A Genome-Wide Scan for Urinary Albumin Excretion in Hypertensive Families

Abstract—Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h2) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the Hyper tension G enetic E pidemiology N etwork (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h2 were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h2 of log urine ACR was 0.49 (P <1×10−7) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40; P =0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75; P =0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.