Common Variants in the TMPRSS6 Gene Alter Hepcidin but not Plasma Iron in Response to Oral Iron in Healthy Gambian Adults: A Recall-by-Genotype Study

Abstract

Background The 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 TMPRSS6 gene that are associated with the risk of anemia. Objectives To investigated the effects of risk alleles for low iron status from TMPRSS6 rs2235321, rs855791 and rs4820268, on responses to oral iron in healthy Gambian adults. Methods Using a recall-by-genotype design, participants were selected from a pre-genotype cohort of 3000 individuals in the Keneba Biobank (MRCG at LSHTM). Participants were invited to participate in the study based on nine genotype combinations obtained from three TMPRSS6 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 hours after the oral iron dose. The effects of genotype on hepcidin and plasma iron parameters were assessed. Results A 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 vs AA 9.50 vs 6.60ng/ml, p = 0.035; rs855791: GG vs AG = 9.50 vs 4.96ng/mL, p = 0.015; rs4820268: AA vs GG = 9.50 vs 3.27ng/mL, p = 0.002) and at subsequent timepoints. There were no differences in delta plasma iron (a proxy for iron absorption) between genotypes. In most subjects, hepcidin levels increased following iron ingestion (overall group mean = 4.98 ± 0.98ng/ml at 5h, p < 0.001), but double heterozygotes at rs2235321 and rs855791 showed no increase (0.36 ± 0.40ng/ml at 5h, p = 0.667). Conclusions This 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.

TMPRSS6 gene polymorphisms associated with iron deficiency anaemia among global population

“…Meanwhile, among the female black South African, rs228918 and rs228921were identified and associated with increased soluble transferrin receptor (sTfR) concentration with homozygous (GG) allele combination compared to the combination of allele AA, reflecting the low iron status [61]. In contrast, healthy African-Gambian adults reported no significant association of genotype SNPs (rs855791, rs4820268 and rs2235321) with SI and haematological traits before and after the iron supplementation [62]. However, Jallow et al [60] studied the effect of genotyped SNPs on the hepcidin concentration during pre-and post-iron supplementation.…”

“…In human GWAS, common genetic variations of TMPRSS6 have been linked to erythrocyte and iron parameters [15,18,59,61,69]. The SNP rs855791 has recently been identified as the top-hit in GWAS linked to changes in SI, TS, erythrocyte MCV, Hb levels, and glycated Hb levels [62,64]. The population frequency of the single nucleotide polymorphism (SNP) rs855791 of TMPRSS6 is approximately 0.5 in Caucasians [16,53], ≈0.6 in Japanese [51], and ≈0.2-0.1 in African Americans.…”

Iron supplementation of breastfed Gambian infants from 6 weeks to 6 months of age: protocol for a randomised controlled trial

“…Infancy (red diamonds; analysis of stored samples 11 . Childhood and adulthood (light green diamonds); unpublished analysis from the Keneba Biobank 12 .…”