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Writer's pictureBIOMILQ Team

Genetics and lactation: maternal gene may influence breastfeeding duration

Updated: Dec 2, 2022

Lactation is a remarkably dynamic process. Interwoven genetic and environmental factors activate different biological signals over time so that mothers produce breast milk perfectly suited to meet their growing babies’ changing dietary needs. Yet, most women stop breastfeeding well before the guidelines recommend (1–3). Now, results from a new study unaffiliated with BIOMILQ say that it’s not only psychological or circumstantial factors that drive breastfeeding behaviors, but also maternal genetics.


Stress and the return to work (4) have been implicated in mothers discontinuing breastfeeding too soon. Additionally, in a phenomenon called PIMS (5), or perceived inadequate milk supply, mothers wean their babies off breast milk based on the belief that their babies aren’t getting enough. This may be based on cues such as an infant crying after a feed, for example (6).


Reports from around the world suggest that over half of all mothers discontinue breastfeeding early due to PIMS (7–11) Meanwhile, research using sensitive analytical techniques to measure lactation yields (such as tracking infant weight gain or weighing babies before and after a feed) show that the proportion of women whose milk supply is truly unable to sustain growth may be closer to 10 to 15 percent (12,13). In the absence of defined reference ranges to describe the normal physiology of human lactation, distinguishing PIMS from a physiological inability to produce enough milk is difficult. Crucially, managing physiologically insufficient milk supply as if it were a matter of the mother’s inaccurate perception can have substantial consequences for both mother and baby. As these two scenarios warrant different types of support, there is a need to identify markers that can distinguish between perceived and objective low milk supply.


In a recent study, Penn State College of Medicine researchers put forward an interesting hypothesis: PIMS could also be influenced by maternal genes (14). Indeed, many genetic correlates of milk production have been identified in dairy species (15), but this hypothesis has rarely been explored in humans. Chandran and colleagues followed a cohort of around 200 breastfeeding mothers, collecting medical, demographic, and breastfeeding data for over a year. They also genetically screened a subset of 88 of the mothers, roughly half of whom had PIMS.


As part of their analysis, the team honed in on a panel of 18 lactation genes, such as prolactin (a lactation hormone). They were on the lookout for single nucleotide polymorphisms, or SNPs, in these genes—naturally occurring gene variations that control many aspects of human health. Some SNPs point to an individual’s risk of developing a chronic disease (16), or their susceptibility to drug side effects (17), for instance.


In a breakthrough finding, the researchers found that mothers with PIMS had a particular SNP in the MFGE8 gene. Women with this gene variant, called rs2271714, breastfed exclusively for an average of 4.7 weeks. Meanwhile, those without the variant breastfed almost three times longer. Mothers with or without the variant produced about the same amount of breast milk daily.

Graphic courtesy of Tara Fernandez


There are about 500 different proteins in breast milk, and MFGE8 (or milk fat globule EGF and factor V/VIII domain-containing gene) holds the genetic code for lactadherin, one of the main proteins in the milk fat globule (MFG). Complex and nutritionally dense, the MFG’s composition is fluid, subtly shifting throughout lactation (18). Lactadherin plays a diverse role within the MFG: it controls milk secretion, defends against bacteria and viruses, and establishes the baby’s immune defenses (19) Beyond lactation, lactadherin also regulates other biological processes such as forming blood vessels and wound healing (20).


How is the MFGE8 gene variant linked to lactation, and why are women with rs2271714 more likely to have PIMS? Unfortunately, we don’t know yet. This avenue of research has yet to be explored in human studies, but research on goats and mice may offer some clues.


One study found four MFGE8 gene variants among goats, three of which were linked to diminished milk yields (21). In mouse models of lactation, mutations in the MFGE8 gene triggered disruptions in mammary gland remodeling, a physiological process that occurs towards the tail end of the lactation period (22). In addition, variants of MFGE8 may impact the functionality of lactadherin, ultimately altering the MFG (23).


Chandran’s study sets the stage for follow-up investigations on how the maternal genetic landscape steers breastfeeding behavior. Still, limitations in the study design leave unanswered questions. For instance, to quantify the amount of breast milk produced daily, the researchers relied on estimated feeding volumes provided by the participants rather than using more objective measurement methods. Consequently, we cannot conclusively determine whether the rs2271714 variant altered breast milk yields. This is a common issue in lactation research. Techniques such as measuring the babies’ weights down to the gram before and after a feed (24) or labeling breastmilk with radioactive tracers (25), while more accurate, aren’t always practical or accessible in the field.


The interplay between genes, lactation, and breastfeeding practices is an exciting new frontier in lactation science that, in the future, could shape better, data-driven frameworks to support nursing mothers. For example, the authors propose that performing routine genetic tests could identify mothers with the rs2271714 variant who have an elevated risk of PIMS. Offering these women targeted lactation advice, nutritional supplementation, and other early interventions to prevent PIMS may help extend their breastfeeding windows.


In addition, the field would benefit greatly from simple and standardized approaches to measuring lactation yields. According to experts, well-defined clinical reference ranges are available for every organ system except lactation (26).


 

This piece was primarily written by Tara Fernandez, Ph.D., with input from the BIOMILQ team. Tara is a Science Communicator sharing stories on the latest discoveries, innovation, and technologies that are set to transform how we protect human health and wellbeing. You can read more of her work here.


References:

1. DeFrancesco MS. Role of the American College of Obstetricians and Gynecologists in Supporting and Encouraging Breastfeeding. Breastfeed Med. 2014;9(7):335-336. doi:10.1089/bfm.2014.0069 2. Organization WH. Breastfeeding Recommendations. World Health Organization Health Topics. Published n.d. Accessed January 30, 2022. https://www.who.int/health-topics/breastfeeding#tab=tab_2 3. (CDC) C for DC and P. 2020 Breastfeeding Report Card, United States.; n.d. https://www.cdc.gov/breastfeeding/data/reportcard.htm 4. Bibi S, Shah M, Malik MO, Goosens KA. T3 is linked to stress‐associated reduction of prolactin in lactating women. J Neuroendocrinol. 2021;33(8):e13003. doi:10.1111/jne.13003 5. Brown CRL, Dodds L, Legge A, Bryanton J, Semenic S. Factors influencing the reasons why mothers stop breastfeeding. C J Public Health. 2014;105(3):e179-e185. doi:10.17269/cjph.105.4244 6. Mohebati LM, Hilpert P, Bath S, et al. 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J Obstetric Gynecol Neonatal Nurs. 2008;37(5):546-555. doi:10.1111/j.1552-6909.2008.00277.x 11. Walburg V, Goehlich M, Conquet M, Callahan S, Schölmerich A, Chabrol H. Breast feeding initiation and duration: comparison of French and German mothers. Midwifery. 2010;26(1):109-115. doi:10.1016/j.midw.2008.04.001 12. Baker JL, Michaelsen KF, Sørensen TI, Rasmussen KM. High prepregnant body mass index is associated with early termination of full and any breastfeeding in Danish women. Am J Clin Nutrition. 2007;86(2):404-411. doi:10.1093/ajcn/86.2.404 13. Neifert M, DeMarzo S, Seacat J, Young D, Leff M, Orleans M. The Influence of Breast Surgery, Breast Appearance, and Pregnancy‐Induced Breast Changes on lactation Sufficiency as Measured by Infant Weight Gain. Birth. 1990;17(1):31-38. doi:10.1111/j.1523-536x.1990.tb00007.x 14. Chandran D, Confair A, Warren K, Kawasawa YI, Hicks SD. Maternal Variants in the MFGE8 Gene are Associated with Perceived Breast Milk Supply. Breastfeed Med. Published online 2021. doi:10.1089/bfm.2021.0216 15. Gutierrez-Reinoso MA, Aponte PM, Garcia-Herreros M. Genomic Analysis, Progress and Future Perspectives in Dairy Cattle Selection: A Review. Animals Open Access J Mdpi. 2021;11(3):599. doi:10.3390/ani11030599 16. Cui P, Zhao Y, Chu X, et al. SNP rs2071095 in LincRNA H19 is associated with breast cancer risk. Breast Cancer Res Tr. 2018;171(1):161-171. doi:10.1007/s10549-018-4814-y 17. Dai D, Tang J, Rose R, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther. 2001;299(3):825-831. 18. Lee H, Padhi E, Hasegawa Y, et al. Compositional Dynamics of the Milk Fat Globule and Its Role in Infant Development. Frontiers Pediatrics. 2018;6:313. doi:10.3389/fped.2018.00313 19. Raymond A, Ensslin MA, Shur BD. SED1/MFG-E8: A Bi-Motif protein that orchestrates diverse cellular interactions. J Cell Biochem. 2009;106(6):957-966. doi:10.1002/jcb.22076 20. Uchiyama A, Yamada K, Ogino S, et al. MFG-E8 Regulates Angiogenesis in Cutaneous Wound Healing. Am J Pathology. 2014;184(7):1981-1990. doi:10.1016/j.ajpath.2014.03.017 21. Qu Y, Liu Y, Ma L, et al. Novel SNPs of butyrophilin (BTN1A1) and milk fat globule epidermal growth factor (EGF) 8 (MFG-E8) are associated with milk traits in dairy goat. Mol Biol Rep. 2011;38(1):371-377. doi:10.1007/s11033-010-0118-y 22. Atabai K, Fernandez R, Huang X, et al. Mfge8 Is Critical for Mammary Gland Remodeling during Involution. Mol Biol Cell. 2005;16(12):5528-5537. doi:10.1091/mbc.e05-02-0128 23. Oshima K, Aoki N, Negi M, Kishi M, Kitajima K, Matsuda T. Lactation-Dependent Expression of an mRNA Splice Variant with an Exon for a MultiplyO-Glycosylated Domain of Mouse Milk Fat Globule Glycoprotein MFG-E8. Biochem Bioph Res Co. 1999;254(3):522-528. doi:10.1006/bbrc.1998.0107 24. Brown KH, Black RE, Robertson AD, Akhtar NA, Ahmed G, Becker S. Clinical and field studies of human lactation: methodological considerations. Am J Clin Nutrition. 1982;35(4):745-756. doi:10.1093/ajcn/35.4.745 25. Butte NF, Garza C, Smith EO, Nichols BL. Evaluation of the deuterium dilution technique against the test-weighing procedure for the determination of breast milk intake. Am J Clin Nutrition. 1983;37(6):996-1003. doi:10.1093/ajcn/37.6.996 26. Boss M, Gardner H, Hartmann P. Normal Human Lactation: closing the gap. F1000research. 2018;7:F1000 Faculty Rev-801. doi:10.12688/f1000research.14452.1

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