Abstract:Iron deficiency anaemia is a major health problem affecting approximately 1.2 billion people worldwide. Young children, women of reproductive age and pregnant women living in sub-Saharan Africa are the most vulnerable. It is estimated that iron deficiency accounts for half of anaemia cases. Apart from nutritional deficiency, infection, inflammation and genetic factors are the major drivers of anaemia. However, the role of genetic risk factors has not been thoroughly investigated. This is particularly relevant … Show more
“…1 ). Among the SNPs we investigated, TMPRSS6 rs2235324 had the highest minor allele frequency (MAF) in our study population (45%), and TMPRSS6 rs855791 and TF rs1799852 had the lowest MAF (7% each) 24 . Figure 1 Linkage disequilibrium analysis between SNPs investigated in this study.…”
Section: Resultsmentioning
confidence: 84%
“…This study population was genotyped using the Illumina Infinium 240 K Human Exome Beadchip (v1.0 and v1.1), as previously described 24 , in which 848 SNPs were genotyped. Genotype calling was performed using data-driven clustering (Genome Studio, Illumina, CA, USA).…”
Section: Methodsmentioning
confidence: 99%
“…Despite efforts to identify genetic risk factors for anaemia, very few such studies have been reported from sub-Saharan Africa 24 . To the best of our knowledge, no study has been done in West Africa to assess the effects of genetic variants in hepcidin and iron regulatory genes on low iron status.…”
Genome-wide association studies in Europeans and Asians have identified numerous variants in the transmembrane protease serine 6 (TMPRSS6) and transferrin (TF) genes that are associated with changes in iron status. We sought to investigate the effects of common TMPRSS6 and TF gene SNPs on iron status indicators in a cohort of healthy Africans from rural Gambia. We measured iron biomarkers and haematology traits on individuals participating in the Keneba Biobank with genotype data on TMPRSS6 (rs2235321, rs855791, rs4820268, rs2235324, rs2413450 and rs5756506) and TF (rs3811647 and rs1799852), n = 1316. After controlling for inflammation, age and sex, we analysed the effects of carrying either single or multiple iron-lowering alleles on iron status. TMPRSS6 rs2235321 significantly affected plasma hepcidin concentrations (AA genotypes having lower hepcidin levels; F ratio 3.7, P = 0.014) with greater impact in individuals with low haemoglobin or ferritin. No other TMPRSS6 variant affected hepcidin. None of the TMPRSS6 variants nor a TMPRSS6 allele risk score affected other iron biomarkers or haematological traits. TF rs3811647 AA carriers had 21% higher transferrin (F ratio 16.0, P < 0.0001), 24% higher unsaturated iron-binding capacity (F ratio 12.8, P < 0.0001) and 25% lower transferrin saturation (F ratio 4.3, P < 0.0001) compared to GG carriers. TF rs3811647 was strongly associated with transferrin, unsaturated iron-binding capacity (UIBC) and transferrin saturation (TSAT) with a single allele effect of 8–12%. There was no association between either TF SNP and any haematological traits or iron biomarkers. We identified meaningful associations between TMPRSS6 rs2235321 and hepcidin and replicated the previous findings on the effects of TF rs3811647 on transferrin and iron binding capacity. However, the effects are subtle and contribute little to population variance. Further genetic and functional studies, including polymorphisms frequent in Africa populations, are needed to identify markers for genetically stratified approaches to prevention or treatment of iron deficiency anaemia.
“…1 ). Among the SNPs we investigated, TMPRSS6 rs2235324 had the highest minor allele frequency (MAF) in our study population (45%), and TMPRSS6 rs855791 and TF rs1799852 had the lowest MAF (7% each) 24 . Figure 1 Linkage disequilibrium analysis between SNPs investigated in this study.…”
Section: Resultsmentioning
confidence: 84%
“…This study population was genotyped using the Illumina Infinium 240 K Human Exome Beadchip (v1.0 and v1.1), as previously described 24 , in which 848 SNPs were genotyped. Genotype calling was performed using data-driven clustering (Genome Studio, Illumina, CA, USA).…”
Section: Methodsmentioning
confidence: 99%
“…Despite efforts to identify genetic risk factors for anaemia, very few such studies have been reported from sub-Saharan Africa 24 . To the best of our knowledge, no study has been done in West Africa to assess the effects of genetic variants in hepcidin and iron regulatory genes on low iron status.…”
Genome-wide association studies in Europeans and Asians have identified numerous variants in the transmembrane protease serine 6 (TMPRSS6) and transferrin (TF) genes that are associated with changes in iron status. We sought to investigate the effects of common TMPRSS6 and TF gene SNPs on iron status indicators in a cohort of healthy Africans from rural Gambia. We measured iron biomarkers and haematology traits on individuals participating in the Keneba Biobank with genotype data on TMPRSS6 (rs2235321, rs855791, rs4820268, rs2235324, rs2413450 and rs5756506) and TF (rs3811647 and rs1799852), n = 1316. After controlling for inflammation, age and sex, we analysed the effects of carrying either single or multiple iron-lowering alleles on iron status. TMPRSS6 rs2235321 significantly affected plasma hepcidin concentrations (AA genotypes having lower hepcidin levels; F ratio 3.7, P = 0.014) with greater impact in individuals with low haemoglobin or ferritin. No other TMPRSS6 variant affected hepcidin. None of the TMPRSS6 variants nor a TMPRSS6 allele risk score affected other iron biomarkers or haematological traits. TF rs3811647 AA carriers had 21% higher transferrin (F ratio 16.0, P < 0.0001), 24% higher unsaturated iron-binding capacity (F ratio 12.8, P < 0.0001) and 25% lower transferrin saturation (F ratio 4.3, P < 0.0001) compared to GG carriers. TF rs3811647 was strongly associated with transferrin, unsaturated iron-binding capacity (UIBC) and transferrin saturation (TSAT) with a single allele effect of 8–12%. There was no association between either TF SNP and any haematological traits or iron biomarkers. We identified meaningful associations between TMPRSS6 rs2235321 and hepcidin and replicated the previous findings on the effects of TF rs3811647 on transferrin and iron binding capacity. However, the effects are subtle and contribute little to population variance. Further genetic and functional studies, including polymorphisms frequent in Africa populations, are needed to identify markers for genetically stratified approaches to prevention or treatment of iron deficiency anaemia.
“…Among global populations, there are known differences between genetic variations involving iron imbalance, though there is a call for further investigation of these genetic influences among Sub-Saharan Africans due to a significant lack of data [ 61 ].…”
Background
Upon re-examination of our human history, evolutionary perspectives, and genetics, a prevailing iron deficiency phenotype appears to have evolved to protect the human race from extinction.
Body
In this review, we summarize the evolutionary and genetic perspectives pointing towards the hypothesis that low iron mitigates infection. The presence of infection promotes the generation of resistance alleles, and there are some evolutionary and genetic clues that suggest the presence of an iron deficiency phenotype that may have developed to protect against infection. Examples include the relative paucity of iron overload genes given the essential role of iron, as well as the persistence of iron deficiency among populations in spite of public health efforts to treat it. Additional examination of geographic areas with severe iron deficiency in the setting of pandemics including H1N1, SARS, and COVID-19 reveals that areas with higher prevalence of iron deficiency are less affected. RNA viruses have several evolutionary adaptations which suggest their absolute need for iron, and this dependency may be exploited during treatment.
Conclusion
RNA viruses pose a unique challenge to modern healthcare, with an average of 2–3 new pathogens being discovered yearly. Their overarching requirements for iron, along with human evolutionary and genetic adaptations which favored an iron deficiency phenotype, ultimately suggest the potential need for iron control in these infections.
“…In Caucasians, rs855791 is reported to be in high linkage disequilibrium (LD) with rs4820268 and rs2235321 ( 9 , 11 ), and is in high LD with rs4820268 in Asians ( 16 ). However, low LD has been observed between these SNPs in the Africans included in the 1000 Genomes project and in Gambians ( 17 ).…”
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.
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