Inter-ethnic differences in genetic variants within the transmembrane protease, serine 6 (TMPRSS6) gene associated with iron status indicators: a systematic review with meta-analyses

Abstract

Transmembrane protease, serine 6 (TMPRSS6), is likely to be involved in iron metabolism through its pleiotropic effect on hepcidin concentrations. Recently, genome-wide association studies have identified common variants in the TMPRSS6 gene to be linked to anaemia and low iron status. To get a more precise evaluation of identified TMPRSS6 single nucleotide polymorphism associations with iron status in cohorts of differing continental ancestry, we conducted a systematic review with metaanalyses. We searched the literature using HuGE Navigator, Pubmed and Scopus databases for primarily genomewide association studies using TMPRSS6 as a free term. Fixed-effects meta-analysis was used to obtain summary estimates of associations. Eleven studies comprised Caucasian populations, four included an Asian population and one study included an African-American population. Differences in minor allele frequencies of 8 TMPRSS6 SNPs (rs855791, rs4820268, rs2111833, rs1421312, rs228921, rs228918, rs228919 and rs575620) across ethnic groups were observed, with the MAF of rs855791 significantly higher in Asian populations than in Caucasians (0.55 vs 0.42, P \ 0.0001). In the meta-analysis, the A allele of rs855791 was associated with lower Hb and ferritin concentrations in all populations. This allele was also associated with increased serum transferrin receptor and transferrin concentrations. We observed similar associations for the G allele in rs4820268. Clear disparities in associations were found for the African-American population, although not statistically significant. Associations between TMPRSS6 SNPs and anaemia are consistent across Caucasian and Asian populations. This study highlights the need to conduct studies in African populations where iron deficiency is of utmost public health significance.

Iron deficiency: new insights into diagnosis and treatment

“…Genome Wide Association Studies, including a recent meta-analysis, indicate that TMPRSS6 genetic variants associate with red cell and iron traits in Caucasian and Asian populations. [21][22][23] The most common associated TMPRSS6 variant (rs855791, A736V) influences serum hepcidin levels. 24 The genetic susceptibility to iron deficiency is of special interest for transfusion medicine because it has implications for blood donation.…”

The V736A TMPRSS6 polymorphism influences liver iron concentration in nontransfusion‐dependent thalassemias

“…We identified three novel (p.Asp680Glufs*111; IVS13 1 1G>A; and p.Arg678Pro) and two already known [3,4] (p.Arg30Profs*31 and p.A621_Q624delAVAQ) TFR2 mutations associated with a juvenile-like clinical presentation in three young women (clinical, biochemical, and molecular data at diagnosis are summarized in Supporting Information Table S1). None of the probands had other known factors able to aggravate iron accumulation.…”

“…Some studies have indicated that TMPRSS6 polymorphisms directly affect hepcidin transcription, while others have suggested that the polymorphisms may addictionally influence iron homeostasis by mechanisms independent of hepcidin expression. The latter theory could explain why rs855791 has not been found to be significantly associated with serum hepcidin in some studies [3].…”

“…Some studies have indicated that TMPRSS6 polymorphisms directly affect hepcidin transcription, while others have suggested that the polymorphisms may addictionally influence iron homeostasis by mechanisms independent of hepcidin expression. The latter theory could explain why rs855791 has not been found to be significantly associated with serum hepcidin in some studies [3].In this study, we evaluated the influence of rs855791 on liver iron concentration (LIC) in patients with different levels of ineffective erythropoiesis: mild and severe thalassemia intermedia (TI) and Hemoglobin H (HbH) disease patients, which are clinically distinct forms of the so-called nontransfusion-dependent thalassemias (NTDTs), a term used to label patients who do not require regular transfusion for survival. We classified TI in agreement with the extent of imbalance between the alpha and non alpha globin chains.…”

“…The common rs855791 polymorphism (NM_153609.3:c.2207C>T) causes a nonsynonymous valine to alanine change (p.V736A), and the T allele (encoding valine) has been associated with lower hemoglobin and ferritin concentrations as well as increased serum transferrin receptor and transferrin concentrations in all populations [3]. Moreover, this polymorphism influences iron overload in hereditary hemochromatosis as well as the development of nonalcoholic fatty liver disease [4,5] and it has been associated with iron deficiency anemia in women of reproductive ages [6].…”