Reference
Male mice from 27 inbred strains used in the current study: (129S1/SvImJ, 129X1/SvJ, A/J, AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, C57BR/cdJ,C58/J, CBA/J, CE/J, DBA/2J, FVB/NJ, KK/HlJ, I/LnJ, LG/J, LP/J,MA/MyJ, NOD/LtJ, NON/LtJ, NZO/HlLtJ, NZW/LacJ, PL/J, PWD/PhJ, SJL/J, SM/J, and SWR/J) (n=6-10/strain).
Experiment
The purpose of the current study was to characterize the genetic contribution to intrinsic vascular function and to identify loci associated with phenotypic variation in vascular reactivity in mice. Impaired endothelial function is a fundamental component of hypertension and atherosclerosis and, hence, a predictive precursor for cardiovascular disease (CVD).
Concentration response curves to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh), and sodium nitroprusside (SNP) were generated in aortic rings from male mice (12 wk old) from 27 inbred mouse strains. Female animals were not included in the present study to improve the consistency for each measurement within strains and to limit any confounding variables that would affect the identification of significant genome-wide associations.
At 13 wks of age, mice were weighed and anesthetized by intraperitoneal injection. Thoracic aortas were dissected, and connective tissue was carefully removed. Then cumulative concentration response curves to PE and KCl were generated to assess vasocontractile functions, while cumulative concentration-response curves to ACh, a muscarinic receptor agonist and SNP were generated to assess endothelium-dependent and independent vasorelaxation, respectively. Quantitative trait loci having P values </=3.95 10(-8) and 1.00(10-5) were considered significant and suggestive, respectively
GWAS results for endothelium-dependent vasorelaxation revealed four significant associations for ACh maximal responses on three different chromosomes [Table 2]:
QTL Edvq1 (endothelium dependent vasorelaxation QTL 1) mapped to Chromosome 1 in an interval between 145.27-145.77 Mb with a peak at rs30978316 (145.57 Mb) and a p value of 0.000000341. The 129X1/SvJ strain had significantly lower maximum ACh when compared with A/J, C57BL/6J, and SWR/J [Fig2. A.]. Proposed candidate genes were: B3galt2, Glrx2, Uchl5.
QTL Edvq2 (endothelium dependent vasorelaxation QTL 2) mapped to Chromosome 1 in an interval between 148.17-148.96 Mb with a peak at rs31892646 (148.66 Mb) and a p value of 0.000000143. The peak SNP for Edvq2 mapped to intron six of the Famc5 gene.
QTL Edvq3 (endothelium dependent vasorelaxation QTL 3) mapped to Chromosome 2 in an interval between 149.58-149.98 Mb with a peak at rs6343262 (149.78 Mb) and a p value of 0.00000228. Proposed candidate genes for Edvq3 were Syndig1, Zfp120 and Tmem90b.
QTL Edvq4 (endothelium dependent vasorelaxation QTL 4) mapped to Chromosome 19 in an interval between 22.20-22.79 Mb with a peak at rs37653496 (22.40 Mb) and a p value of 0.00000121. The peak SNP for QTL Edvq4 mapped within the first intron of Trpm3.
In addition 18 suggestive associations for Ach were identified on Chromosomes 1,2,4,5,6,7,9,11,12,13,16,17,18 [Table 2].
One significant QTL was identified for vasocontractile functions in response to the half-maximal inhibitory concentration of potassium chloride (KCI EC50). QTL Vcfq1 (vasocontractile function QTL 1) mapped to Chromosome X in an interval between 101.61 and 102.40 Mb with a peak at rs29078805 and a p value of 0.00000324.
Suggestive QTL for vasocreactivity in response SNP, PE and KCI were also mapped [Table 3.]
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