Defining a rat blood pressure quantitative trait locus to a <81.8 kb congenic segment: comprehensive sequencing and renal transcriptome analysis.

Evidence from multiple linkage and genome-wide association studies suggest that human chromosome 2 (HSA2) contains alleles that influence blood pressure (BP). Homologous to a large segment of HSA2 is rat chromosome 9 (RNO9), to which a BP quantitative trait locus (QTL) was previously mapped. The objective of the current study was to further resolve this BP QTL. Eleven congenic strains with introgressed segments spanning <81.8 kb to <1.33 Mb were developed by introgressing genomic segments of RNO9 from the Dahl salt-resistant (R) rat onto the genome of the Dahl salt-sensitive (S) rat and tested for BP. The congenic strain with the shortest introgressed segment spanning <81.8 kb significantly lowered BP of the hypertensive S rat by 25 mmHg and significantly increased its mean survival by 45 days. In contrast, two other congenic strains had increased BP compared with the S. We focused on the <81.8 kb congenic strain, which represents the shortest genomic segment to which a BP QTL has been mapped to date in any species. Sequencing of this entire region in both S and R rats detected 563 variants. The region did not contain any known or predicted rat protein coding genes. Furthermore, a whole genome renal transcriptome analysis between S and the <81.8 kb S.R congenic strain revealed alterations in several critical genes implicated in renal homeostasis. Taken together, our results provide the basis for future studies to examine the relationship between the candidate variants within the QTL region and the renal differentially expressed genes as potential causal mechanisms for BP regulation.

Association of von Willebrand factor activity with ACE I/D and MTHFR C677T polymorphisms in migraine.

Angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms are linked to endothelial dysfunction and to cerebral white matter lesions. Objectives of this study were to determine if ACE and MTHFR gene polymorphisms are associated with von Willebrand factor (vWF) activity, an endothelial dysfunction marker, and with a distinct headache phenotype. We enrolled 64 women (18-50 years old) with International Classification of Headache Disorders, 2nd edn migraine without aura (MoA) and 61 with aura (MA). Genotypic frequencies: ACE DD 35%, ID 42%, II 23%, and MTHFR TT 17%, CT 40%, CC 43%. Those with ACE DD genotype had higher levels of vWF activity (152%) compared with ID and II genotypes. Levels were highest (179%) with combined ACE DD and MTHFR TT genotypes. ACE DD was associated with higher headache frequency, and MTHFR TT was associated with MA. In migraine, vWF activity may be a marker of endothelial-mediated genetic risk for ischaemic conditions.