Title: Interactive influences of environmental and genetic factors on the properties of large arteries in relation to sodium handling
Other Titles: Kenmerken van de grote arteries in relatie tot de natriumhomeostase - interactieve invloed van genetische variabiliteit en omgevingsfactoren
Authors: Seidlerova, Jitka; S0112219
Issue Date: 3-Apr-2009
Abstract: In line with Guyton’s work, the goal of our research was to explore in t hree European populations whether the properties of large arteries are a ssociated with renal sodium handling, which itself changes with environm ental factors and with variation in a large number of genes. Before enga ging in the genetic analyses proper, we first studied the familial aggre gation and the heritability of arterial properties. In all our analyses, we accounted for relatedness among participants and for covariables and confounders. In a first study, we compared the arterial characteristics and blood pre ssure (BP) in normotensive offspring of two normotensive parents (OFF/NT ) and normotensive offspring, who had at least one hypertensive parent ( OFF/HT). We measured peripheral pulse pressure (PPp) by conventional and 24-h ambulatory BP. A SphygmoCor device was used to determine the centr al (CAIx) and peripheral (PAIx) systolic augmentation indexes, central p ulse pressure (PPc), and aortic pulse wave velocity (aPWV). Compared wit h OFF/NT (n=59; 16 to 34 years of age), the OFF/HT (n=174; 17 to 40 year s) had higher (0.14<P<0.0007) in OFF m 6.6 vs. (7.4 aPWV (108.8% CAIx 44 .9%), (54.7% PAIx Hg), mm 26 (28 PPc (0.05<P<0.0008) Hg). 47 48 and Hg 6 7 114 70 (118 24-h Hg) 42 46 71 75 (121 PPp BP aPWV.In a family-based po pulation sample consisting of 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years), we investigated the heritability and familial a ggregation of PPp, CAIx, PAIx and aPWV. We partitioned the phenotypic co rrelation between these traits into shared genetic and environmental com ponents. We found significant heritability for PPp, CAIx, PAIx, and mean arterial pressure ranging from 0.37 to 0.41; P&#8804;0.0001. The parent -offspring correlation coefficients were significant for all arterial in dexes (r&#8805;0.12; P&#8804;0.02) with the exception of PPc (P=0.90). T he sib-sib correlations were also significant for CAIx (r=0.22; P=0.001) . The genetic correlation between aPWV and the other arterial indexes we re significant (&#961;G&#8805;0.29, P<0.0001). The corresponding environ mental correlations were only significantly positive for PPp (&#961;E=0. 10. P=0.03). In the Flemish population sample, we also ultrasonographically measured diameter, cross-sectional compliance (CC) and distensibility (DC) of the carotid, brachial, and femoral arteries. In multivariable-adjusted anal yses of 1069 untreated subjects (mean age, 41.6 years), CC and DC of the femoral artery increased with higher fractional distal sodium reabsorpt ion (RNadist), as assessed by the clearance of endogenous lithium. Diffe rences associated with a 1&#8209;SD change in RNadist were 51.7 mm2 /kPa &acute;10-3 (P=0.0002) and 0.56&acute;10-3/kPa (P=0.004) for femoral CC and DC, respectively. In women as well as in men, a 1-SD increment in fractional proximal sodium reabsorption (RNaprox) was associated with d ecreases in femoral and brachial diameter, amounting to 111.6 mm (P=0.00 3) and 52.5 mm (P=0.016), respectively. There was no consistent associat ion between the properties of the elastic carotid artery and renal sodiu m handling. In 1126 subjects from the same Flemish population (mean age, 43.8 years) , we investigated whether arterial characteristics are related to the ge nes encoding ADD1 (Gly460Trp), ADD2 (C1797T) and ADD3 (A386G). In s ingle gene analyses, brachial diameter was 0.15 mm (P=0.0022) larger, an d brachial CC and DC were 0.017 mm2/kPa (P=0.0029) and 1.55 10-3/kPa (P= 0.013) lower in ADD3 AA than ADD3 GG homozygotes with an additive effect of the G allele. In multiple-gene analyses, the association of brachial diameter and DC with the ADD3 G allele only occurred in ADD1 GlyGly hom ozygotes. Otherwise, the associations between the arterial phenotypes in the three vascular beds and the ADD1 or ADD2 polymorphisms were not sig nificant. There was no evidence for population stratification (0.07&#880 4;P&#8804;0.96). Transmission of the mutated ADD3 G allele was associate d with smaller brachial diameter in 342 informative offspring (–0.12&plusmn;0.0 4 mm; P=0.0085) and in 209 offspring, who were ADD1 GlyGly homozygo tes (–0.14&plusmn;0.06 mm; P=0.018). Finally, in 1064 Flemish subjects (mean age, 43.6 years), we assessed th e multiple-gene effects of ADD1 (Gly460Trp), AGT (C–532T and G–6A) and A T1R (A1166C). In ADD1 Trp allele carriers, but not in ADD1 GlyGly h omozygotes (P-value for interaction &#8804;0.014), femoral CC was s ignificantly higher (0.74 vs. 0.65 mm2/kPa; P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femo ral DC (11.3 vs. 10.2 10-3/kPa; P=0.055). Family-based analyses confirme d these results. Brachial diameter (4.35 vs. 4.18 mm) and plasma renin a ctivity (PRA, 0.23 vs. 0.14 ng/ml/h) were increased (P&#8804;0.005) in A GT CG haplotype homozygotes compared with non-carriers, whereas the oppo site was true for brachial DC (12.4 vs. 14.4 10-3/kPa; P=0.011). There w as no interaction between AGT and any other gene in relation to the meas ured phenotypes. In conclusion, in this doctoral dissertation, we demonstrated significan t familial aggregation and significant heritability of arterial properti es. We also noticed that higher RNadist was associated with higher femoral CC and DC, and that higher RNaprox was associated with decr eased diameters of muscular arteries. The aforementioned observations ju stified our analyses of genes, which are involved in renal sodium handli ng. In ADD1 GlyGly homozygotes, the properties of the brachial artery we re related to the ADD3 (A386G) polymorphism. Furthermore, ADD1 and AT1R interactively determined the elastic properties of the femoral artery. T here was a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA. Overall, our findings suggest, that there might be a genetically determined influence of renal sodium handling on arterial properties, or vice versa, or that common genetic pathways might influen ce both arterial and renal function.
Table of Contents: Acknowledgements VII
List of abbreviations IX
Chapter 1 Introduction 1
Chapter 2 Arterial characteristics in normotensive offspring of parents
with or without a history of hypertension 33
Chapter 3 Heritability and intrafamilial aggregation of arterial
characteristics 51
Chapter 4 Association between arterial properties and renal sodium
handling in a general population 75
Chapter 5 Relation between local arterial stiffness and genetic variation
in adducin subunit and renin-angiotensin system
Part 1 Arterial properties in relation to genetic variation in the
adducin subunits in a White population 99
Part 2 Arterial properties in relation to genetic variation in
alpha-adducin and the renin-angiotensin-system in a
White population 117
Chapter 6 General discussion 141
Chapter 7 Summary 159
Samenvatting 165
Souhrn 169
Curriculum Vitae 173
List of publications
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Hypertension and Cardiovascular Epidemiology

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