Women with a Common Genetic Variant in ZnT2 (T288S) Have Altered Breast Milk Composition: Implications for Suboptimal Lactation

Abstract

Few studies have explored the role of nutrigenomics in lactation biology. Recent studies from our lab found that non‐synonymous genetic variation in the zinc (Zn) transporter ZnT2 (SLC30A2) is common in women and is associated with both low and elevated milk Zn concentrations. Of those variants, a threonine to serine substitution at amino acid 288 (T288S) was detected in 12% of women and milk from these women had abnormally low milk Zn and significantly elevated milk sodium levels. Because elevated milk sodium has been associated with breast dysfunction, in this study, we characterized the functional consequence of expressing the T288S variant on breast milk composition in women and in mammary epithelial cells (MECs) ectopically expressing this variant in vitro. We hypothesized that mothers with T288S variant would express biological factors in milk that reflect suboptimal lactation performance. We found that protein, lactose and fat concentrations in milk from women with T288S were similar to women expressing wild‐type ZnT2. However, milk from women expressing T288S had significantly higher levels of citrate, lactoferrin, MMP‐2 activity, 4‐HNE, mucin‐4 and endoplasmin, all of which increase in response to reactive oxygen species (ROS). Consistent with the milk analyses, MECs transfected to express T288S in vitro had significantly greater ROS levels and expression of oxidative stress markers, mucin‐4 and endoplasmin, compared to MECs expressing wild‐type ZnT2. To determine if this increase in oxidative stress is associated with mammary gland involution, we measured p‐STAT3, a marker of involution and found that STAT3 activation was significantly increased in T288S‐expressing MECs compared to MECs expressing wild‐type ZnT2. Collectively, our data suggest that women expressing the T288S variant in ZnT2 may have enhanced oxidative stress in the breast that may lead to precocious involution and suboptimal lactation. Importantly, this study suggests that nutrigenomics may have important implications for breast function and implicates factors in breast milk as useful bioreporters of breast (dys)function and lactation performance.Support or Funding InformationIntramural funds to SLK