Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality

Davey Smith, George, Lawlor, Debbie A., Harbord, Roger, Timpson, Nic, Rumley, Ann, Lowe, Gordon D.O., Day, Ian N.M. and Ebrahim, Shah (2005) Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality. Arteriosclerosis, Thrombosis, and Vascular Biology, 25 (5), 1051-1056. (doi:10.1161/01.ATV.0000160351.95181.d0).

Abstract

Background: C-reactive protein (CRP) has repeatedly been associated with blood pressure and prevalent and incident hypertension, but whether a causal link exists is uncertain.
Methods and Results: We assessed the cross-sectional relations of CRP to systolic blood pressure, pulse pressure, and prevalent hypertension in a representative sample of >3500 British women aged 60 to 79 years. For both outcomes, substantial associations were observed. However, these associations were greatly attenuated by adjustment for a wide range of confounding factors acting over the life course. We further investigated causality using a Mendelian randomization approach by examining the association of the 1059G/C polymorphism in the human CRP gene with CRP and with blood pressure, pulse pressure, and hypertension. The polymorphism was associated with a robust difference in CRP, and the expectation would be for higher blood pressure and pulse pressure and greater prevalence of hypertension among those carrying the genetic variant associated with higher CRP levels. This was not observed, and the predicted causal effects of CRP on blood pressure, pulse pressure, and hypertension using instrumental variables methods were close to 0, although with wide CIs.
Conclusions: CRP levels are associated with blood pressure, pulse pressure, and hypertension, but adjustment for life course confounding and a Mendelian randomization approach suggest the elevated CRP levels do not lead to elevated blood pressure.
In a large study, we demonstrate that CRP levels but not a genetic variant associated with CRP levels were related to hypertension. Furthermore, the CRP association with hypertension was essentially abolished by statistical adjustment for confounding factors. We conclude that elevated CRP levels do not lead to elevated blood pressure.

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