(Hypertension. 2000;35:1291.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
A Genome-Wide Search For Susceptibility Loci to Human Essential Hypertension
From the Clinical Pharmacology Unit (P.S., J.F., F.F., H.J., S.M., C.B., K.O., M.J.B.), University of Cambridge, Addenbrooke’s Hospital; and MRC Biostatistics Unit (D.C.), Cambridge, UK.
Correspondence to Dr Pankaj Sharma, Clinical Pharmacology Unit, University of Cambridge, Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail psharma{at}hgmp.mrc.ac.uk
Abstract—We undertook a systematic search of the entire human genome with the affected sibling-pair model to identify major susceptibility loci to essential hypertension. Affected nuclear families (n=263) were recruited and divided according to definite or probable genetic contribution to hypertension depending on number of hypertensive siblings. The largest nuclear families were first screened with a set of microsatellite markers. Regions on the genome with P<0.05 were tested against the second set of smaller families. An exclusion map was generated to identify regions in which hypertension-causing genes are unlikely to reside. Sibling-pair linkage analysis identified a single locus on chromosome 11q (P<0.004) in the first pass. A second pass with nuclear families that had only affected sibling pairs was, as expected, insufficient to support linkage to 11q. Multipoint exclusion-linkage analysis showed that 3 genetic loci are necessary to explain familial aggregation of essential hypertension. Our preliminary findings suggest that no single region within the human genome contains genes with a major contribution to essential hypertension. We show that the disease is indeed polygenic, with each gene providing a relatively small risk. Our exclusion map will help future investigators to concentrate on areas likely to contain these genes. The region on chromosome 11 is the first to point to a new candidate gene for hypertension that has arisen out of a genome search, but replication of these results at a higher significance is necessary before positional cloning can be justified.
Key Words: genes • genetics • hypertension, essential • ROMK
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