To evaluate the impact of insulin-like growth factor 1 receptor variant rs2016347 on the risk for breast and nonbreast cancers and cardiovascular disease in women with a history of hypertensive disorders of pregnancy (HDP).
Patients and Methods
This retrospective cohort study included all parous women in the UK Biobank with prior rs2016347 genotyping (N=204,155), with enrollment taking place from March 2006 to July 2010. History of HDP was self-reported, and outcomes included breast and all nonbreast cancers, hospital diagnoses of hypertension and cardiovascular disease, and direct blood pressure measurements.
Women with previous HDP had a higher risk for future hypertension and cardiovascular diagnoses, increased blood pressures, and lower risk for breast cancer compared with women without HDP, consistent with prior studies. Hazard ratios for all nonbreast cancers were unchanged. However, when taking genotype into account, HDP-positive women carrying at least 1 thymine (T) allele of rs2016347 had a lower risk for nonbreast cancer (hazard ratio, 0.59; 95% CI, 0.37 to 0.92; P=.02) and lower systolic blood pressure (-2.08±0.98 mm Hg; P=.03) compared with women with the guanine/guanine (GG) genotype with positive evidence of interaction (HDP:T allele) for both outcomes; P=.04 and P=.03, respectively.
Women who experience HDP and carry a T allele of rs2016347 have 41% lower risk for developing nonbreast cancer and a lower systolic blood pressure of 2.08 mm Hg when compared with those with the GG genotype, suggesting a possible role of the insulin-like growth factor 1 axis for both cardiovascular and cancer risk in women with HDP.
Future risk of cancer and cardiovascular disease in women who experience a hypertensive disorder of pregnancy, and its modification by a common, functional, IGF1R variant
Pregnancy has long been known to have a major impact on the developing breast and the future risk of breast cancer. Many studies have shown that hypertensive disorders of pregnancy (HDP) occur in as many as 10% of pregnancies, and are associated with lower future risk of breast cancer. HDP consists of gestational hypertension and preeclampsia, and both are characterized by the development of high blood pressure in pregnancy, usually after the 20th week of gestation. Our recent research has shown that the reduction for breast cancer can be as high as 90% in women with HDP that carry a specific common gene variant, and the initial objective of this study is to reconfirm these findings in the larger UK Biobank cohort. There is also evidence that HDP is associated with a lower risk of other cancers, and we will be examining whether this same gene variant impacts these risks as well.
Interestingly, HDP has also been shown to be associated with increased later life risk of hypertension, heart disease, and stroke, indicating that experiencing HDP can have both good and bad long-term health outcomes. Therefore, a second objective is to further explore this association and determine if this same gene variant predicts the future risk of developing cardiovascular disease in women who experience HDP.
The gene variant we will be studying is part of the insulin-like growth factor (IGF-1) system, which has a well-established role in both the development of cancer and cardiovascular disease. HDP are associated with inadequate blood flow to the placenta, which results in alterations of many hormones and growth factors, including lower levels of IGF-1. It appears that these lower levels interact with our observed genetic variant to protect the breast tissue in pregnancy, which is known to be a very vulnerable and critical time in breast development.
Achieving the aims of this study could improve the ability to predict the future risk of developing the two most significant age-associated health outcomes that women face, and thereby lead to more effective personalized screening and open the door to novel prevention strategies.
The size and data composition of the UK Biobank make it a perfect place to study the important relation of HDP and genetics to future health, and we expect the study to be completed in 12 months.
|Lead investigator:||Dr Mark Powell|
|Lead institution:||Zero Breast Cancer|
|3763||Cancer and Cardiovascular Risk in Women With Hypertensive Disorders of Pregnancy Carrying a Common IGF1R Variant||Powell MJ et al.||2020||Mayo Clin Proc|