Genome-Wide Search for Nonadditive Allele Effects Identifies PSKH2 as Involved in the Variability of Factor V Activity.

Autor: Gendre B; INSERM, Bordeaux Population Health Research Center, UMR 1219, ELEANOR, University of Bordeaux Bordeaux France., Martinez-Perez A; Unit of Genomics of Complex Diseases, Institut de Recerca Sant Pau (IR SANT PAU) Barcelona Spain.; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain., Kleber ME; Department of Medicine V, Medical Faculty Mannheim University of Heidelberg Mannheim Germany.; SYNLAB Center of Human Genetics Mannheim Manheim Germany., van Hylckama Vlieg A; Department of Clinical Epidemiology Leiden University Medical Center Leiden Netherlands., Boland A; CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay Evry France.; Laboratory of Excellence GENMED (Medical Genomics) Evry France., Olaso R; CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay Evry France.; Laboratory of Excellence GENMED (Medical Genomics) Evry France., Germain M; INSERM, Bordeaux Population Health Research Center, UMR 1219, ELEANOR, University of Bordeaux Bordeaux France., Munsch G; INSERM, Bordeaux Population Health Research Center, UMR 1219, ELEANOR, University of Bordeaux Bordeaux France., Moissl AP; Department of Medicine V, Medical Faculty Mannheim University of Heidelberg Mannheim Germany., Suchon P; Cardiovascular and Nutrition Research Center (C2VN), INSERM, INRAE, Aix-Marseille University Marseille France., Souto JC; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain.; Thrombosis and Haemostasis Unit Hospital de la Santa Creu i Sant Pau and Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau) Barcelona Spain., Soria JM; Unit of Genomics of Complex Diseases, Institut de Recerca Sant Pau (IR SANT PAU) Barcelona Spain.; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain., Deleuze JF; CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Université Paris-Saclay Evry France.; Laboratory of Excellence GENMED (Medical Genomics) Evry France., März W; Department of Medicine V, Medical Faculty Mannheim University of Heidelberg Mannheim Germany.; Clinical Institute of Medical and Chemical Laboratory Diagnostics Medical University of Graz Graz Austria.; SYNLAB Academy, SYNLAB Holding Germany Mannheim and Augsburg Germany., Rosendaal FR; Department of Clinical Epidemiology Leiden University Medical Center Leiden Netherlands., Sabater-Lleal M; Unit of Genomics of Complex Diseases, Institut de Recerca Sant Pau (IR SANT PAU) Barcelona Spain.; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III Madrid Spain.; Cardiovascular Medicine Unit, Department of Medicine Karolinska Institutet Stockholm Sweden., Morange PE; Cardiovascular and Nutrition Research Center (C2VN), INSERM, INRAE, Aix-Marseille University Marseille France., Trégouët DA; INSERM, Bordeaux Population Health Research Center, UMR 1219, ELEANOR, University of Bordeaux Bordeaux France.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2024 Nov 05; Vol. 13 (21), pp. e034943. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1161/JAHA.124.034943
Abstrakt: Background: Factor V (FV) is a key molecular player in the coagulation cascade. FV plasma levels have been associated with several human diseases, including thrombosis, bleeding, and diabetic complications. So far, 2 genes have been robustly found through genome-wide association analyses to contribute to the inter-individual variability of plasma FV levels: structural F5 gene and PLXDC2.
Methods and Results: The authors used the underestimated Brown-Forsythe methodology implemented in the QuickTest software to search for non-additive genetic effects that could contribute to the inter-individual variability of FV plasma activity. QUICKTEST was applied to 4 independent genome-wide association studies studies (LURIC [Ludwigshafen RIsk and Cardiovascular Health Study], MARTHA [Marseille Thrombosis Association], MEGA [Multiple Environmental and Genetic Assessment], and RETROVE [Riesgo de Enfermedad Tromboembolica Venosa]) totaling 4505 participants of European ancestry with measured FV plasma levels. Results obtained in the 4 cohorts were meta-analyzed using a fixed-effect model. Additional analyses involved exploring haplotype and gene×gene interactions in downstream investigations. A genome-wide significant signal at the PSKH2 locus on chr8q21.3 with lead variant rs75463553 with no evidence for heterogeneity across cohorts was observed ( P =0.518). Although rs75463553 did not show an association with mean FV levels ( P =0.49), it demonstrated a robust significant ( P =3.38x10 -9 ) association with the variance of FV plasma levels. Further analyses confirmed the reported association of PSKH2 with neutrophil biology and revealed that rs75463553 likely interacts with two loci, GRIN2A and POM121L12 , known for their involvement in smoking biology.
Conclusions: This comprehensive approach identifies the role of PSKH2 as a novel molecular player in the genetic regulation of FV, shedding light on the contribution of neutrophils to FV biology.
Databáze: MEDLINE
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