Linkage analysis for plasma amyloid beta levels in persons with hypertension implicates Aβ-40 levels to presenilin 2.
Ibrahim-Verbaas CA., Zorkoltseva IV., Amin N., Schuur M., Coppus AMW., Isaacs A., Aulchenko YS., Breteler MMB., Ikram MA., Axenovich TI., Verbeek MM., van Swieten JC., Oostra BA., van Duijn CM.
Plasma concentrations of Aβ40 and Aβ42 rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease (AD). Amyloid beta (Aβ) plasma levels were successfully used as an (endo)phenotype for gene discovery using a linkage approach in families with dominant forms of disease. Here, we searched for loci involved in Aβ plasma levels in a series of non-demented patients with hypertension in the Erasmus Rucphen Family study. Aβ40 and Aβ42 levels were determined in 125 subjects with severe hypertension. All patients were genotyped with a 6,000 single nucleotide polymorphisms (SNPs) illumina array designed for linkage analysis. We conducted linkage analysis of plasma Aβ levels. None of the linkage analyses yielded genome-wide significant logarithm of odds (LOD) score over 3.3, but there was suggestive evidence for linkage (LOD > 1.9) for two regions: 1q41 (LOD = 2.07) and 11q14.3 (LOD = 2.97), both for Aβ40. These regions were followed up with association analysis in the study subjects and in 320 subjects from a population-based cohort. For the Aβ40 region on chromosome 1, association of several SNPs was observed at the presenilin 2 gene (PSEN2) (p = 2.58 × 10(-4) for rs6703170). On chromosome 11q14-21, we found some association (p = 3.1 × 10(-3) for rs2514299). This linkage study of plasma concentrations of Aβ40 and Aβ42 yielded two suggestive regions, of which one points toward a known locus for familial AD.