Brain, Nicholas John Richard
Genetic dissection of essential hypertension and familial intracranial aneurysm.
PhD thesis, University of Glasgow.
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The studies of hypertension, described herein, combined complementary strategies to examine the relevance of human chromosome 5q31.1-qter to blood pressure as a quantitative trait, and hypertension as a qualitative trait. This distal region of chromosome 5 was focused upon due to its implication by other human and animal model studies and the cluster of cardiovascular candidate genes located there.
Eleven microsatellites across 55 cM of 5q31.1 to qter were genotyped in 212 hypertensive nuclear families of the Silesian Hypertension Study. Two-point and multipoint analyses showed linkage of a 7 cM region to both hypertensive status and blood pressure phenotypes. A maximal multipoint Z-score of 2.2 for systolic blood pressure (SBP) was obtained proximal to the marker D5s1480. In light of the debate regarding significance in linkage studies, this quantitative trait locus (QTL) was confirmed in a second sample derived from the Scottish population. Genotyping of the same markers was done for 1,469 individuals from sibships of the MIDSPAN Family Study. Two-point and multipoint analyses confirmed a reproducible 7 cM QTL with a maximum multipoint logarithm of odds (LOD) score of 1.8 obtained for mean arterial pressure.
Several putative candidate genes were located within the QTL including the b2-adrenergic receptor gene, ADRB2, which is known to have a major role in cardiovascular physiology. Three functional loci, Arg16Gly, Gln27Glu and Thr164Ile, were genotyped within the ADRB2 gene using the Silesian sample. Single locus and haplotype analyses using transmission disequilibrium tests and family-based association methods showed no association to hypertension status (P>0.05), effectively excluding this gene in the Silesian sample.
The fibroblast growth factor 1 gene, FGF1, is located at the centre of the QTL. This gene had previously been cited as a putative blood pressure candidate gene in the 5q region but not studied in humans. With roles in endothelial cell proliferation, possible oxidative stress defence and proven direct effects on blood pressure in rodent models, we considered it a possible novel candidate. Coding regions and 3’ UTR were sequenced and family-based association analyses performed for three polymorphisms which were discovered in the 3’ UTR.
Association of SBP (P=0.045), pulse pressure (P=0.019) and hypertension status (P=0.038) was demonstrated to the most proximal locus. Association of hypertension to a three-locus haplotype was also shown (P=0.020).
The work on essential hypertension demonstrated the merit of confirming linkage in independent populations, implicating a 7 cM region of 5q31.1-q33 linked to blood pressure. Subsequent candidate gene studies utilised the added value of haplotype analyses, excluding the ADRB2 locus but showing interesting data to implicate the novel FGF1 locus as a putative positional candidate. Further fine mapping strategies are now underway to define, more clearly, the haplotype tag across the FGF1 locus.
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