Heather Eliassen

Genome-wide association study of circulating vitamin D levels

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10−17) and rs10882272 (P =6.04× 10−12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses’ Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10−5), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10−5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

Genome-wide association study identifies common variants associated with circulating vitamin E levels

In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10−8) and rs11057830 on 12q24.31 (P= 2.0 × 10−8) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10−10). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10−12 (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10−10 (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10−9 (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P< 1 × 10−4 identified.

Polyclonal human antibodies against glycans bearing red meat-derived non-human sialic acid N-glycolylneuraminic acid are stable, reproducible, complex and vary between individuals: Total antibody levels are associated with colorectal cancer risk

Background N-glycolylneuraminic acid (Neu5Gc) is a non-human red-meat-derived sialic acid immunogenic to humans. Neu5Gc can be metabolically incorporated into glycan chains on human endothelial and epithelial surfaces. This represents the first example of a “xeno-autoantigen”, against which circulating human “xeno-autoantibodies” can react. The resulting inflammation (“xenosialitis”) has been demonstrated in human-like Neu5Gc-deficient mice and contributed to carcinoma progression via antibody-mediated inflammation. Anti-Neu5Gc antibodies have potential as biomarkers for diseases associated with red meat consumption such as carcinomas, atherosclerosis, and type 2 diabetes. Methods ELISA assays measured antibodies against Neu5Gc or Neu5Gc-glycans in plasma or serum samples from the Nurses’ Health Studies, the Health Professionals Follow-up Study, and the European Prospective Investigation into Cancer and Nutrition, including inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over 1–3 years in archived samples. We also assessed associations between antibody levels and coronary artery disease risk (CAD) or red meat intake. A glycan microarray was used to detected antibodies against multiple Neu5Gc-glycan epitopes. A nested case-control study design assessed the association between total anti-Neu5Gc antibodies detected in the glycan array assay and the risk of colorectal cancer (CRC). Results ELISA assays showed a wide range of anti-Neu5Gc responses and good inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over time, but these antibody levels did not correlate with CAD risk or red meat intake. Antibodies against Neu5Gc alone or against individual Neu5Gc-bearing epitopes were also not associated with colorectal cancer (CRC) risk. However, a sialoglycan microarray study demonstrated positive association with CRC risk when the total antibody responses against all Neu5Gc-glycans were combined. Individuals in the top quartile of total anti-Neu5Gc IgG antibody concentrations had nearly three times the risk compared to those in the bottom quartile (Multivariate Odds Ratio comparing top to bottom quartile: 2.98, 95% CI: 0.80, 11.1; P for trend = 0.02). Conclusions Further work harnessing the utility of these anti-Neu5Gc antibodies as biomarkers in red meat-associated diseases must consider diversity in individual antibody profiles against different Neu5Gc-bearing glycans. Traditional ELISA assays for antibodies directed against Neu5Gc alone, or against specific Neu5Gc-glycans may not be adequate to define risk associations. Our finding of a positive association of total anti-Neu5Gc antibodies with CRC risk also warrants confirmation in larger prospective studies.

Abstract 2278: Risk factors by molecular subtypes of breast cancer: a pooled analysis of nine cohorts

Etiological differences between molecular subtypes of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), have been examined in previous studies but results are inconsistent, most likely due to small numbers of rarer subtypes. In a recent systematic review of these studies, only six of the possible 44 associations had consistent findings, primarily with the most common luminal A subtype (ER+ or PR+/HER2-). To provide larger numbers from prospective studies for these associations, we utilized a harmonized dataset of nine cohort studies (Cancer Prevention Study-II Nutrition Cohort, Melbourne Cancer Cohort Study, the National Cancer Institute-American Association of Retired Persons cohort study, Nurses’ Health Study, Nurses’ Health Study-2, Prostate, Lung, Colorectal, and Ovarian Cancer Screening cohort, Swedish Mammographic Cohort, Swedish Women’s Lifestyle and Health Study, and Women’s Health Initiative) that had case data on ER, PR, and HER2 from medical records or state tumor registry records. Multivariate, joint Cox proportional hazard regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI), and to compare associations across subtypes. Among 616,109 study participants, 11,861 invasive breast cancer cases were diagnosed, including 8,777 luminal A, 1,388 luminal B (ER+ or PR+/ HER2+), 532 HER2-enhancing (ER-/PR-/HER2+), and 1,164 triple negative (ER-/PR-/HER2-) subtypes. The mean age at baseline of the study participants was 54.8 (SD=12.2) years for cases and 54.2 (SD=14.4) years for controls, and the majority self-described as white. We found that the associations of race, benign breast disease, parity, number of live births, age at first birth, age at menopause, alcohol consumption, and smoking initiation relative to first birth were statistically-significantly different for at least one of the molecular subtypes compared to the associations for the ER+ or PR+/HER2- subtype (p-value for tumor homogeneity Citation Format: Mia M. Gaudet, Gretchen Gierach, Brian Carter, Juhua Luo, Roger Milne, Elisabete Weiderpass, Graham Giles, Wendy Chen, Rulla Tamimi, Heather Eliassen, Diane Feskanich, Alicja Wolk, Hans-Olov Adami, Karen Margolis, Susan Gapstur, Montserrat Garcia-Closas, Louise Brinton. Risk factors by molecular subtypes of breast cancer: a pooled analysis of nine cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2278. doi:10.1158/1538-7445.AM2017-2278

Abstract B142: Physical activity and risk of breast cancer among postmenopausal women

B142 Physical activity is beneficial for many reasons, including weight loss and maintenance, improved insulin sensitivity, and improved lipid profile. Studies of the effect of physical activity on the risk of breast cancer have had conflicting results. We assessed the associations of specific activities and total activity within the prospective Nurses’ Health Study cohort. Amount and type of physical activity was queried every two to four years starting in 1986. The specific activities included walking, jogging, running, swimming, bicycling, tennis, aerobics, lawn mowing, yoga, and arm or leg weights. Total activity was calculated as the sum of time spent doing each individual activity. Cumulative averages were calculated for each 2-year follow-up period. Cox proportional hazards models, adjusting for age, follow-up period, and several breast cancer risk factors, were used to calculate relative risks (RR) and 95% confidence intervals (CI). A total of 95,485 postmenopausal women were followed for up to 20 years (1986-2006). Overall 4,810 cases of invasive breast cancer were documented during follow-up. Compared with those whose total activity summed to less than 10 minutes per day, women who engaged in higher amounts of total physical activity were at lower risk of breast cancer (RR (95%CI) were 1.00 (0.92-1.08) for 10- Citation Information: Cancer Prev Res 2008;1(7 Suppl):B142.