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. 2012 May;87(5):461-74.
doi: 10.1016/j.mayocp.2012.01.016.

Genetic Loci implicated in erythroid differentiation and cell cycle regulation are associated with red blood cell traits

Keyue Ding  1 , Khader Shameer, Hayan Jouni, Daniel R Masys, Gail P Jarvik, Abel N Kho, Marylyn D Ritchie, Catherine A McCarty, Christopher G Chute, Teri A Manolio, Iftikhar J Kullo
Affiliations

Genetic Loci implicated in erythroid differentiation and cell cycle regulation are associated with red blood cell traits

Keyue Ding et al. Mayo Clin Proc. 2012 May.

Abstract

Objective: To identify common genetic variants influencing red blood cell (RBC) traits.

Patients and methods: We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record-based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss.

Results: We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells.

Conclusion: Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits.

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Figures

FIGURE 1
FIGURE 1
Manhattan plots for genomewide association analysis of red blood cell (RBC) traits. The vertical axis indicates (–log10 transformed) observed P values, and the horizontal line indicates the genomewide significance level of P<5E-08. HCT = hematocrit; HGB = hemoglobin; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume.
FIGURE 2
FIGURE 2
Regional plots of 4 novel loci associated with red blood cell (RBC) traits on chromosomes 3p24.2 (mean corpuscular volume [MCV]), 15q22.3 (mean corpuscular hemoglobin [MCH]), 16q24.2 (mean corpuscular hemoglobin concentration [MCHC]), and 16q24.3 (MCHC). Single-nucleotide polymorphisms (SNPs) are plotted by position on the chromosome (x-axis) vs association with RBC traits (–log10P value) on the y-axis. The rs number for the most significant SNP in the joint analysis is shown on the plot. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local linkage disequilibrium (LD) structure. The SNPs near the most significant SNP are color coded to reflect their LD with this SNP (taken from pairwise r2 values from the HapMap CEU data). Genes, the position of exons and the direction of transcription from the University of California, Santa Cruz genome browser are also plotted. ▾ = nonsynonymous; • = no annotation; ☒ = conserved in mammals; * = conserved TFBS (transcription factor binding site). cM/Mb = centimorgan/megabase; Mb = megabase.
FIGURE 3
FIGURE 3
Genes implicated in erythroid differentiation are associated with red blood cell (RBC) traits. Three novel genes (THRB, PTPLAD1, CDT1) shaded in blue and 6 replicated loci (KLF1, ALDH8A1, SPTA1, FBXO7, CCND3, TFR2/EPO) shaded in brown are shown. A, Different stages of erythroid differentiation. Hematopoietic stem cells committed to erythroid lineage, followed by erythroid terminal differentiation (from burst-forming units–erythroid [BFU-E] to RBC). Adapted and modified from Curr Opin Hematol, with permission. B, Genes involved in regulation of cell cycle (M, G1, S, and G2 phase). The inserted table lists the 3 novel genes associated with RBC traits in the present study. Adapted from J Mol Cell Biol, with permission. Baso EB = basophilic erythoblasts; HSC = hematopoietic stem cell; CFU_E = colony-forming units—erythroid; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; ORC = origin of replicative complex; Ortho EB = orthochromatic erythroblast; Poly EB = polychromatic erythroblasts; Pro EB = proerythroblasts; RET = reticulocytes; (?) = indicates expression stage cannot be specified.
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References

    1. Ascenzi P., Bellelli A., Coletta M. Multiple strategies for O2 transport: from simplicity to complexity. IUBMB Life. 2007;59(8-9):600–616. - PubMed
    1. Sarnak M.J., Tighiouart H., Manjunath G. Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol. 2002;40(1):27–33. - PubMed
    1. Lin J.P., O'Donnell C.J., Jin L., Fox C., Yang Q., Cupples L.A. Evidence for linkage of red blood cell size and count: genome-wide scans in the Framingham Heart Study. Am J Hematol. 2007;82(7):605–610. - PubMed
    1. Ganesh S.K., Zakai N.A., van Rooij F.J. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet. 2009;41(11):1191–1198. - PMC - PubMed
    1. Soranzo N., Spector T.D., Mangino M. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet. 2009;41(11):1182–1190. - PMC - PubMed

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