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Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.

Benyamin B, Esko T, Ried JS, Radhakrishnan A, Vermeulen SH, Traglia M, Gögele M, Anderson D, Broer L, Podmore C, Luan J, Kutalik Z, Sanna S, van der Meer P, Tanaka T, Wang F, Westra HJ, Franke L, Mihailov E, Milani L, Hälldin J, Häldin J, Winkelmann J, Meitinger T, Thiery J, Peters A, Waldenberger M, Rendon A, Jolley J, Sambrook J, Kiemeney LA, Sweep FC, Sala CF, Schwienbacher C, Pichler I, Hui J, Demirkan A, Isaacs A, Amin N, Steri M, Waeber G, Verweij N, Powell JE, Nyholt DR, Heath AC, Madden PA, Visscher PM, Wright MJ, Montgomery GW, Martin NG, Hernandez D, Bandinelli S, van der Harst P, Uda M, Vollenweider P, Scott RA, Langenberg C, Wareham NJ, InterAct Consortiumvan Duijn C, Beilby J, Pramstaller PP, Hicks AA, Ouwehand WH, Oexle K, Gieger C, Metspalu A, Camaschella C, Toniolo D, Swinkels DW, Whitfield JB - Nat Commun (2014)

Bottom Line: We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14).SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis.These results will facilitate investigation of the roles of iron in disease.

View Article: PubMed Central - PubMed

Affiliation: 1] The University of Queensland, Queensland Brain Institute, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.

ABSTRACT
Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

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Comparison of results for serum iron with regulatory features at the chromosome 7 (TFR2) locusFrom bottom: regional association plot with recombination rate and −log(p) values for serum iron; documented eQTL locations for TFR2 expression (from left to right: rs10247962, rs4729598, rs7457868, rs4729600, rs1052897); ENCODE data on histone modification. P-values for serum iron at rs7385804 and rs2075672 are shown as text (Final p) for the Discovery + Replication dataset, but positions for all SNPs on the y-axis are determined by the Discovery dataset only.
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Figure 2: Comparison of results for serum iron with regulatory features at the chromosome 7 (TFR2) locusFrom bottom: regional association plot with recombination rate and −log(p) values for serum iron; documented eQTL locations for TFR2 expression (from left to right: rs10247962, rs4729598, rs7457868, rs4729600, rs1052897); ENCODE data on histone modification. P-values for serum iron at rs7385804 and rs2075672 are shown as text (Final p) for the Discovery + Replication dataset, but positions for all SNPs on the y-axis are determined by the Discovery dataset only.

Mentions: We next checked for data which may help explain the biological role of the significant SNPs or identify the causal variants which they tag, using sources listed in the Methods. The synthesis of information from our results and external sources is exemplified in Fig. 2, which shows the alignment of data at the TFR2 locus. The region which includes genome-wide-significant SNPs (after replication) for serum iron contains documented eQTLs for TFR2, and H3K27Ac histone modification sites (documented in data from ENCODE). In this case, there is striking alignment at the region around 100.2 Mbp at one end of the TFR2 gene, which includes the most significant SNPs at this locus, documented eQTLs for this gene, and the histone modification in K562 (erythroleukaemia) cells.


Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.

Benyamin B, Esko T, Ried JS, Radhakrishnan A, Vermeulen SH, Traglia M, Gögele M, Anderson D, Broer L, Podmore C, Luan J, Kutalik Z, Sanna S, van der Meer P, Tanaka T, Wang F, Westra HJ, Franke L, Mihailov E, Milani L, Hälldin J, Häldin J, Winkelmann J, Meitinger T, Thiery J, Peters A, Waldenberger M, Rendon A, Jolley J, Sambrook J, Kiemeney LA, Sweep FC, Sala CF, Schwienbacher C, Pichler I, Hui J, Demirkan A, Isaacs A, Amin N, Steri M, Waeber G, Verweij N, Powell JE, Nyholt DR, Heath AC, Madden PA, Visscher PM, Wright MJ, Montgomery GW, Martin NG, Hernandez D, Bandinelli S, van der Harst P, Uda M, Vollenweider P, Scott RA, Langenberg C, Wareham NJ, InterAct Consortiumvan Duijn C, Beilby J, Pramstaller PP, Hicks AA, Ouwehand WH, Oexle K, Gieger C, Metspalu A, Camaschella C, Toniolo D, Swinkels DW, Whitfield JB - Nat Commun (2014)

Comparison of results for serum iron with regulatory features at the chromosome 7 (TFR2) locusFrom bottom: regional association plot with recombination rate and −log(p) values for serum iron; documented eQTL locations for TFR2 expression (from left to right: rs10247962, rs4729598, rs7457868, rs4729600, rs1052897); ENCODE data on histone modification. P-values for serum iron at rs7385804 and rs2075672 are shown as text (Final p) for the Discovery + Replication dataset, but positions for all SNPs on the y-axis are determined by the Discovery dataset only.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4215164&req=5

Figure 2: Comparison of results for serum iron with regulatory features at the chromosome 7 (TFR2) locusFrom bottom: regional association plot with recombination rate and −log(p) values for serum iron; documented eQTL locations for TFR2 expression (from left to right: rs10247962, rs4729598, rs7457868, rs4729600, rs1052897); ENCODE data on histone modification. P-values for serum iron at rs7385804 and rs2075672 are shown as text (Final p) for the Discovery + Replication dataset, but positions for all SNPs on the y-axis are determined by the Discovery dataset only.
Mentions: We next checked for data which may help explain the biological role of the significant SNPs or identify the causal variants which they tag, using sources listed in the Methods. The synthesis of information from our results and external sources is exemplified in Fig. 2, which shows the alignment of data at the TFR2 locus. The region which includes genome-wide-significant SNPs (after replication) for serum iron contains documented eQTLs for TFR2, and H3K27Ac histone modification sites (documented in data from ENCODE). In this case, there is striking alignment at the region around 100.2 Mbp at one end of the TFR2 gene, which includes the most significant SNPs at this locus, documented eQTLs for this gene, and the histone modification in K562 (erythroleukaemia) cells.

Bottom Line: We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14).SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis.These results will facilitate investigation of the roles of iron in disease.

View Article: PubMed Central - PubMed

Affiliation: 1] The University of Queensland, Queensland Brain Institute, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.

ABSTRACT
Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

Show MeSH
Related in: MedlinePlus