Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels

Abstract

We carried out a genome-wide association study of hemoglobin levels in 16,001 individuals of European and Indian Asian ancestry. The most closely associated SNP (rs855791) results in nonsynonymous (V736A) change in the serine protease domain of TMPRSS6 and a blood hemoglobin concentration 0.13 (95% CI 0.09–0.17) g/dl lower per copy of allele A (P = 1.6 × 10−13). Our findings suggest that TMPRSS6, a regulator of hepcidin synthesis and iron handling, is crucial in hemoglobin level maintenance.

Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice

“…In humans, genomewide association studies show that common TMPRSS6 variants influence iron parameters, Hb, and erythrocyte traits. [7][8][9][10] All these findings suggest that susceptibility to iron deficiency may be modulated by TMPRSS6 mutations even at the heterozygous state. …”

The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice

“…[22][23][24][25][26][27] By studying Tmprss6 haploinsufficient mice 28 and hepcidin levels of normal individuals and the TMPRSS6 common single nucleotide polymorphism (rs855791) 29 we demonstrated that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis.…”

“…[22][23][24][25][26][27] By studying Tmprss6 haploinsufficient mice 28 and hepcidin levels of normal individuals and the TMPRSS6 common single nucleotide polymorphism (rs855791) 29 we demonstrated that even a partial inability to modulate hepcidin influences iron parameters and, indirectly, erythropoiesis.The regulation of TMPRSS6 and its activity is incompletely understood: besides hypoxia, 30 iron and BMP6, through the BMP-SMAD pathway, induce TMPRSS6 expression, likely as a negative feedback loop to limit excessive increases of HAMP. 31 However, the regulation of TMPRSS6 in vivo according to iron needs remains to be clarified.…”

Common genetic factors for hematological traits in Humans

“…Associations at the TMPRSS6 locus Large-scale GWAS for RBC-related hematological traits were first conducted in European populations, [28][29][30][31][32] and then in a Japanese population. 34 These studies identified dozens of novel loci, including the TMPRSS6 locus.…”