Anti-CNTN4 monoclonal antibody Made to order

Background and aims: Elevated urinary 11-dehydro thromboxane B-2 (TxB(2)), a measure of thromboxane A(2) formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB(2) and their associations with cardiovascular morbidity were investigated in this study. Methods: Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. Results: The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB(2) formation. Haplotypes of 11-dehydro TxB(2) increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB(2), explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p = 0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB(2) were individually associated with greater incidences of cardiovascular events -rs10515638 (HR = 1.31, p = 0.01) and rs10510230 (HR = 1.25, p = 0.007); effect sizes were larger in those not taking aspirin. Conclusions: PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention. (c) 2017 Elsevier B.V. All rights reserved.

The contactins are members of a protein subfamily of neural immunoglobulin (Ig) domain-containing cell adhesion molecules. Their architecture is based on six N-terminal Ig domains, four fibronectin type III domains, and a C-terminal glycophosphatidylinositol (GPI)-anchor to the extracellular part of the cell membrane. Genetics of neuropsychiatric disorders, particularly autism spectrum disorders, have pinpointed contactin-4, -5, and -6 (CNTN4, -5, and -6) as potential disease genes in neurodevelopmental disorders and suggested that they participate in pathways important for appropriate brain development. These contactins have distinct but overlapping patterns of brain expression, and null-mutation causes subtle morphological and functional defects in the brain. The molecular basis of their neurodevelopmental functions is likely conferred by heterophilic protein interactions. Cntn4, -5, and -6 interact with protein tyrosine phosphatase receptor gamma (Ptptg) using a shared binding site that spans their second and third Ig repeats. Interactions with amyloid precursor protein (APP), Notch, and other IgCAMs have also been indicated. The present data indicate that Cntn4, -5, and -6 proteins may be part of heteromeric receptor complexes as well as serve as ligands themselves.