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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.

SUBMITTER: Ye K

PROVIDER: S-EPMC4460683 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.

Ye Kaixiong K Cao Chang C Lin Xu X O'Brien Kimberly O KO Gu Zhenglong Z

BMC genetics 20150610

<h4>Background</h4>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 dif ...[more]

PMID: 26054392

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Project description:BackgroundScreening program participants with iron overload (IO) phenotypes without HFE p.C282Y/p.C282Y are incompletely characterized.MethodsWe studied white participants who had IO phenotypes without p.C282Y/p.C282Y in post-screening clinical examinations (CE). We defined IO phenotypes as a) elevated serum ferritin (SF) and transferrin saturation (TS) at screening and CE, and b) absence of IO treatment, anemia, transfusion >10 units, alcohol intake >30 g/d, hepatitis B or C, and pregnancy. We defined IO-related disease as elevated alanine or aspartate aminotransferase (ALT/AST) or swelling/tenderness of 2nd/3rd metacarpophalangeal (MCP) joints. All participants had HFE p.C282Y and p.H63D genotyping.ResultsThere were 32 men and 26 women (mean age 54±16 y). Median food/supplemental iron intakes were 14.3/0.0 mg/d. Relative risks of HFE genotypes were 12.9 (p.C282Y/p.H63D), 3.0 (p.H63D/p.H63D), 1.9 (p.C282Y/wt), 0.9 (p.H63D/wt), and 0.5 (wt/wt) compared to 42,640 white screening participants without IO phenotypes or p.C282Y/p.C282Y. Regression on SF revealed positive associations: MCV (p = 0.0006; β coefficient = 0.4531); swelling/tenderness of MCP joints (p = 0.0033; β = 0.3455); and p.H63D/wt (p = 0.0015; β = 0.4146). IO-related disease (18 elevated ALT/AST, one swelling/tenderness of MCP joints) occurred in 19 participants (7 men, 12 women). Median MCV was higher in participants with IO-related disease (97 fL vs. 94 fL; p = 0.0007). Logistic regression on IO-related disease revealed a significant association with diabetes (p = 0.0416; odds ratio 18.9 (95% confidence interval 1.0, 341.1)).ConclusionsIn the present 58 screening program participants who had IO phenotypes without HFE p.C282Y/p.C282Y, relative risks of HFE genotypes p.C282Y/p.H63D, p.H63D/p.H63D, and p.C282Y/wt were significantly higher than in 42,640 white screening participants with neither IO phenotypes nor p.C282Y/p.C282Y. SF was significantly associated with MCV, swelling/tenderness of 2nd/3rd MCP joints, and p.H63D/wt. IO-related disease was significantly associated with MCV and diabetes.

Dataset Information

Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.

Publications

Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.

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