SALT SUSCEPTIBILITY MAPS TO CHROMOSOME-1 AND CHROMOSOME-17 WITH SEX SPECIFICITY IN THE SABRA RAT MODEL OF HYPERTENSION

Random genome screening was initiated in the Sabra rat model of hypert ension in search oi genes that account for salt sensitivity or salt re sistance in terms of the development of hypertension, Female salt-sens itive Sabra hypertension-prone (SBH/y) rats were crossed with male sal t-resistant Sabra hypertension-resistant (SBN/y) rats, resulting in an F2 cohort consisting of 100 males and 132 females. Systolic blood pre ssure (BP) was measured in rats at 6 weeks of age under basal conditio ns and after 4 weeks of salt loading. Genotypes for 24 polymorphic mic rosatellite markers localized to chromosome 1 and for 8 markers locali zed to chromosome 17 were determined in F2 and cosegregation with BP w as evaluated by ANOVA and multipoint linkage analysis. Basal BP did no t cosegregate with any locus on chromosomes 1 or 17. In contrast, BP a fter salt loading showed significant cosegregation with three QTLs, tw o on chromosome 1 and one on chromosome 17, designated SS1a, SS1b, and SS17, respectively; the maximal logarithm of the odds (LOD) scores we re 4.71, 4.91, and 3.43, respectively. Further analysis revealed sexua l dimorphism. In male F2, BP response to salt loading cosegregated wit h one QTL (LOD score 4.52) and a second QTL (LOD score 2.98), both on chromosome 1 and coinciding with SS1a and SS1b, respectively. In femal e rats, BP response cosegregated with one QTL on chromosome 1 (LOD sco re 3.08) coinciding with SS1b, and with a second QTL on chromosome 17 (LOD score 3.66) coinciding with SS17. In males, the additive effects of the two QTLs on chromosome 1 accounted for most of the BP variance to salt loading, whereas in females the additive effects of the QTLs o n chromosomes 1 and 17 accounted for over two thirds of the variance. These results identify three putative gene loci on chromosomes 1 and 1 7 that contribute importantly to salt sensitivity and/or resistance an d uncover sex specificity in the role that salt susceptibility genes f ulfill in the development of hypertension.