Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

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.

Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression

“…A GWAS study reported that an SNP (rs11107) causing a Met115Ile change in Fbxo7 is associated with a 0.35-fl decrease in MCV [11]. Given our findings, we tested whether p27 binding was sensitive to this residue in Fbxo7.…”

Genetic Variants That Confer Resistance to Malaria Are Associated with Red Blood Cell Traits in African-Americans: An Electronic Medical Record-based Genome-Wide Association Study

“…To do this, we employed a previously developed algorithm based on billing codes and natural language processing of unstructured clinical notes to exclude RBC traits values affected by comorbidities, medications, or blood loss (Ding et al 2012; Kullo et al 2010, 2011). The phenotyping algorithm is available online (www.gwas.org), and the values of RBC traits before and after implementing the algorithm are provided in Supporting Information, Table S1).…”

“…Genome-wide association studies (GWAS) have revealed multiple loci that influence interindividual variation in RBC traits in individuals of European and Asian ancestry (Ding et al 2012; Ganesh et al 2009; Kamatani et al 2010; Kullo et al 2010; Soranzo et al 2009). Whether these and additional novel loci influence RBC traits in individuals of recent African ancestry is unknown.…”

“…The network (www.gwas.org) was established by the National Human Genome Research Institute to develop and implement approaches for leveraging biorepositories associated with EMR systems for large-scale genomic research (Kho et al 2011; Manolio 2009; McCarty et al 2011). We have previously reported results of a GWAS for RBC traits in 3012 patients of European ancestry in the Mayo eMERGE cohort (Kullo et al 2011), and in 12,486 patients of European ancestry from the entire eMERGE network (Ding et al 2012). We investigated whether loci identified in these and other cohorts of European and Asian ancestry were associated with RBC traits in African-Americans.…”

MicroRNA 200a inhibits erythroid differentiation by targeting PDCD4 and THRB

“…Previous studies revealed that adding T3 to the culture medium of erythroid progenitors promoted erythroid differentiation (Angelin-Duclos et al, 2005). A genome-wide association study indicated that an intronic single nucleotide polymorphism (rs9310736) in THRB was significantly associated with mean corpuscular volume (Ding et al, 2012). These data implied that THRB plays a role in erythroid differentiation.…”