Background:
Women who enter the menopause at a younger age, are at an increased risk of cardiovascular disease (CVD) and type 2 diabetes (T2D) in later life. However, we have previously reported that development of an unfavourable cardiovascular risk profile premenopausally accelerates the onset of menopause. Furthermore, we reported that women who were diagnosed with diabetes at a very young age also reached menopause earlier. Hence, the direction of the relationship between coronary heart disease (CHD), T2D and the onset of menopause is unclear, and whether the associations are causal is also unclear.
Hypothesis:
In this study we hypothesize that CHD and/or T2D are causally related to the age of menopause, and studied this using genetic risk scores for CHD and T2D.
Methods:
Single nucleotide polymorphisms which had previously reached genome-wide significance for CHD and T2D were, individually and as a genetic risk score, tested for an association with age at natural menopause in over 50,000 women from three large consortia: the ITMAT/Broad/CARe (IBC) consortium, the ReproGen consortium, and the EPIC-InterAct consortium. From these consortia all women with a known age at natural menopause between 40 and 60 years were included. We used the genotyping array of the IBC consortium for the selection of the SNPs. The IBC array is a gene-centric genotyping array developed for replication and fine mapping and incorporates about 50K SNPs that capture information on 2000 genetic regions related to cardiovascular, inflammatory, and metabolic regions. The selected SNPs were also requested for analyses in the other two consortia. A total of 18 single nucleotide polymorphisms for CHD and 28 for T2D were selected. In the EPIC-InterAct study we used these SNPs to calculate unweighted individual level genetic risk scores.
Results:
No statistically significant associations were found for any of the CHD SNPs, nor for the T2D SNPs, nor for the genetic risk scores.
Conclusions:
Previous findings that women with an increased risk of CHD or T2D also have an increased risk of entering the menopause at younger ages, could not be supported by our data. Furthermore, the association between cardiometabolic disease and earlier timing of menopause does not seem to be causal. However, this finding does not exclude the possibility that the reverse association can be causal.
Genetic risk scores based on risk-associated single nucleotide polymorphisms can reveal inherited risk of bladder cancer in Chinese population
