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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 meta-analyses. We searched the literature using HuGE Navigator, Pubmed and Scopus databases for primarily genome-wide 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.

SUBMITTER: Gichohi-Wainaina WN

PROVIDER: S-EPMC4240767 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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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.

Gichohi-Wainaina Wanjiku N WN Towers G Wayne GW Swinkels Dorine W DW Zimmermann Michael B MB Feskens Edith J EJ Melse-Boonstra Alida A

Genes & nutrition 20141122 1

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 meta-analyses. ...[more]

PMID: 25416640

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Project description:PURPOSE:Matriptase-2 (also known as TMPRSS6) is a critical regulator of the iron-regulatory hormone hepcidin in the liver; matriptase-2 cleaves membrane-bound hemojuvelin and consequently alters bone morphogenetic protein (BMP) signaling. Hemojuvelin and hepcidin are expressed in the retina and play a critical role in retinal iron homeostasis. However, no information on the expression and function of matriptase-2 in the retina is available. The purpose of the present study was to examine the retinal expression of matriptase-2 and its role in retinal iron homeostasis. METHODS:RT-PCR, quantitative PCR (qPCR), and immunofluorescence were used to analyze the expression of matriptase-2 and other iron-regulatory proteins in the mouse retina. Polarized localization of matriptase-2 in the RPE was evaluated using markers for the apical and basolateral membranes. Morphometric analysis of retinas from wild-type and matriptase-2 knockout (Tmprss6(msk/msk) ) mice was also performed. Retinal iron status in Tmprss6(msk/msk) mice was evaluated by comparing the expression levels of ferritin and transferrin receptor 1 between wild-type and knockout mice. BMP signaling was monitored by the phosphorylation status of Smads1/5/8 and expression levels of Id1 while interleukin-6 signaling was monitored by the phosphorylation status of STAT3. RESULTS:Matriptase-2 is expressed in the mouse retina with expression detectable in all retinal cell types. Expression of matriptase-2 is restricted to the apical membrane in the RPE where hemojuvelin, the substrate for matriptase-2, is also present. There is no marked difference in retinal morphology between wild-type mice and Tmprss6(msk/msk) mice, except minor differences in specific retinal layers. The knockout mouse retina is iron-deficient, demonstrable by downregulation of the iron-storage protein ferritin and upregulation of transferrin receptor 1 involved in iron uptake. Hepcidin is upregulated in Tmprss6(msk/msk) mouse retinas, particularly in the neural retina. BMP signaling is downregulated while interleukin-6 signaling is upregulated in Tmprss6(msk/msk) mouse retinas, suggesting that the upregulaton of hepcidin in knockout mouse retinas occurs through interleukin-6 signaling and not through BMP signaling. CONCLUSIONS:The iron-regulatory serine protease matriptase-2 is expressed in the retina, and absence of this enzyme leads to iron deficiency and increased expression of hemojuvelin and hepcidin in the retina. The upregulation of hepcidin expression in Tmprss6(msk/msk) mouse retinas does not occur via BMP signaling but likely via the proinflammatory cytokine interleukin-6. We conclude that matriptase-2 is a critical participant in retinal iron homeostasis.

Dataset Information

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.

Publications

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.

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