Key result
Rare coding variants in HYAL2 and GSTZ1 were significantly associated with increased ADP-induced and epinephrine-induced platelet aggregation (p=1.07×10–7 and p=1.62×10–6, respectively).
Cohort (n=1,211)
Gene-based association testing identified rare variants in HYAL2 and GSTZ1 that significantly influence platelet reactivity, revealing potential new biological mechanisms and therapeutic targets.
Answers are grounded in this paper and cite their sources.
May identify novel platelet reactivity targets; hypothesis-generating and requires replication before clinical consideration.
Summary Inhibition of platelet reactivity is a common therapeutic strategy in secondary prevention of cardiovascular disease. Genetic and environmental factors influence inter-individual variation in platelet reactivity. Identifying genes that contribute to platelet reactivity can reveal new biological mechanisms and possible therapeutic targets. Here, we examined rare coding variation to identify genes associated with platelet reactivity in a population-based cohort. To do so, we performed whole exome sequencing in the Framingham Heart Study and conducted single variant and gene-based association tests against platelet reactivity to collagen, adenosine diphosphate (ADP), and epinephrine agonists in up to 1,211 individuals. Single variant tests revealed no significant associations (p<1.44×10–7), though we observed a suggestive association with previously implicated MRVI1 (rs11042902, p = 1.95×10–7). Using gene-based association tests of rare and low-frequency variants, we found significant associations of HYAL2 with increased ADP-induced aggregation (p = 1.07×10–7) and GSTZ1 with increased epinephrine-induced aggregation (p = 1.62×10–6). HYAL2 also showed suggestive associations with epinephrine-induced aggregation (p = 2.64×10–5). The rare variants in the HYAL2 gene-based association included a missense variant (N357S) at a known N-glycosylation site and a nonsense variant (Q406*) that removes a glycophosphatidylinositol (GPI) anchor from the resulting protein. These variants suggest that improper membrane trafficking of HYAL2 influences platelet reactivity. We also observed suggestive associations of AR (p = 7.39×10–6) and MAPRE1 (p = 7.26×10–6) with ADP-induced reactivity. Our study demonstrates that gene-based tests and other grouping strategies of rare variants are powerful approaches to detect associations in population-based analyses of complex traits not detected by single variant tests and possible new genetic influences on platelet reactivity. Supplementary Material to this article is available online at www.thrombosis-online.com.
No takes yet. Share an insight, caveat, or question.
Eicher et al. (2017) conducted a cohort in Platelet reactivity (n=1,211). Rare coding variation (e.g., HYAL2, GSTZ1) vs. Absence of rare coding variation was evaluated on Platelet reactivity to collagen, adenosine diphosphate (ADP), and epinephrine agonists (p=1.07×10–7). Rare coding variants in HYAL2 and GSTZ1 were significantly associated with increased ADP-induced and epinephrine-induced platelet aggregation (p=1.07×10–7 and p=1.62×10–6, respectively).
Synapse has enriched 10 related papers. Consider them for comparative context: