Mendelian randomization study of the relevance of blood pressure to vascular mortality among 150,000 participants in the mexico city prospective study

Abstract Background Mendelian randomization (MR) studies are commonly used to reduce confounding and reverse-causality when estimating the effects of risk factors on disease and provide estimates of effects over the whole life-course. However, most previous MR studies have been conducted in populations of European-ancestry. We used MR to investigate the effect of systolic blood pressure (SBP) on vascular mortality at ages 35-74 in a large prospective study of Mexican adults. Methods Between 1998 and 2004, 150,000 adults aged ≥35 years were recruited into the Mexico City Prospective Study and followed for median 19 years(1,2). Using 886 externally-selected single nucleotide polymorphisms (SNPs)(3) we created a genetic risk score for SBP (GRS-SBP). Those taking an antihypertensive drug at recruitment had their SBP adjusted by +6 mmHg(2) (adjustment by +15 mmHg rather than +6 mmHg was done in a sensitivity analysis). Cox regression and the MR ‘ratio’ method were then used to estimate the causal effect of SBP on vascular mortality at ages 35-74 years. Analyses were adjusted for age at risk, sex, residential district, education, smoking, alcohol consumption, physical activity, adiposity, diabetes mellitus and the first 7 genetic principal components. They excluded those aged ≥75 years, had incomplete data, or had prior vascular disease or any other chronic condition (except diabetes). Alternative MR approaches (inverse-variance-weighted, weighted median and MR Egger) were used for sensitivity analyses. Conventional epidemiological analyses of the association between SBP and mortality after correction for regression dilution bias were also done. Results Among 127,849 included individuals, the GRS-SBP explained 1.9% of baseline SBP variation. Those in the top fifth of the GRS-SBP distribution had 6.6 mmHg higher SBP and twice the prevalence of self-reported hypertension and antihypertensive drug use than those in the bottom fifth, but the GRS-SBP was uncorrelated with other factors. The strength of association between GRS-SBP and measured SBP was broadly similar in men and women, at different ages, and between people with different proportions of Amerindian genetic ancestry. Using the ratio method and a single estimate of the association of GRS-SBP with SBP, each 10 mmHg higher genetically predicted SBP was associated with 58% higher vascular mortality at ages 35-74 years (RR 1.58, 95% CI 1.27-1.96), including 69% higher ischaemic heart disease mortality (RR 1.69, 95% CI 1.31-2.16) and 65% higher stroke mortality (RR 1.65, 1.15-2.33). These genetic estimates were somewhat larger than conventional observational associations of usual SBP to risk. Alternative MR approaches found no evidence of pleiotropy and yielded similar conclusions. Conclusions These MR analyses confirm that blood pressure is a major cause of premature death from vascular diseases in Mexican adults.