Faculty Opinions recommendation of Genome-wide association studies identify genetic loci for low von Willebrand factor levels.

AbstractGenome-wide association studies (GWASs) have identified genes that affect plasma von Willebrand factor (VWF) levels. ABO showed a strong effect, whereas smaller effects were seen for VWF, STXBP5, STAB2, SCARA5, STX2, TC2N, and CLEC4M. This study screened comprehensively for both common and rare variants in these eight genes by resequencing their coding sequences in 104 Swedish von Willebrand disease (VWD) patients. The common variants previously associated with the VWF level were all accumulated in the VWD patients compared to three control populations. The strongest effect was detected for blood group O coded for by the ABO gene (71 vs. 38% of genotypes). The other seven VWF level associated alleles were enriched in the VWD population compared to control populations, but the differences were small and not significant. The sequencing detected a total of 146 variants in the eight genes. Excluding 70 variants in VWF, 76 variants remained. Of the 76 variants, 54 had allele frequencies > 0.5% and have therefore been investigated for their association with the VWF level in previous GWAS. The remaining 22 variants with frequencies < 0.5% are less likely to have been evaluated previously. PolyPhen2 classified 3 out of the 22 variants as probably or possibly damaging (two in STAB2 and one in STX2); the others were either synonymous or benign. No accumulation of low frequency (0.05–0.5%) or rare variants (<0.05%) in the VWD population compared to the gnomAD (Genome Aggregation Database) population was detected. Thus, rare variants in these genes do not contribute to the low VWF levels observed in VWD patients.

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Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Genome Biology ◽

10.1186/s13059-021-02398-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Daniel L. McCartney ◽

Josine L. Min ◽

Rebecca C. Richmond ◽

Ake T. Lu ◽

Maria K. Sobczyk ◽

...

Keyword(s):

Dna Methylation ◽

Genome Wide Association Study ◽

Association Studies ◽

Genome Wide Association ◽

Biological Aging ◽

Genome Wide Association Studies ◽

Genetic Loci ◽

Biomarkers Of Aging ◽

Genome Wide ◽

Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rate

Blood ◽

10.1182/blood.2020008345 ◽

2021 ◽

Author(s):

Gaia Zirka ◽

Philippe Robert ◽

Julia Tilburg ◽

Victoria Tishkova ◽

Chrissta X Maracle ◽

...

Keyword(s):

Transmembrane Protein ◽

Association Studies ◽

Genome Wide Association Studies ◽

Wild Type ◽

Shear Rates ◽

Extracellular Traps ◽

Genome Wide ◽

Healthy Donors ◽

Von Willebrand ◽

Willebrand Factor

Genome wide association studies linked expression of the human neutrophil antigen 3b (HNA-3b) epitope on the Slc44a2 protein with a 30% decreased risk of venous thrombosis (VT) in humans. Slc44a2 is a ubiquitous transmembrane protein identified as a receptor for Von Willebrand factor (VWF). To explain the link between Slc44a2 and VT we wanted to determine how Slc44a2 expressing either HNA-3a or HNA-3b on neutrophils could modulate their adhesion and activation on VWF under flow. Transfected HEK293T cells or neutrophils homozygous for the HNA-3a- or the HNA-3b-coding allele were purified from healthy donors and perfused in flow chambers coated with VWF at venous shear rates (100s-1). HNA-3a expression was required for Slc44a2-mediated neutrophil adhesion to VWF at 100s-1. This adhesion could occur independently of β2 integrin and was enhanced when neutrophils are preactivated with lipopolysaccharide (LPS). Moreover, specific shear conditions with high neutrophil concentration could act as a "second hit", inducing the formation of neutrophil extracellular traps. Neutrophil mobilization was also measured by intravital microscopy in venules from SLC44A2-knockout and wild-type mice after histamine-induced endothelial degranulation. Mice lacking Slc44a2 showed a massive reduction in neutrophil recruitment in inflamed mesenteric venules. Our results show that Slc44a2/HNA-3a is important for the adhesion and activation of neutrophils in veins under inflammation and when submitted to specific shears. Neutrophils expressing Slc44a2/HNA-3b not being associated with these observations, these results could thus explain the association between HNA-3b and a reduced risk for VT in humans.

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Abstract 18836: Integrative Pathway Analysis of Genome-wide Association Studies of Carotid Plaque Phenotypes

Circulation ◽

10.1161/circ.132.suppl_3.18836 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Yuqi Zhao ◽

Sander M van der Laan ◽

Hester M den Ruijter ◽

Saskia Haitjema ◽

Gerard Pasterkamp ◽

...

Keyword(s):

Smooth Muscle ◽

Cardiovascular Events ◽

Association Studies ◽

Genome Wide Association ◽

Sphingolipid Metabolism ◽

Genome Wide Association Studies ◽

Plaque Composition ◽

Genetic Loci ◽

Genetic Components ◽

Genome Wide

Introduction: The composition of atherosclerotic plaques differs between individuals and contributes to the incidence of cardiovascular events. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases. We carried out genome-wide association studies (GWAS) to investigate the genetic underpinnings of the plaque. Methods: We included carotid endarterectomy patients from the Athero-Express Biobank Study (n = 1,439). We quantified the percentage of macrophages and smooth muscle cells, the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. GWAS was performed for all 9 plaque traits, and combined with summary level from GWAS consortia data on coronary artery disease (CAD), and ischemic stroke. Next, these data were integrated with data from human expression quantitative trait loci analyses, and pathway analyses of the plaque traits. Results: No individual locus reached genome-wide significance, likely due to the moderate sample size involved. However, it is plausible that perturbations of diverse pathways by a large number of genetic loci with small effects together contribute to the regulation of plaque composition. We identified 42-97 pathways significantly associated with each plaque phenotype, with many specific to each trait, supporting the presence of unique genetic components of individual plaque phenotypes. We also detected 39 pathways associated with at least four plaque phenotypes, among which were CAD-associated processes such as “extracellular matrix”, “complement and coagulation cascades” and stroke-associated pathways such as “Toll-like receptor signaling”. Interestingly, we found that smooth muscle cell percentage and atheroma size shared more genetic loci and pathways with intraplaque hemorrhage (such as “Sphingolipid metabolism”); the latter trait is associated with secondary cardiovascular events. Conclusion: There are genetic correlations among plaque phenotypes as well as between plaque phenotypes that provide mechanistic insight into the composition of the plaque and progression to secondary events.

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Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study

American Journal of Nephrology ◽

10.1159/000488946 ◽

2018 ◽

Vol 47 (5) ◽

pp. 304-316 ◽

Cited By ~ 5

Author(s):

Asahi Hishida ◽

Masahiro Nakatochi ◽

Masato Akiyama ◽

Yoichiro Kamatani ◽

Takeshi Nishiyama ◽

...

Keyword(s):

Renal Function ◽

Japanese Population ◽

Gene Locus ◽

Association Studies ◽

East Asian ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genetic Loci ◽

Asian Populations ◽

Genome Wide

Background: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. Methods: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. Results: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10–6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10–8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. Conclusion: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

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