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Title: Genetic and environmental determinants of the circulation in a Flemish population - a discovery trial from microvessels to larger arteries
Other Titles: Een zoektocht in de Vlaamse bevolking naar genen en omgevingsfactoren met invloed op de micro- en macrocirculatie
Authors: Liu, Yanping; S0214328;
Issue Date: 12-Dec-2014
Abstract: In this doctoral dissertation, we investigated the genetic and environment determinants of the micro- and macro-circulation. Since the diameter of the retinal microvessels was a new phenotype in our study, we first calculated the reproducibility to ensure quality and we ascertained that we could reproduce the correlates of these traits as reported in the literature. Next, we assessed the heritability and familial aggregation of the retinal microvasculature to justify further genetic analyses. We choose the 1675G/A polymorphism in the angiotensin II type-2 receptor (AT2R) as a candidate gene, because the retina expresses the protein. In our research of the properties of large arteries, we focused on lifestyle, including sodium intake, vitamin K status, and the leve and variability of blood pressure. In all the analysis, we adjusted for covariables and confounders, and accounted for relatedness as necessary. In the first study, we applied the state-of-the-art Bland and Altman approach to calculate the reproducibility of the central retinal arteriole equivalent (CRAE), the central retinal venule equivalent (CRVE), and arteriole-to-venule ratio (AVR). Two observers measured these phenotypes in duplicate in a random subset of 84 study participants. For observer 1, the intra-observer reproducibility was 13.2% for CRAE, 8.4% for CRVE and 9.0% for AVR; for observer 2, these estimates were 10.3%, 10.8% and 16.0%, respectively. The inter-observer reproducibility was 10.8% for CRAE, 9.9% for CRVE and 14.6% for AVR. CRAE increased with female sex and current smoking, and decreased with age and mean arterial pressure. CRVE decreased with age. These correlates were consistent with previous reports. We assessed the heritability of CRAE, CRVE and AVR in 413 randomly recruited participants from 70 families. With full adjustment, heritability of CRAE, CRVE, and AVR was 0.213 (p=0.044), 0.339 (p=0.010), and 0.272 (p=0.004), respectively. The parent-offspring correlations for CRAE, CRVE, and AVR were 0.118 (p=0.16), 0.225 (p<0.01), and 0.215 (p<0.05), respectively. The corresponding values for sib–sib correlations were 0.222 (p<0.05), 0.213 (p<0.05), and 0.390 (p<0.001). The genetic and environmental correlations between CRAE and CRVE were 0.360 and 0.545 (p<0.001 for both). Next, we investigated the association of retinal microvascular diameter with the 1675G/A polymorphism in the first intron of the AT2R gene. We applied a mixed model to assess phenotype-genotype associations, while accounting for relatedness and covariables. In 340 subjects randomly selected from a Flemish population, CRAE was 5.5 μm greater in women than men (p<0.001). In multivariable-adjusted analyses, the 1675 A allele was associated with larger CRAE in both sexes combined (+4.49 μm; p=0.014) and in men (+4.91 μm;p=0.032), with a similar trend in women (+3.41 μm; p=0.14). AVR was increased in the presence of the A allele compared with male G hemizygotes and female GG homozygotes (+0.024 for women and men combined; p=0.008). CRVE was not related to the 1675G/A polymorphism. Moving to the macrocirculation, we assessed the association between arterial stiffness and urinary sodium, both cross-sectionally and prospectively. In 630 participants (mean age 40.6 years; 51% women), we measured sodium in 24-hour urine samples at baseline and follow-up (median, 9.7 years) and the carotid and aortic augmentation indexes (AIs) at follow-up only. In multivariable-adjusted longitudinal analyses, a 40-mmol/l increase in the urinary sodium concentration was associated with a 1.38% and 1.54% decrease in the carotid AI (p=0.04) and aortic AI (p=0.02). In cross-sectional analyses of follow-up data, these estimates were 1.26% (p=0.07) and 1.52% (p=0.04), respectively. The carotid and aortic AIs were unrelated to the 24-hour urinary excretion of sodium. The inactive matrix Gla protein (dp-ucMGP) reflects the vitamin K status. We explored the association between circulating dp-ucMGP at baseline and adverse health outcomes at follow-up in 2318 participants randomly recruited from a Flemish population. The risk of death and non-cancer mortality curvilinearly increased (p≤0.008) by 15.0% and by 21.5% for a doubling of the nadir: 1.43 and 0.97 μg/l, respectively. With higher dp-ucMGP, cardiovascular mortality increased, but coronary events decreased. Hazard ratios for a doubling of dp-ucMGP were 1.14 (p=0.027) and 0.93 (p=0.021), respectively. Circulating dp-ucMGP levels were associated (p≤0.001) with MGP variants rs2098435, rs4236 and rs2430692. We used these SNPs as instrumental variables in a Mendelian randomisation analysis. Non-cancer mortality and coronary events (p≤0.022) were causally related to dp-ucMGP, but not to total and cardiovascular mortality (p≥0.13). We assessed the longitudinal association over time of arterial properties, including carotid intima-media thickness (cIMT), carotid distensibility (cD) and carotid-femoral pulse wave velocity (cfPWV) with level (SBPL) and within-visit variability (SBPV) of systolic blood pressure at baseline. Among 1087 participants (mean age, 41.8 years; 50.4% women), followed up for 2.55 years (median), a 15-mm Hg increase in SBPL (p≤0.019) predicted a 15-µm increment in cIMT, a 1.53-10–3/kPa decrease in cD, and 0.285-m/s increase in cfPWV, whereas none of the SBPV indexes (p≥0.11) at baseline predicted any arterial trait at follow-up. In a subset of 713 participants, followed up for a further 3.14 years, lower cD predicted (p<0.01) higher SBPL (2.57 mm Hg), larger variability independent of the mean (0.531 units), greater difference between maximum and minimum SBPL (1.75 mm Hg) and higher average real variability (0.654 mm Hg). Higher baseline cfPWV predicted a 1.11-mmHg increase SBPL (p=0.031). In summary, we demonstrated moderate heritability and significant familial aggregation of the retinal microvasculature. CRAE was associated with the 1675G/A polymorphism in the AT2R gene. Turning to the properties of the larger arteries, we found a significant and inverse association between the central systolic AI and the urinary sodium concentration, but not sodium excretion. High levels of circulating inactive MGP, which indicate vitamin K deficiency, predicted total, non-cancer and cardiovascular mortality. In contrast, the incidence of coronary events was inversely related to the baseline level of inactive MGP. A Mendelian randomisation analysis suggested a causal relation of non-cancer mortality and coronary events with inactive MGP. Carotid stiffness predicted higher within-visit systolic blood pressure variability. However, within-visit systolic blood pressure variability was not associated with any arterial properties at follow-up. This doctoral dissertation focused on the determinants of micro- and macro-circulation, and our observations are clinically relevant. The association between the properties of the retinal vessels and genetic variation points to the potential importance of the local renin-angiotensin system in the pathogenesis of retinal disease. The inverse relation of the central systolic augmentation index with the urinary sodium concentration does not support the recommendation to lower sodium intake population-wide to less than 1500 mg per day. High circulating levels of inactive MGP, a risk factor for adverse health outcomes, is amenable to prevention by vitamin K supplementation. Last but not least, the “vicious cycle” between arterial properties and the blood pressure level suggest that drugs that can lower both blood pressure and arterial stiffness might be particularly beneficial in the primary and secondary prevention of cardiovascular complications. Finally, blood pressure level-not blood pressure variability as suggested by other investigators, should remain the target of treatment.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Hypertension and Cardiovascular Epidemiology
Department of Cardiovascular Sciences - miscellaneous
Molecular and Vascular Biology

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