Abstract
BackgroundHFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation.ResultsUsing data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35–54.71 %) but rare in Europeans (5.98 %) and Africans (4.35 %). The T allele at tag SNP rs9366637 (C/T) captured 95.8 % of this Asian-common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22 % higher absorption in women homozygous for the Asian-common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption.ConclusionsOur results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0223-y) contains supplementary material, which is available to authorized users.
Highlights
HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations
As a reduced expression of HFE theoretically would lower the expression of hepcidin and lead to enhanced non-heme Fe absorption [9], we further investigated the impact of this Asiancommon haplotype on Fe absorption and Fe status
An additional search in GRASP (Genome-Wide Repository of Associations Between single nucleotide polymorphism (SNP) and Phenotypes) [48] with SNPs in high linkage disequilibrium (r2 > 0.8) with rs9366637 in Asian populations revealed that one SNP rs7753826 is associated with mean corpuscular hemoglobin concentration (MCHC), Hb, and mean corpuscular volume (MCV) [49, 50], supporting the involvement of rs9366637 and its linked SNPs in Fe homeostasis regulation
Summary
HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. For individuals (e.g. vegetarians) or populations consuming predominantly plant-based diets and relying solely on the non-heme form of Fe, they have a much higher risk for ID [24]. In certain Asian populations (e.g. Chinese) with a long tradition of consuming plant-based, iron-poor diets [24,25,26], genetic variations enhancing non-heme Fe absorption could have been especially beneficial and subject to positive natural selection. No such genetic variations have been revealed to date. In the modern Fe-replete dietary environment, identifying genetic variation enhancing Fe absorption is especially important for future prevention of Fe overload and its associated disorders
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