Abstract
The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5–10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E–09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.
Highlights
Erythrocytes comprise 40–50% of blood volume and are key components for the transport of oxygen and carbon dioxide for cellular respiration
GWAS of haemoglobin concentration and related parameters was performed in 1664 genotyped individual from INGI-VB and many of the SNPs previously identified [15,16,17] as associated to RBC related traits were replicated
We report here a new locus, associated with mean corpuscular hemoglobin concentration (MCHC) levels identified by GWAS of red blood cell traits in the INGI-VB founder population
Summary
Erythrocytes comprise 40–50% of blood volume and are key components for the transport of oxygen and carbon dioxide for cellular respiration. In healthy individuals the red blood cellrelated traits (hemoglobin (Hb), hematocrit (Hct), red cell count (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC)) are variable and are determined by both inherited and environmental factors. A better knowledge of the inherited factors determining variation of erythrocyte traits will be relevant to understand the physiology of red blood cell production and the relationship between red cell size and Hb content. This might have implication for the so-called anemia of the elderly [2,3,4] contributing to cognitive impairment and impaired physical capacity in older people
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