Associations between Common Variants in Iron-Related Genes with Haematological Traits in Populations of African Ancestry

Gichohi-Wainaina, Wanjiku N.; Tanaka, Toshiko; Towers, G. Wayne; Verhoef, Hans; Veenemans, Jacobien; Talsma, Elise F.; Harryvan, J.L.; Boekschoten, Mark V.; Feskens, Edith J. M.; Melse‐Boonstra, Alida

doi:10.1371/journal.pone.0157996

Cited by 13 publications

(13 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since there is evidence of genetic differences among population subgroups with regard to iron metabolism [ 66 ], we also compared levels of CSF iron, transferrin, and H-ferritin between self-reported HIV+ White, Black, and Hispanic study participants and were able to discern ancestry-related differences. As shown in Table 4 and Fig.…”

Section: Resultsmentioning

confidence: 99%

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Patton

Wang

Hulgan

et al. 2017

Fluids Barriers CNS

View full text Add to dashboard Cite

BackgroundHIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND.MethodsWe quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood–CSF-barrier.ResultsAmong 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/µL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 µg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 µg/dL in Hispanics and Whites, respectively, vs. 3.7 µg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p < 0.05), and transferrin 14% higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50% higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for QAlb and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05).ConclusionsCSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.Electronic supplementary materialThe online version of this article (doi:10.1186/s12987-017-0058-1) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Patton

Wang

Hulgan

et al. 2017

Fluids Barriers CNS

View full text Add to dashboard Cite

show abstract

“…The majority of the studies (59/64) were conducted in Europe, Asia and the USA (Fig 1, S2 Table). Only five studies were conducted in Africa, two in Rwanda [49,50], one in Zimbabwe [51], one in South Africa [52] and one meta-analysis across Kenya, Tanzania and South Africa [30]. Across the 64 studies, 50 SNPs were identified in six genes (TMPRSS6, HAMP, TF, TFR2, SLC40A1 and HFE) (S1 Table).…”

Section: Genetic Variants Associated With Iron Imbalancesmentioning

confidence: 99%

“…iron status measures and severity of haemochromatosis [50,51,[55][56][57]. One SNP was identified in HAMP (rs10421768) [30,55,[58][59][60] and one in TFR2 (rs7385804) (6,7,33,34,37,38), both of which were found to be associated with increases in haemoglobin and alterations serum in ferritin concentrations [30,55,56,58,[61][62][63]. For the HFE gene, we found four SNPs that have been associated with alterations in haemoglobin and/or an increase in the genetic risk of hereditary haemochromatosis [13,14,19,20,24,26,29,56,62,[64][65][66][67][68][69][70][71][72][73][74].…”

Section: Plos Onementioning

confidence: 99%

“…African populations have been greatly under-represented in such studies. A GWAS using an African population cohort replicated only the association of two SNPs in TMPRSS6 with lowered haemoglobin concentration, and one SNP in TF with increased ferritin concentrations [30]. Differences in the frequencies of risk alleles and linkage disequilibrium patterns might explain the limited replication of association results between European, Asian and African populations.…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Differences in the frequency of genetic variants associated with iron imbalance among global populations

et al. 2020

View full text Add to dashboard Cite

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 in African populations, as they carry high genetic diversity and have a high prevalence of anaemia. Multiple genetic variations in iron regulatory genes have been linked to impaired iron status. Here we conducted a literature review to identify genetic variants associated with iron imbalance among global populations. We compare their allele frequencies and risk scores and we investigated populationspecific selection among populations of varying geographic origin using data from the Keneba Biobank representing individuals in rural Gambia and the 1000 Genomes Project. We identified a significant lack of data on the genetic determinants of iron status in sub-Saharan Africa. Most of the studies on genetic determinants of iron status have been conducted in Europeans. Also, we identified population differences in allele frequencies in candidate putative genetic risk factors. Given the disproportionately high genetic diversity in African populations coupled with their high prevalence of iron deficiency, there is need to investigate the genetic influences of low iron status in Sub-Saharan Africa. The resulting insights may inform the future implementation of iron intervention strategies.

show abstract

“…We will employ a recall-by-genotype study design, in which participant selection will be based on TMPRSS6 SNPs reported to be associated with the risk of iron-deficiency anaemia: rs855791, rs4820268 and rs2235321 10,14,15 . We will utilize the West African BioResouce (WABR), which contains the Kiang West Longitudinal Population Study (KWLPS) as the basis for selection of pre-genotyped participants 16 .…”

Section: Methodsmentioning

confidence: 99%

A recall-by-genotype study on polymorphisms in the TMPRSS6 gene and oral iron absorption: a study protocol

et al. 2021

View full text Add to dashboard Cite

Background: Oral iron supplementation is commonly used to treat and prevent anaemia. The transmembrane protease serine 6 gene (TMPRSS6), which encodes matriptase 2, is a negative regulator of hepcidin, the key controller of iron homeostasis. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene that are associated with an increased risk of iron-deficiency anaemia. We will investigate the in vivo effects of three previously reported TMPRSS6 variants (rs855791, rs4820268 and rs2235321) on oral iron absorption in non-anaemic volunteers in The Gambia. Methods: A recall-by-genotype study design will be employed. Pre-genotyped participants will be recruited from the West African BioResouce (WABR), which currently contains over 3000 genotyped individuals. Male and female volunteers will be selected based on polymorphisms (rs855791, rs4820268 and rs2235321) in the TMPRSS6 gene in the Gambian population. The effects of a single variant allele at one SNP and the additive effect of two or three variant alleles from either two or all three SNPs will be investigated. Study participants will be given a single oral dose of 400mg ferrous sulfate, and blood samples will be collected at baseline, two hours and five hours post supplementation. Differences in iron absorption between genotype groups will be assessed by measuring the increase in serum iron concentration at five hours post iron ingestion. Discussion: This study will increase understanding of the role of genetic variations in TMPRSS6 on oral iron absorption in subjects of West African origin. This will test for the biological basis for the association of each of the three TMPRSS6 variants with iron absorption. This may help in guiding future iron intervention strategies, particularly in populations with a high frequency of these SNPs and a high frequency of anaemia. Study registration: ClinicalTrials.gov NCT03341338 14/11/17.

show abstract

Associations between Common Variants in Iron-Related Genes with Haematological Traits in Populations of African Ancestry

Cited by 13 publications

References 58 publications

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Differences in the frequency of genetic variants associated with iron imbalance among global populations

A recall-by-genotype study on polymorphisms in the TMPRSS6 gene and oral iron absorption: a study protocol

Contact Info

Product

Resources

About