Department of Epidemiology, University of California Irvine, Irvine, California, United States of America.
PLoS One. 2011 Mar 31;6(3):e17390. doi: 10.1371/journal.pone.0017390.
The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged≥25 y and women≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF)≤12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7) for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9), corrected P=0.012) was replicated within the VA samples (observed P=0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.
人类、啮齿动物和其他脊椎动物中存在多种遗传性铁代谢紊乱，这表明铁缺乏与遗传因素有关。为了确定与铁缺乏相关的新基因组位置，我们对参加铁过剩和血色病筛查（HEIRS）研究的年龄≥25 岁的白人男性和年龄≥50 岁的白人女性进行了全基因组关联研究（GWAS），这些参与者的血清铁蛋白（SF）≤12μg/L（病例），铁含量充足的对照者（男性 SF＞100μg/L，女性 SF＞50μg/L）。采用回归分析的方法，对病例对照状态（336 例，343 例对照）与定量血清铁指标之间的关系进行了研究，同时还对 331060 个单核苷酸多态性（SNP）基因型进行了分析。在一个由参加美国退伍军人事务部（VA）医疗中心的白人男性和女性退伍军人筛查的人群中，对来自 GWAS 的 71 例病例和 161 例对照的样本进行了复制分析。在全基因组关联分析中，有 5 个 SNP 与至少一项铁指标显著相关，这些 SNP 位于 2p14 上的 rs2698530、3q22 上的 rs3811647（转铁蛋白（TF）基因区域中的一个已知 SNP）、6p22 上的 rs1800562、7p21 上的 rs7787204 和 22q11 上的 rs987710（全基因组关联分析观察到的 P＜1.51×10（-7））。在 TF 基因中的 rs3811647 与总铁结合能力之间存在关联（全基因组关联分析观察到的 P=7.0×10（-9），校正后的 P=0.012），这在 VA 样本中得到了复制（观察到的 P=0.012）。HFE 基因中的 C282Y 突变也存在关联。HEIRS 和 VA 样本的联合分析显示，2p14 上的 rs2698530 与铁状态结果之间存在强烈关联。这些结果证实了之前描述的 TF 多态性，并暗示了一个潜在的新基因座可能是基因鉴定的目标。
