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Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
Comparative studies of age-related methylation patterns in various tissues showed these patterns to be highly tissue specific. Nevertheless, there are some loci that have methylation levels significantly correlated with age in various tissues. Obviously, these common methylated loci are of the highest relevance to the mechanisms of aging per se, and their methylation status could be used as an epigenetic signature to estimate the biological age. The first non-cell-type-dependent epigenetic aging signature was elaborated based on the DNA methylation datasets from several independent studies that used the Illumina HumanMethylation27 BeadChip platform [33]. Of more than 450 age-correlated CpG sites found, most were hypermethylated with age and only 25 were hypomethylated. This is in accord with the view noted above that hypermethylation at specific sites is a predominant trend upon aging, whereas hypomethylation seems to be less stringently regulated. Most accurate age predictions were obtained when a set of four hypermethylated loci, TRIM58, KCNQ1DN, NPTX2, and GRIA2, has been used. To further enhance the prediction accuracy, a hypomethylated locus BIRC4BP was added to the set. When all five loci were used, the average prediction accuracy across all datasets was ±12.7 years, whereas the use of only the three most reliable of them (NPTX2, GRIA2, and KCNQ1DN) enhanced the accuracy to ±11.4 years. It should be noted that, in the work described, the age prediction was applicable to various tissues and was gender independent, whereas in the previous study described above [32], the prediction was based only on the saliva samples. When the blood samples were investigated, the set of CpG loci with a high predictive capability could be narrowed down to just three (ITGA2B, ASPA, and PDE4C), and the accuracy of age prediction was ±4.5 years [34].
High-throughput measurement of human platelet aggregation under flow: application in hemostasis and beyond
Published in Platelets, 2018
Sanne L. N. Brouns, Johanna P. van Geffen, Johan W. M. Heemskerk
Platelets from patients with bleeding and Glanzmann’s thrombasthenia, carrying loss-of-function mutations in the ITGA2B or ITGB3 genes, are characterized by absence of integrin αIIbß3 or a qualitative defect of integrin activation and, hence, inability to aggregate. Affected aggregate formation and integrin activation in Glanzmann patients has also been observed using flow assays assessing platelet adhesion and thrombus formation on collagen and other surfaces, independent of shear rate (15,42). Similarly, patients with a combined immune disease and bleeding disorder, i.e., leukocyte adhesion deficiency-III, due to homozygous dysfunctional mutations in FERMT3 (a gene coding for the integrin-regulating protein kindlin-3), have platelets that are unable of αIIbß3 activation and aggregation. High-throughput flow assays with blood from such a patient or the heterozygous parents showed a marked reduction for all parameters of thrombus formation on collagen-I and other surfaces (30).
ITGA2B and ITGB3 gene mutations associated with Glanzmann thrombasthenia
Published in Platelets, 2018
Alan T. Nurden, Xavier Pillois
In type I or type II GT there is no evidence to relate the nature of the mutation with the extent of bleeding; once platelets have insufficient αIIbβ3 to allow aggregation other genetic and epidemiological factors control disease severity; the identification of these factors should now be a priority [5]. Both ITGA2B and ITGB3 are highly polymorphic genes and genetic variants are widespread in the general population; for example, 114 heterozygous missense mutations were detected in ITGA2B and 68 in ITGB3 after whole exome or whole genome analysis of more than 16,000 individuals [10]. The rarity of their minor allele frequencies suggested the bulk to be of recent origin. Our analysis of all synonymous and non-synonymous single nucleotide polymorphisms within the “Genoscope” GT cohort showed that multiple GT-causing mutations shared haplogroups that spread across families of wide geographical origins; a result that agrees with many GT-causing mutations being contemporary [18]. So outside ethnic groups the GT genotype will be constantly changing. Not least, studies on ITGA2B and ITGB3 are important for their encoded proteins give rise to αIIbβ3 and, for ITGB3, αvβ3; receptors with wide implications not only for bleeding but also for cancer, inflammation, cardiovascular disease and many key biological processes [5,19,20].
Screening and diagnosis of inherited platelet disorders
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Alex Bourguignon, Subia Tasneem, Catherine P. Hayward
Several platelet disorders result from mutations of platelet receptors that increase ligand binding, which interestingly, manifest with bleeding and not thrombosis. For example, gain-of-function mutations of GPIbα that increase von Willebrand factor (VWF) binding cause platelet-type von Willebrand disease (VWD) [38,107]. Activating mutations of the αIIb or β3 chain of αIIbβ3 cause ITGA2B/ITGB3-related thrombocytopenia, also known as variant GT, a dominant PFD that impairs platelet cytoskeletal rearrangement, reduces αIIbβ3 expression on platelets, and impairs platelet aggregation [108].