Possible Locus on Chromosome 18q Influencing Postural Systolic Blood Pressure Changes

Abstract

Abstract-We conducted a genome-wide scan for quantitative trait loci influencing the systolic blood pressure, diastolic blood pressure, and pulse responses to a postural challenge in 498 white sibling-pairs from the Hypertension Genetic Epidemiology Network, a multicenter study of the genetic susceptibility to hypertension. All participants were hypertensive (systolic blood pressure Ն140 mm Hg, diastolic blood pressure Ն90 mm Hg, or on antihypertensive medications) with diagnosis before age 60. Blood pressure and pulse were measured by an oscillometric method after a 5-minute rest in a supine position and again immediately on standing. The genome scan included a total of 387 autosomal short-tandem-repeat polymorphisms typed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield. We used multipoint variance-components linkage analysis to identify possible quantitative trait loci influencing postural change phenotypes after adjusting for sex, age, and use of antihypertensive medications. There was suggestive evidence for linkage on chromosome 18q for the postural systolic blood pressure response (maximum logarithm of the odds scoreϭ2.6 at 80 centiMorgans). We also observed a maximum logarithm of the odds score of 1.9 for the systolic blood pressure response and 1.7 for the diastolic blood pressure response on chromosome 6p. The marker that demonstrated the strongest evidence for linkage for the systolic blood pressure response (D18S858) lies within 20 centiMorgans of a marker previously linked to rare familial orthostatic hypotensive syndrome. Our findings indicate that there may be 1 or more genes on chromosome 18q that regulate systolic blood pressure during the physiological recovery period after a postural stressor. Key Words: posture Ⅲ blood pressure Ⅲ heart rate Ⅲ hypertension Ⅲ linkage Ⅲ chromosome mapping T here is some evidence that blood pressure and heart rate responses to psychological and physical stressors are associated with adverse health outcomes. For example, prospective studies have found that a decrease in blood pressure on standing (orthostatic hypotension) is associated with increased coronary heart disease morbidity and mortality 1,2 and all-cause mortality. 3,4 Elderly individuals with postural hypotension accompanied by dizziness are also at greater risk of recurrent falls. 5 Family and twin studies suggest that blood pressure and heart rate responses to laboratory stressors such as a mental arithmetic or cold pressor test are partly under genetic control. 6 -12 By contrast, fewer studies have evaluated familial patterns of blood pressure or heart rate responses to postural stressors. A relatively severe form of orthostatic hypotension with an autosomal dominant mode of transmission has been described in 4 families. 13 Recently, a genome-wide scan in 2 of these families found significant evidence for linkage of this hypotensive trait in a region on chromosome 18q. 14 Unlike most other laboratory stressors designed to evaluate cardiovascular reactivity, ...

Quantitative genetic analysis of blood pressure reactivity to orthostatic tilt using principal components analysis

“…For example, some studies have found that DSBP to postural change (standing) is influenced by cigarette smoking, 3,5 certain antihypertensive medication 8,43 and BMI. 3,5,8 However, other studies indicate that BP response to postural change is not influenced by cigarette smoking, 8,13,43 hypertensive medication 3,5 or BMI. 4,13 It is possible that the covariate effects observed in some of these studies are influenced or obfuscated by multicollinearity among BP measures, and that the observed significant covariate effect may reflect an association with the portion of the variance of BP reactivity that is correlated with resting or general BP.…”

“…9,10 One reason for these equivocal results is the fact that genetic factors are rarely accounted for in studies of BP reactivity. 11,12 A few studies have shown evidence for genes influencing BP changes in response to orthostasis (i.e., postural change), [13][14][15] but one aspect of this research that has been largely ignored is the identification of unique or shared genetic influences on different BP measures at rest and during orthostasis. In other words, do the same genes regulate BP both at rest and during orthostasis?…”

Polymorphisms of angiotensin-converting enzyme (ACE) and ACE2 are not associated with orthostatic blood pressure dysregulation in hypertensive patients

“…The genetic influence on orthostatic BP dysregulation (OH or OHT) remains understudied. Previous familial studies indicate that genes responsible for orthostatic SBP disorder may be on chromosome 13q or 18q [33,34] . However, no exact candidate genes have been identified as being responsible for orthostatic SBP regulation.…”

Trapping and sequence analysis of 1138 putative exons from human chromosome 18

“…Such polymorphisms may be subsequently genotyped in populations with genetic disorders that map to the chromosome, and used for further association studies in complex inheritance diseases such as bipolar disorder, and other disorders, including autosomal dominant orthostatic hypotensive disorder, 28 a locus for postural systolic blood pressure response, 29 IDDM6, 30 Grave's disease, 31 Paget disease of bone, 32 and dyslexia 33 that have been mapped on this chromosome.…”