GNPAT variant is associated with iron phenotype in healthy Taiwanese women: A population without the HFE C282Y mutation
Authors: Shu‐Chen Hsiao, Chien‐Te Lee, Sung‐Nan Pei
Journal: Hepatology (2016)

This work was supported by grants from Chang Gung Memorial Hospital (grant no. CMRPG8D0421). Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. TO THE EDITOR: McLaren et al.1 recently used whole‐exome sequencing to show that GNPAT p.D519G (rs11558492) is associated with a high‐iron phenotype in HFE C282Y homozygous men. Three other studies examined this association in different Caucasian populations with conflicting results.2 However, the role of GNPAT in the absence of iron overload or in the HFE wild‐type population remains unclear. Here, we investigated iron indices before and after iron supplementation and their association with genetic polymorphisms. This study was approved by the ethics committee, and informed consent was obtained from all participants. We screened healthy reproductive‐age women and excluded those with renal insufficiency, anemia, gastrointestinal bleeding, or chronic inflammation and those that were pregnant or breastfeeding; thus, 83 healthy female volunteers were eligible for analysis. Participants fasted overnight, and baseline iron parameters were measured at 8 am. They were then administered sodium ferrous citrate (element iron, 100 mg), and blood was sampled 2 hours later. Data are presented in Table 1. Table 1 - Group Characteristics: Baseline Variables and Changes in Iron‐Status Biomarkers After Iron Supplementation Characteristic GNPAT rs11558492 TMPRSS6 rs855791 Wild type (n = 64) Variants (n = 19) P Value C/C (n = 16) T/C (n = 42) T/T (n = 25) P Valuea Age, years 36.0 ± 6.3 37.4 ± 5.0 0.394 36.4 ± 7.7 35.3 ± 5.8 38.0 ± 5.1 0.474 Menstruation amountb 137.6 ± 81.7 137.6 ± 114.2 0.999 171.8 ± 125.8 124.1 ± 68.7 138.4 ± 91.0 0.331 RBC, million/μL 4.50 ± 0.28 4.53 ± 0.26 0.667 4.52 ± 0.27 4.52 ± 0.27 4.48 ± 0.29 0.656 HGB, g/dL 13.47 ± 0.71 13.53 ± 0.51 0.722 13.51 ± 0.78 13.51 ± 0.65 13.43 ± 0.66 0.745 HCT, % 40.21 ± 1.92 40.85 ± 1.44 0.181 40.70 ± 2.13 40.37 ± 1.74 40.09 ± 1.81 0.334 MCV, fL 89.41 ± 3.53 89.77 ± 4.52 0.720 90.16 ± 3.54 89.16 ± 4.10 89.63 ± 3.33 0.632 MCHC, g/dL 33.44 ± 0.92 33.13 ± 0.72 0.176 33.18 ± 0.57 33.35 ± 1.01 33.50 ± 0.81 0.171 RDW‐CV, % 12.78 ± 0.59 12.96 ± 0.63 0.267 13.04 ± 0.65 12.77 ± 0.58 12.77 ± 0.57 0.160 Ferritin, ng/mL 45.78 ± 30.85 47.08 ± 35.54 0.876 39.68 ± 29.88 47.03 ± 32.26 48.58 ± 32.78 0.386 Fe, baseline, μg/dL 110.42 ± 36.33 131.16 ± 47.27 0.045 111.13 ± 32.89 122.02 ± 46.86 106.24 ± 28.31 0.616 TS, baseline, % 33.67 ± 11.82 38.18 ± 12.57 0.153 33.53 ± 8.71 36.69 ± 14.09 32.12 ± 9.82 0.641 Fe, after iron supplement, μg/dL 284.50 ± 59.56 320.16 ± 61.04 0.025 298.31 ± 64.24 297.45 ± 58.67 281.00 ± 64.97 0.408 TS, after iron supplement, % 78.94 ± 13.42 85.84 ± 9.61 0.040 80.92 ± 10.80 81.85 ± 12.86 78.05 ± 14.36 0.499 Data are presented as mean ± standard deviation. Differences between groups were analyzed by an independent t test.aIndependent t test used to examine the differences between C/C and T/T homozygotes.bMenstruation amount was estimated by the pictorial blood‐loss assessment chart score.Abbreviations: RBC, red blood cell; HGB, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentration; RDW‐CV, red blood cell distribution width/coefficient of variation. Regarding TMPRSS6 rs855791, iron parameters at baseline or after iron challenge did not significantly differ between genotypes. For GNPAT rs11558492, 64 participants were wild type (A/A) and 19 carried variants (18 A/G and 1 G/G). The G allele frequency was 12% (20 of 166), similar to 14% in the general population in 1000 Genomes (chi‐square test: P = 0.416). Fasting serum iron levels were higher in subjects with GNPAT variants than in wild‐type subjects (131.2 vs. 110.5 μg/dL; P = 0.045), but there was no significant difference in fasting transferrin saturation (TS; 38.2% vs. 33.7%; P = 0.153). After iron supplementation, serum iron levels and TS were both significantly higher in GNPAT variants (iron, 320.2 vs. 284.5 μg/dL; P = 0.025; TS, 85.8% vs. 78.9%; P = 0.040). Furthermore, multivariate analysis showed that the GNPAT genotype was an independent factor associated with baseline iron levels (P = 0.045; adjusted R2 = 0.037); the factors analyzed included age, menstruation amount, and the TMPRSS6 rs855791 and GNPAT rs11558492 polymorphisms. Our data showed that the GNPAT variant plays a role in iron phenotype (increased serum iron levels at fasting and after supplementation) in healthy young Taiwanese women, a population that does not carry the HFE C282Y mutation.5 Our findings suggest that GNPAT p.D519G is not an "HFE modifier," as proposed by McLaren et al., but is an independent player in hepcidin regulation. Further in vitro and human studies will be required to clarify the exact role of GNPAT in iron phenotype.