W39 - Relationship of 27-hydroxycholesterol to CHD Risk and its Interaction with Hormone Therapy on CHD Risk

This page provides study documentation for the W39 Core Study. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Core study approved by WHI Steering Committee


In the W6 - CVD Biomarker Study, elevated baseline lipid levels have been demonstrated to be associated with an increase in CVD risk with HT. Animal and human data suggest that the mechanism for this interaction may be through 27-hydroxycholesterol (27HC), an endogenous competitor to estradiol.  To further explore the intervention effect of HT on CVD outcomes, we propose to measure baseline 27HC in the 359 CHD cases and 820 controls (N=1279) in the CVD Biomarker Study.
In both WHI HT trials there was an increased risk for CHD on HT compared to placebo in the first several years after randomization. The potential mechanisms underlying this early increase in risk are unknown. In the WHI CVD Biomarker Study we have examined more than 20 biomarkers, as well as 7 candidate genetic markers, for their association with CHD risk and interaction with HT compared to placebo during the first 4 years after randomization. Several biomarkers were associated with CHD risk, but only baseline LDL cholesterol (and LDL/HDL ratio) has shown statistically significant interaction with HT effect on CHD risk. Two manuscripts describing these findings have been submitted for publication (Rossouw et al; Bray et al), and Paul Bray’s manuscript focusing specifically on the lipid interactions has been accepted for publication (Bray et al, Am J Cardiol). Bray found that women without prior CVD who had baseline LDL-C levels below 130 mg/dl tended to have reduced CHD risk on HT, with the converse being true in women with baseline LDL-C levels above 130 mg/dl.
A possible mechanism by which high levels of LDL-C may block a beneficial effect of estrogen on arteries has recently been described (Umetani et al, Nature Medicine, 2007). The authors demonstrated in rat models that 27HC, an abundant cholesterol metabolite that is elevated in hypercholesterolemia, acts as an endogenous SERM in being a competitive agonist to estradiol in the vasculature (and as a partial agonist in breast tissue). In mice, increasing levels of 27HC decreased estrogen-dependent expression of NO synthase and repressed carotid re-endothelialization. In humans, levels of 27HC are correlated with those of cholesterol. The authors hypothesize that the trials of estrogen such as WHI and HERS have failed to demonstrate benefit because of the substantial proportion of participants with high cholesterol levels. In WHI we have the opportunity to test this hypothesis directly and expeditiously, since we have measured lipid levels in the cases and controls included in the CVD Biomarker Study (and have evidence of effect modification by LDL level consistent with the hypothesis).
Objectives of the proposed core study are:
a) To test whether 27HC is a risk factor for CHD, and evaluate whether its association with CHD is at least as strong or stronger than that of LDL-C (as might be expected from a more proximal risk factor).
b) Similarly, if 27HC levels mediate the modification of estrogen effect by LDL-C on CHD, then as a more proximal factor it should show a stronger interaction with estrogen effect on CHD than LDL-C.


See Publication: 1300.  WHI publications by study lists published WHI papers that have been generated by ancillary studies. A complete list of WHI papers is available in the Bibliography section of this website.