Abstract
Epidemiological studies have consistently found that hypertension is associated with poor cognitive performance. We hypothesize that a putative causal mechanism underlying this association is due to genetic loci affecting both blood pressure and cognition. Consistent with this notion, we reported several blood pressure (BP) quantitative trait loci (QTLs) that co-localized with navigational performance (Nav)-QTLs influencing spatial learning and memory in Dahl rats. The present study investigates a chromosome 2 region harboring BP-f4 and Nav-8 QTLs. We developed two congenic strains, S.R2A and S.R2B introgressing Dahl R-chromosome 2 segments into Dahl S chromosome 2 region spanning BP-f4 and Nav-8 QTLs. Radiotelemetric blood pressure analysis identified only S.R2A congenic rats with lower systolic blood pressure (females: −26.0 mmHg, P = 0.003; males: −30.9 mmHg, P<1×10−5), diastolic blood pressure (females: −21.2 mmHg, P = 0.01; males: −25.7 mmHg, P<1×10−5), and mean arterial pressure (females: −23.9 mmHg, P = 0.004; males: −28.0 mmHg, P<1×10−5) compared with corresponding Dahl S controls, confirming the presence of BP-f4 QTL on rat chromosome 2. The S.R2B congenic segment did not affect blood pressure. Testing of S.R2A, S.R2B, and Dahl S male rats in the Morris water maze (MWM) task revealed significantly decreased spatial navigation performance in S.R2A male congenic rats when compared with Dahl S male controls (P<0.05). The S.R2B congenic segment did not affect performance of the MWM task in males. The S.R2A female rats did not differ in spatial navigation when compared with Dahl S female controls, indicating that the Nav-8 effect on spatial navigation is male-specific. Our results suggest the existence of a single QTL on chromosome 2 176.6–179.9 Mbp region which affects blood pressure in both males and females and cognition solely in males.
Highlights
Essential hypertension is a leading risk factor for myocardial infarction and stroke [1,2], and epidemiologic studies have shown that cardio- and cerebrovascular diseases are related to cognitive decline [3,4,5,6]
Our two previous linkage studies performed on two F2 (Dahl S6R)-intercross rat populations, one cohort phenotyped for blood pressure [12] and another population characterized for navigational performance [13], delineated the potential existence of two closely linked QTLs on chromosome 2, one affecting blood pressure (BP-f4) [12] and the other affecting navigational performance (Nav-8) [13] (Table 1)
Blood pressure analysis of the congenic lines harboring the chromosome 2 region spanning putative BP-f4 and Nav-8 QTLs (Figure 1) substantiated the existence of BP-f4 QTL in this region as demonstrated by the significantly lower systolic, diastolic, and mean blood pressures exhibited by SR.2A congenic rats compared with Dahl S controls (Table 2)
Summary
Essential hypertension is a leading risk factor for myocardial infarction and stroke [1,2], and epidemiologic studies have shown that cardio- and cerebrovascular diseases are related to cognitive decline [3,4,5,6]. High systolic blood pressure (SBP) occurring in midlife increases the risk of developing clinical dementia at older ages [7,8] These findings have been extended even to the normotensive range, in which increasing systolic blood pressure in the high-normal blood pressure range is associated with poor cognitive performance [9]. Hypertension and dementia are conditions that exhibit highly complex inheritance involving environmental, genetic, and epigenetic mechanisms These disorders are further compounded by phenotype variation due to its relatively late onset, variable disease course, sex-specific differences, and emerging impact of gestational environmental factors. We detected several blood pressures (BP)-QTLs [12] that co-localized with spatial navigation (Nav)-QTLs affecting spatial learning and memory performance [13] This raises the possibility that genes underlying these overlapping QTLs might represent pleiotropic effects of single gene variants. The present study was undertaken to initially test this hypothesis by 1) confirming the presence of one BP-QTL and one Nav-QTL in a chromosome 2 region harboring BP-f4 [12] and Nav-8 [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
