![]() While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10 rs1376606, DER元 rs5030613, and RGS6 rs9323567). Incorporating local ancestry adjustment notably enhanced our ability to detect associations. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico.Local Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR).The LAI GWAS identified variants within the CYP2C19 region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. A., Ruaño, G., Roche-Lima, A., Alarcon, C., Ritchie, M. medRxiv : the preprint server for health sciences Yang, G., González, P., Moneró, M., Carrasquillo, K., Renta, J. Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics.As H310Y stabilizes the voltage-sensor active conformation and abolishes N-type inactivation, it can serve as an investigative tool for functional and pharmacological studies. The p.H310R variant caused 'dual loss of function', diminishing the presence of KV 1.2 subunits on the cell surface and inhibiting voltage-dependent channel opening. ![]() H310Y abolished 'ball and chain' (N-type) inactivation of KV 1.2 by KV beta1 subunits, enhancing the gain-of-function phenotype. The p.H310Y variant caused 'dual gain of function', increasing both KV 1.2-channel activity and the number of KV 1.2 subunits on the cell surface. Both variants affect position H310, highly conserved in KV channels. We characterize two KCNA2 variants from patients with developmental delay and epilepsy. KEY POINTS: KCNA2 encodes the subunits of KV 1.2 voltage-activated, K+ -selective ion channels, which regulate electrical signalling in neurons. We discuss the implications for KV -channel biogenesis and function, an emergent hotspot for disease-associated variants, and mechanisms of epileptogenesis. In contrast, p.H310R caused 'dual loss of function', diminishing surface levels by multiple impediments to trafficking and inhibiting voltage-dependent channel opening. Additionally, H310Y abolished 'ball and chain' inactivation of KV 1.2 by KV beta1 subunits, enhancing gain of function. We found that the latter is due to the formation of a hydrogen bond that stabilizes the active state of the voltage-sensor domain. The p.H310Y variant produced 'dual gain of function', increasing both cell-surface trafficking and activity, delaying channel closure. Despite affecting the same channel, at the same position, and being associated with severe neurological disease, the two variants had diametrically opposite effects on KV 1.2 functional expression. We investigated both variants in heterologously expressed, human KV 1.2 channels by immunocytochemistry, electrophysiology and voltage-clamp fluorometry. Both gain and loss of KV 1.2 function cause epilepsy, precluding the prediction of variant effects and while H310 is conserved throughout the KV -channel superfamily, it is largely understudied. KCNA2 encodes KV 1.2-channel subunits, which regulate neuronal excitability. Two KCNA2 variants (p.H310Y and p.H310R) were discovered in paediatric patients with epilepsy and developmental delay. Vice Provost for Undergraduate Education.Office of Vice President for Business Affairs and Chief Financial Officer.Office of VP for University Human Resources.Stanford Woods Institute for the Environment.Stanford Institute for Economic Policy Research (SIEPR).Institute for Stem Cell Biology and Regenerative Medicine.Institute for Human-Centered Artificial Intelligence (HAI). ![]()
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