Common variants in TMPRSS6 are associated with iron status and erythrocyte volume.
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ABSTRACT:
SUBMITTER: Benyamin B
PROVIDER: S-EPMC3135421 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
Publications
Common variants in TMPRSS6 are associated with iron status and erythrocyte volume.
Benyamin Beben B Ferreira Manuel A R MA Willemsen Gonneke G Gordon Scott S Middelberg Rita P S RP McEvoy Brian P BP Hottenga Jouke-Jan JJ Henders Anjali K AK Campbell Megan J MJ Wallace Leanne L Frazer Ian H IH Heath Andrew C AC de Geus Eco J C EJ Nyholt Dale R DR Visscher Peter M PM Penninx Brenda W BW Boomsma Dorret I DI Martin Nicholas G NG Montgomery Grant W GW Whitfield John B JB
Nature genetics 20091011 11
We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5 x 10(-20)), transferrin saturation (combined P = 2.2 x 10(-23)) and erythrocyte mean cell volume (MCV, combined P = 1.1 x 10(-10)). We also find suggestive evidence of association with blood hemoglobin levels (combined P = 5.3 x 10(-7)). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis. ...[more]
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Project description:BackgroundGenome-wide association studies have convincingly shown that single nucleotide polymorphisms (SNPs) in HFE and TMPRSS6 are associated with iron parameters. It was commonly thought that these associations could be explained by the intermediate effect on hepcidin concentration. A recent study in an isolated Italian population, however, concluded that these associations were not exclusively dependent on hepcidin values. We report here the second study to investigate the role of hepcidin in the associations between common variants in HFE and TMPRSS6 with iron parameters.MethodsWe extracted 101 SNPs in HFE and TMPRSS6 from genome-wide imputed SNP data of 1832 individuals from the general population (Nijmegen Biomedical Study). Single locus and haplotype associations with serum iron parameters and hepcidin were studied using linear regression analyses.ResultsWe found that HFE rs1800562 and TMPRSS6 rs855791 are the main determinants of HFE and TMPRSS6 related variation in serum iron, ferritin, transferrin saturation, and total iron binding capacity. These SNPs are associated with the ratios hepcidin/ferritin (p<1×10(-5)) and hepcidin/transferrin saturation (p<1×10(-3)), but not with serum hepcidin (p>0.2). Adjustment for hepcidin or the ratio hepcidin/ferritin did not decrease the strength of the SNP-iron parameter associations.ConclusionsOur results do not support an intermediate role for hepcidin in the SNP-iron parameter associations, which confirms previous findings, and indicate a pleiotropic SNP effect on the hepcidin ratios and the iron parameters. Taken together, this suggests that there might be other, yet unknown, serum hepcidin independent mechanisms which play a role in the association of HFE and TMPRSS6 variants with serum iron parameters.
| S-EPMC7784039 | biostudies-literature
Project description:BackgroundThe role of genetic determinants in mediating iron status in Africans is not fully understood. Genome-wide association studies in non-African populations have revealed genetic variants in the transmembrane protease serine 6 gene (TMPRSS6) that are associated with the risk of anemia.ObjectivesTo investigate the effects of risk alleles for low iron status, namely TMPRSS6 rs2235321, rs855791, and rs4820268, on responses to oral iron in healthy Gambian adults.MethodsUsing a recall-by-genotype design, participants were selected from a pregenotype cohort of 3000 individuals in the Keneba Biobank (Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine). Participants were invited to participate in the study based on 9 genotype combinations obtained from 3 TMPRSS6 single nucleotide polymorphisms (SNPs): rs2235321, rs855791, and rs4820268. The participants fasted overnight and then ingested a single oral dose of ferrous sulfate (130 mg elemental iron). Blood samples were collected prior to iron ingestion and at 2 and 5 h after the oral iron dose. The effects of genotype on hepcidin and plasma iron parameters were assessed.ResultsA total of 251 individuals were enrolled. Homozygous carriers of the major TMPRSS6 alleles at each of the SNPs had higher plasma hepcidin at baseline (rs2235321: GG compared with AA = 9.50 compared with 6.60 ng/ml, P = 0.035; rs855791: GG compared with AG = 9.50 compared with 4.96 ng/mL, P = 0.015; rs4820268: AA compared with GG = 9.50 compared with 3.27 ng/mL, P = 0.002) and at subsequent timepoints. In most subjects, hepcidin concentrations increased following iron ingestion (overall group mean = 4.98 ± 0.98 ng/mL at 5 h, P < 0.001), but double heterozygotes at rs2235321 and rs855791 showed no increase (0.36 ± 0.40 ng/mL at 5 h, P = 0.667).ConclusionsThis study revealed that common TMPRSS6 variants influence hepcidin concentrations, but not iron status indicators either at baseline or following a large oral dose of iron. These results suggest that genetic variations in the TMPRSS6 gene are unlikely to be important contributors to variations in iron status in Africans.This study was registered at clinicaltrials.gov (# NCT03341338).
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