Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m2) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8 AM, noon, and 4 PM. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.

Abstract-Genetic variability, which influences cardiovascular phenotypes in normal persons, is likely to be relevant to cardiovascular disease. We studied normal monozygotic and dizygotic twins and found strong genetic influences on blood pressure and heart size. We then relied on the dizygotic twins and their parents to apply molecular genetic techniques. We performed a linkage analysis with markers close to the ␤-2 adrenergic receptor (AR) gene locus in the dizygotic twins and their parents and found strong evidence for linkage to the quantitative traits of blood pressure and heart size. We then used allele-specific polymerase chain reaction to genotype the subjects further. We performed an association analysis and found that 4 functionally relevant polymorphisms in the ␤-2 AR gene, namely Arg16/Gly, Gln27/Glu, Thr164/Ile, and a variant in the promoter region (Ϫ47C/T), were variably associated with blood pressure and heart size differences but were in linkage dysequilibrium with each other. A subsequent conditional analysis suggested that the Arg16/Gly polymorphism exerted the predominant effect. These findings underscore the importance of the ␤-2 AR gene to blood pressure regulation, heart size, and probably to the development of hypertension. We suggest that a combined linkage and association approach will elucidate the genetic variability influencing blood pressure and other cardiovascular phenotypes. (Hypertension. 2000;35:555-560.)Key Words: receptors, adrenergic, beta Ⅲ genetics Ⅲ hypertension, genetic Ⅲ twins Ⅲ blood pressure T he ␤-2 adrenergic receptor (␤-2 AR) has been implicated in the pathogenesis of hypertension, both on the basis of studies suggesting altered ␤-2-mediated vasodilation 1 and on the basis of molecular genetic association studies. 2,3 Recently, Kotanko et al 4 found an association between the Arg16/Gly polymorphism in the ␤-2 AR gene and hypertension in an African Caribbean population. They showed that the Gly16 allele was more common in hypertensive subjects than in normotensive African Caribbean control subjects. Since the Gly16 allele indicates an increased propensity for downregulation of the receptor, 5 the authors raised the possibility that an impaired vasodilation in peripheral arteries in response to ␤-2 AR agonists may play a role in the hypertension of individuals carrying the Gly16 allele. We subsequently examined the firstborn normotensive adult children of couples documented to be normotensive or hypertensive in the Bergen Blood Pressure Study. 6 Offspring of 2 hypertensive parents had higher blood pressures and a preponderance of the Arg16 allele compared with offspring of 2 normotensive parents. To further examine the genetic variability at the ␤-2 AR locus and its relevance for the cardiovascular system in northern Europeans, we performed a combined linkage and association study in normotensive twin subjects. We used allele-specific polymerase chain reaction (PCR), which allowed us to examine other polymorphisms in the ␤-2 AR gene. MethodsWe recruited 166 pairs of t...

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