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Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples sequenced using approaches that cover the whole genome, whole exome or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germline variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and novel population-based associations to increase the accuracy of CHIP calls. We apply this approach to ascertain CHIP in ∼550,000 individuals in the UK Biobank complete whole exome cohort and the All of Us Research Program initial whole genome release cohort. CHIP ascertainment on this scale unmasks recurrent artifactual variants and highlights the importance of specialized filtering approaches for several genes includingTET2andASXL1. We show how small changes in filtering parameters can considerably increase CHIP misclassification and reduce the effect size of epidemiological associations. Our high-fidelity call set refines prior population-based associations of CHIP with incident outcomes. For example, the annualized incidence of myeloid malignancy in individuals with small CHIP clones is 0.03%/year, which increases to 0.5%/year amongst individuals with very large CHIP clones. We also find a significantly lower prevalence of CHIP in individuals of self-reported Latino or Hispanic ethnicity in All of Us, highlighting the importance of including diverse populations. The standardization of CHIP calling will increase the fidelity of CHIP epidemiological work and is required for clinical CHIP diagnostic assays.

Elevated plasma plasminogen activator inhibitor-1 (PAI-1) concentration is associated with cardiovascular disease risk. PAI-1 is the primary inhibitor of fibrinolysis within both the circulation and the arterial wall, playing roles in both atherosclerosis and thrombosis. To define the heritable component, subjects within the population-based SHARE (Study of Health Assessment and Risk in Ethnic groups) and SHARE-AP (Study of Health Assessment and Risk Evaluation in Aboriginal Peoples) studies, composed of Canadians of South Asian (n = 298), Chinese (n = 284), European (n = 227), and Aboriginal (n = 284) descent, were genotyped using the gene-centric Illumina HumanCVD BeadChip. After imputation, more than 150 000 single nucleotide polymorphisms (SNPs) in more than 2000 loci were tested for association with plasma PAI-1 concentration. Marginal association was observed with the PAI-1 locus itself (SERPINE1; P < .05). However, 5 loci (HABP2, HSPA1A, HYAL1, MBTPS1, TARP) were associated with PAI-1 concentration at a P < 1 × 10−5 threshold. The protein products of 2 of these loci, hyaluronan binding protein 2 (HABP2) and hyaluronoglucosaminidase 1 (HYAL1), play key roles in hyaluronan metabolism, providing genetic evidence to link these pathways.

Background: The common genetic test for hemochromatosis involves the genotyping of two polymorphisms in the HFE gene (C282Y and H63D). Current guidelines suggest testing of patients with ferritin greater than 300 µg/L and transferrin saturation greater than 45%. Testing of first degree relatives of confirmed HFE positive cases is also endorsed. However, the current test has poor sensitivity and specificity for iron overload causing end organ damage. We sought to evaluate biochemical parameters of patients referred for HFEtesting and identify those who received phlebotomy. Methods: After receiving ethics approval, electronic charts of patients referred to Hamilton Health Sciences, Hamilton, Ontario, Canada for HFE genetic testing between January 1, 2012 and December 31, 2012 were reviewed. Results: HFE genetic testing in 642 patients yielded 100 (15.6%) positive C282Y homozygote or C282Y/H63D compound heterozygote results. In patients with biochemical markers of iron overload available (n=160), patients with a risk HFE genotype had significantly higher iron saturation, serum iron, and hemoglobin (P 45% and ferritin > 300). Of patients who required phlebotomy, only 27 of 40 (67.5%) were HFEpositive. Conclusion: Many factors affect the decision to phlebotomize a patient with suspected iron overload. However, it appears that most of the current HFE genetic testing being performed did not alter patient management. Disclosures Crowther: Asahi Kasai: Membership on an entity's Board of Directors or advisory committees; Bayer: Speakers Bureau; Celgene: Speakers Bureau; Shire: Speakers Bureau; Boehriniger Ingelheim: Consultancy; CSL Behring: Speakers Bureau; Leo Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Membership on an entity's Board of Directors or advisory committees; Viropharma: Membership on an entity's Board of Directors or advisory committees.