Hematological traits are important medical parameters. novel missense or splice site variants in important hematopoiesis regulators (p.Val617Phe mutation and platelet count (and (rs62483572 p.Asp70Asn) that encodes the main cytokine that settings erythrocyte production and lower hematocrit and hemoglobin levels (Fig. 1A and Table 1). Carriers of the missense variant experienced 0.35 g/dl lesser hemoglobin and 1% lesser hematocrit compared to noncarriers. To our knowledge the p.Asp70Asn variant is the 1st naturally-occurring coding variant associated with any hematologic phenotype. In the mature EPO protein p.Asp70Asn (amino acid 43 after cleavage of the signal peptide) is part of the high-affinity receptor binding site (Supplementary Fig. 4)4. Rare gain-of-function coding variants of the erythropoietin receptor gene (is located near transferrin receptor 2 (region are associated Rabbit polyclonal to OSGEP. with red blood cell phenotypes3. Conditional analysis around the sentinel SNP is usually independently associated with hematocrit and hemoglobin (Fig. 1A). This conditional analysis also identified a low-frequency 5’ donor splice site variant of (rs139178017) independently associated with higher hematocrit and hemoglobin (Fig. 1A and Supplementary Table 2). Other splice site variants have been reported in patients with atypical (mutation unfavorable) hemochromatosis6 7 Physique 1 Association results in the meta-analysis MHI+WHI (N=24 814 for (A) hematocrit at the locus on chromosome 7 and (B) platelet count at the locus on chromosome 12. The gene (variant was previously identified in Mediterranean patients with β°-thalassemia8 which may explain why it is present in North American cohorts (MHI and WHI) due to immigration but absent from Northern Germany SHIP. Using criteria from the World Health Business to define anemia (hemoglobin <12 g/dl in women and <13 g/dl in men) we confirmed that this p.Asp70Asn variant is HOE-S 785026 usually associated with clinical anemia in the combined analysis of MHI+WHI (1 866 cases and 22 397 controls odds ratio=1.7 splice variant is likewise strongly associated with clinical anemia (odds ratio = 36.1 (which encodes a megakarocyte-specific form of β-tubulin a microtubule protein involved in pro-platelet production) cause autosomal dominant macrothrombcytopenia in humans (MIM 612901) and Cavalier King Charles Spaniel dogs9. We HOE-S 785026 report a new low-frequency missense variant (rs41303899 p.Gly109Glu MAF=0.16%) associated with μ33 0 lower mean platelet count HOE-S 785026 (Table 1). The rs41303899-platelet count association is usually impartial from a common missense variant (rs6070697 p.Arg307His MAF=18% Supplementary Table 3) previously associated with mean platelet volume (for rs41303899 meta-analysis p.Val617Phe is the main cause of myeloproliferative neoplasms (MPNs)10-13. In our discovery sample p.Val617Phe was strongly associated with platelet count (p.Val617Phe was rare in MHI and WHI (MAF=0.05%) consistent with prior frequency estimates obtained by whole-exome sequencing14 or allele-specific PCR15 using peripheral blood samples from unselected individuals. The clinical characteristics serial blood counts and clinical follow-up information obtained for the 19 mutation carriers in the MHI and WHI studies suggest early-stage MPN in these individuals and also exemplify the phenotypic diversity of the p.Val617Phe mutation (Supplementary Table 5). Notably the frequency of the p.Val617Phe mutation appeared to be 10-fold higher in SHIP (MAF=0.4%) (Table 1); however this spuriously high frequency value resulted from genotype mis-calling as inspection of the genotyping intensity plots does not HOE-S 785026 reveal clearly distinguishable clusters (Supplementary Fig. 5). These observations are consistent with both the variable sensitivity to p.Val617Phe detection across genotyping platforms and also heterogeneity of allelic burden across individuals16 17 These issues raise a number of complexities to be considered in the decision to return results of such incidental findings to research participants. encodes the adaptor protein LNK which regulates T and B cell development and myelopoiesis18. LNK inhibits JAK2-STAT and other downstream signaling pathways to modulate hematopoietic cytokine receptor signaling19. Both somatic and germline mutations in have been reported in patients with MPNs20 21 In addition to confirming the association of a missense SNP (rs3184504 p.Trp262Arg MAF=50%) with all four.