Anti-BCAR1 (C-terminal) monoclonal antibody, clone 3D2.2

Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 x 10(-5) (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.

Context: Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry. Objective: The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants. Design and Participants: A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes. Results: We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 with T2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14 rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation. Conclusions: BCAR1 rs7202877 may mediate its diabetogenic impact through impaired beta-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance. (J Clin Endocrinol Metab 98: E801-E806, 2013)