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Cristiano Fava

Heritability of blood pressure monogenes and polygenes

High blood pressure (BP) is associated with cardiovascular morbidity and mortality. Both genetic and environmental factors are implicated in BP homeostatsis and hypertension development. The aims of the present theisis were: (a) to test if ambulatory BP (ABP) is better than office BP (OBP) to capture the heritable part of BP and if BP variability (BPV) measured by ABP monitoring is a heritable trait (studies 1 and 2). (b) To investigate if two functional single nucleotide polymorphisms (SNPs), T481S of the CLC-Kb gene and G460W of the adducin-1 (ADD-1) gene, are associated with cross sectional BP and BP changes over time and if these SNPs interact with anthropometric/demographic factors to influence BP level (studies 3 and 4). (c) To identify causative Na-Cl cotransporter (NCCT) mutations in a collection of 30 patients affected by Gitelman syndrome (GS; study 5). (d) To investigate whether subjects carrying one mutated NCCT allele have a phenotype resembling that of patients treated with low-dose thiazide diuretics (study 6). We found significant heritability for most of the BP phenotypes obtained by ABP monitoring ranging from 19% to 63%. None of the OBP phenotypes had a significant heritability. After adjustment for significant covariates the Nocturnal BP dipping (NBPD) of systolic BP was significantly heritable as well as night-time BPV of diastolic and mean BP and nigh-time HRV (studies 1 and 2).


BP and BP change over time were similar in all genotype groups for the T481S of the CLC-Kb and for the G460W of the ADD-1 genes (studies 3-4). There was no difference in the prevalence of hypertension between carriers of the different genotypes. No significant interaction between the CLC-Kb T481S polymorphism and sex, age or Body Mass Index (BMI) on BP was found. BP was influenced by significant interaction between the G460W and BMI as well as by interaction between G460W and sex, indicating that the 460W variant together with female sex and 460W variant together with increasing BMI is associated with higher systolic and diastolic BP and higher prevalence of hypertension, a result further confirmed by stratified analysis (study 4). In 30 patients with GS we found 22 different mutations in the NCCT gene including 11 previously reported variants and 11 new variants consisting in 8 missense mutations (Glu68Lys, His69Asn, Arg145His, Val153Met, Gly230Asp, Gly342Ala, Val677Leu, Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667+1T>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13) (study 5). GS heterozygotes had highly significantly lower BP compared to controls. There was no significant difference in plasma level of aldosterone and renin as well as in plasma concentration and urinary excretion of electrolytes. GS heterozygotes had higher glomerular filtration rate and higher fasting plasma glucose concentration when compared to matched controls. (study 6). These results suggest that: (1) ABP monitoring may be a more exact estimate of an individual's true BP, and genetic studies using ABP are more powerful than those using OBP; (2) genetic factors controlling BPV and HRV may be mapped by linkage analyses; (3) the CLC-Kb T481S polymorphism is not associated with BP or hypertension; (4) the G460W polymorphism of the ADD-1 could be of importance for BP homeostasis and hypertension prevalence in obese females probably joined by a salt-sensitive background (5) mutations in genes responsible for monogenic autosomic recessive pro-hypotensive or pro-hypertensive disorders may confer decreased or increased risk of hypertension and other metabolic disturbances. Even if such mutations are relatively rare, they may be of great clinical importance as their effects on BP are substantially greater than that of common polygenes.

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