The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption – A stable iron isotope study in Taiwanese women

Abstract

Genome wide studies have associated TMPRSS6 rs855791 (2321 C>T) with iron status and hepcidin. It is unclear whether this polymorphism affects iron absorption. We administered standardized rice-based test meals containing 4 mg of labeled 57Fe or 58Fe as FeSO4 on alternate days in non-anemic Taiwanese women (n=79, 44 TT variant, 35 CC variant). Fractional iron absorption was measured by erythrocyte incorporation of the tracers 14 days after administration. Compared to the CC variant, iron and transferrin saturation were lower (P=0.001; P<0.001, respectively) and serum hepcidin/transferrin saturation and serum hepcidin/serum iron ratios were higher (P=0.042; P=0.088, respectively) in the TT variant. Serum hepcidin did not differ between the groups (P=0.862). Geometric mean (95% Confidence Interval [CI]) fractional iron absorption, corrected to a serum ferritin of 15 mg/L, was 26.6% (95% CI: 24.0-29.5) in the CC variant and 18.5% (95% CI: 16.2-21.1) in the TT variant (P=0.002). Overall, predictors of iron absorption were: serum ferritin (P<0.001); genetic variant (P=0.032); and hepcidin (P<0.001). In the models by variant, in the CC variant the model explained 67-71% of variability in absorption and serum ferritin was the only significant predictor (P<0.001); while in the TT variant, the model explained only 35-43% of variability, and hemoglobin (P=0.032), soluble transferrin receptor (P=0.004) and hepcidin (P<0.001) were significant predictors. Women with the TMPRSS6 rs855791 (2321 C>T) polymorphism show altered iron homeostasis which affects oral iron absorption and may increase their risk for iron deficiency. The trial was registered as clinicaltrials gov. Identifier: NCT03317873, and funded by the Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, (grant CMRPG8F0721) and ETH Zurich, Switzerland.