Exclusion of angiotensinogen gene in molecular basis of human hypertension: Sibpair linkage and association analyses in Australian Anglo-Caucasians

Linkage with essential hypertension has been claimed for a microsatellite m arker near the angiotensinogen gene (AGT; chromosome 1q42), as has associat ion for the AGT variants M235T, G(-6)A and A(-20)C, To more rigorously eval uate AGT as a candidate gene for hypertension we performed sibpair analysis with multiple microsatellite markers surrounding this locus and using more sophisticated analysis programs. We also performed an association study of the AGT variants in unrelated subjects with a strong family history (two a ffected parents), For the linkage study, single and multiplex polymerase ch ain reaction (PCRs) and automated genescan analysis were conducted on DNA f rom 175 Australian Anglo-Celtic Caucasian hypertensives for the following m arkers: D1S2880-(2.1 cM)-D1S213 -(2.8 cM)-D1S251-(6.5 cM)-AGT-(2.0 cM) -D1S 235, Statistical evaluation of genotype data by nonparametric methods resul ted in the following scores: Single-point analysis SPLINK, P > 0.18; APM me thod, P > 0.25; ASPEX, MLOD < 0.28; SIE-PAIR, P > 0.24; Multipoint analysis - MAPMAKER/SIBS, MLOD < 0.24; GENEHUNTER, P > 0.35, Exclusion scores of Lo d -4.1 to -5.1 were obtained for these markers using MAPMAKER/SIBS for a la mbda(s) of 1.6, The association study of G(-6)A, A(-20)C and M235T variants in 111 hypertensives with strong family history and 190 normotensives with no family history showed significant linkage disequilibrium between partic ular haplotypes, but we could find no association with hypertension, The pr esent study therefore excludes AGT in the etiology of hypertension, at leas t in the population of Australian Angle-Celtic Caucasians studied. Am. J. M ed. Genet. 87:53-60, 1999, (C) 1999 Wiley-Liss, Inc.