Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium.

BACKGROUND: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. METHOD AND RESULTS: Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65-75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. CONCLUSIONS: For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

Comment on 'Empirical versus modelling approaches to the estimation of measurement uncertainty caused by primary sampling' by J. A. Lyn, M. H. Ramsey, A. P. Damant and R. Wood.

Recently, Lyn et al. (Analyst, 2007, 132, 1231) compared two ways of estimating the standard uncertainty of sampling pistachio nuts for aflatoxins--a modelling method and an empirical method. Their case study used robust analysis of variance (RANOVA) to derive the uncertainty estimates, highlighting a substantial difference between the two: the estimate of sampling uncertainty derived from the modelling method was six-fold greater than that using the empirical approach (cf. 136% and 22.5%, respectively, when expressed as relative standard deviations (RSDs) at 68% confidence). A further analysis of this case study is reported here and suggests that the estimation uncertainty during RANOVA in the empirical approach could account for this difference.