Abstract 691: Associations of genetically-predicted circulating immunoglobulin traits with breast cancer risk
Authors: Wang Shuyang , Wang Shuyang , Yang Yaohua , Long Jirong , Shu Xiao-ou , Zheng Wei , Cai Qiuyin 
Published: August 2018

Abstract
The adaptive immune system plays an important role in cancer development. B cell infiltration has been observed in breast cancer tissues. However, it is unclear whether levels of circulating immunoglobulin (Ig) secreted by B cells may be related to breast cancer risk. A recent study has discovered 35 genetic variants that contribute to variability in eight circulating immunoglobulin traits, including three immunoglobulin levels (IgA, IgG, and IgM) and five composite immunoglobulin traits (total immunoglobulin levels (AGM) and ratios of IgAIgG/IgM, IgA/IgM, IgG/IgM and IgA/IgG) in serum. We utilized the genetic variants for these eight circulating immunoglobulin traits as instruments to evaluate their relationship with breast cancer risk. Beta coefficients and standard errors for the genetic variants for these eight immunoglobulin traits were extracted (Jonsson et al. Nat Genet, 2017). Summary statistics data for association of these genetic variants with breast cancer risk were obtained from 122,977 breast cancer cases and 105,974 controls of European descent in the Breast Cancer Association Consortium (BCAC). Associations of genetically-predicted levels of these eight immunoglobulin traits with breast cancer risk were evaluated using an inverse-variance weighted method. Significant associations with breast cancer risk were observed at Bonferroni-corrected threshold (P &lt; 6.2×10-3) for IgA/IgM ratio and IgG/IgM ratio, two isotype-specific class switching proxy immunoglobulin traits that have distinct effector functions during an immune response. The genetically-predicted value of the IgA/IgM ratio was associated with an increased risk of breast cancer with odds ratio (OR) of 1.13 per unit increase in genetic risk score (P = 2.67x10-5). The genetically-predicted IgG/IgM ratio was associated with a decreased risk of breast cancer with OR of 0.55 per unit increase in genetic risk score (P = 2.83x10-12). We also conducted stratified analyses to evaluate the associations of predicted immunoglobulin traits with breast cancer risk by estrogen receptor (ER) status. The associations for both IgA/IgM ratio and IgG/IgM ratio were observed for ER-positive disease, with ORs of 1.15 and 0.55 and P values of 1.62x10-4 and 2.65x10-9, respectively. For ER-negative disease, a significant association was observed for the IgG/IgM ratio with OR of 0.63 and P value of 2.37x10-3, but the association for the IgA/IgM ratio did not reach significance (P =0.11). Our study provides first evidence that isotype-specific class switching proxy immunoglobulin traits may be related to the risk of breast cancer.
Citation Format: Shuyang Wang, Shuyang Wang, Yaohua Yang, Jirong Long, Xiao-ou Shu, Wei Zheng, Qiuyin Cai. Associations of genetically-predicted circulating immunoglobulin traits with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 691.