg/l of DBP: −1.3×10⁻⁴ (95% CI −0.001, 3.9×10⁻⁴), <i>p</i> = 0.63, and 0.001 (95% CI −0.001, 0.002), <i>p</i> = 0.47, test for endogenicity, <i>p</i> = 0.33; they were also similar for fasting insulin. Excluding participants with diabetes, effect estimate per 50 mg/l of DBP: −2.4×10⁻⁴ (95% CI −0.001, 3.4×10⁻⁴), <i>p</i> = 0.42, and 0.001 (95% CI −1.9×10⁻⁴, 0.003), <i>p</i> = 0.09, test for endogenicity, <i>p</i> = 0.03.</p><p>Observational and instrumental variable analyses for the causal association of vitamin D binding protein with 25-hydroxy-vitamin D and common diseases and related traits in the CaMos cohort.</p

Additional file 6: of X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells

Table S4. Methylation percentages at the analyzed ZPBP2 DMR CGs from human non-transformed fibroblast cell lines, and the first PC of these values. (DOCX 14 kb