title: Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.
abstract: BACKGROUND
  HFE, 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.
  
  
  RESULTS
  Using 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA. ky279@cornell.edu.
authors.forename: Kaixiong
authors.initials: K
authors.lastname: Ye
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA. cc748@cornell.edu.
authors.forename: Chang
authors.initials: C
authors.lastname: Cao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate University of the Chinese Academy of Sciences, Shanghai, China. xlin@sibs.ac.cn.
authors.forename: Xu
authors.initials: X
authors.lastname: Lin
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA. koo4@cornell.edu.
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: O'Brien
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA. zg27@cornell.edu.
authors.forename: Zhenglong
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D005260:Female; D005293:Ferritins / Q000097:blood; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006418:Heme; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000097:blood; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D012737:Sex Factors; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D006418:Heme; D005293:Ferritins; D007501:Iron