Analyse de liaison dynamique entre genes candidats et phenotypes associes a la pression arterielle au cours de tests physiologiques

Blood pressure (BP) is a complex trait resulting from several gene-environment interactions. It is likely that loci (a fixed position on a chromosome) involved in BP variation under physiological stimuli may also be involved in the development of blood pressure disorders and its complications. First, we hypothesized that the degree of genetic linkage varies with physiological responses. Second, we hypothesized that reduction techniques which reflect the common variance or the correlation between blood pressure intermediate phenotypes may improve the results of association tests. 258 individuals selected from a cohort of French Canadian families were subjected to orthostatic maneuvers, and systolic (SBP), diastolic (DBP) and mean arterial BP (MAP) and intermediate phenotypes (total peripheral resistance (TPR), heart rate (HR) and stroke volume (SV) were measured every 5 and 2 minutes during supine (30min) and after adopting the standing position (10 min) using cardiac impedance. Standing was associated with drastic changes in all phenotypic means and an increased variance compared with the supine period. BP was highly correlated with TPR and moderately correlated with SV and HR, whereas TPR and SV were also highly correlated. 1000 candidate genetic markers related to cardiac and vascular function were tested for genetic linkage at each measure in time. To test the first hypothesis, and to find the genetic markers that give rise to the effect of physiological stimuli, we used a step-down permutation test on the correlation between the experimental condition and the linkage statistics and on the difference between the linkage statistics into the different periods. We used a resampling based strategy to assess the significance of the linkage in each period and to confirm the dynamic linkage in some interesting markers. To test the second hypothesis we compared the average method, principal components (PC), and factor analysis (FA) to generate univariate traits for FBAT association studies during physiological testing on more than 300 markers selected from the linkage tests. The overall P-values obtained from FBAT with each method were compared using a means difference test. For both the supine and standing periods FA, PC and average method provided better overall FBAT p-values compared with the traditional Bonferroni adjustment. Using a permutation procedure we confirmed that the selected methods controls the type-I error and we compute an approximate signification threshold for each method. These observations suggested that reduction techniques which reflect the common variance or the correlation between blood pressure intermediate phenotypes may improve the results of association tests. Linkage analysis during physiological testing (dynamic linkage) reported significant markers and complete chromosomal regions lately reported as related to cardiovascular processes. On unknown or newly discovered regions dynamic linkage may uncover genetic factors that drive physiological responses.