Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website https://gr.elmerpub.com

Original Article

Volume 000, Number 000, March 2025, pages 000-000

Associations Between the HFE Genotypes and Iron Status Markers in an Apparently Healthy Population

Figure 1. Associations between HFE genotypes and iron status markers in men, non-blood donors. Genotype numbers denote: 1 wt/wt; 2 H63D/wt; 3 C282Y/wt; 4 H63D/H63D; 5 C282Y/H63D; 6 C28Y/C282Y. With increasing genotype number, there is a gradual increase in serum iron, transferrin saturation and serum ferritin, and a gradual decrease in serum transferrin.

Figure 2. Associations between HFE genotypes and iron status markers in women, non-blood donors. Genotype numbers denote: 1 wt/wt; 2 H63D/wt; 3 C282Y/wt; 4 H63D/H63D; 5 C282Y/H63D; 6 C28Y/C282Y. With increasing genotype number, there is a gradual decrease in serum transferrin and increase in transferrin saturation. Serum iron is elevated only in the C282Y/H63D and C28Y/C282Y genotypes, while serum ferritin is by and large similar in all genotypes.

**Table 1.** Distribution of *HFE* Genotypes in the Entire Series
HFE genotype	Men, n	Women, n	Total, n (%)
Fisher’s exact test: no significant differences in genotype distribution between men and women. wt: wildtype.
1. wt/wt	891	818	1,709 (65.40%)
2. H63D/wt	287	292	579 (22.16%)
3. C282Y/wt	118	120	238 (9.11%)
4. H63D/H63D	26	16	42 (1.61%)
5. C282Y/H63D	16	20	36 (1.38%)
6. C282Y/C282Y	4	5	9 (0.34%)
Total, n	1,342	1,271	2,613

Table 1. Distribution of HFE Genotypes in the Entire Series

HFE genotype

Men, n

Women, n

Total, n (%)

Fisher’s exact test: no significant differences in genotype distribution between men and women. wt: wildtype.

1. wt/wt

891

818

1,709 (65.40%)

2. H63D/wt

287

292

579 (22.16%)

3. C282Y/wt

118

120

238 (9.11%)

4. H63D/H63D

42 (1.61%)

5. C282Y/H63D

36 (1.38%)

6. C282Y/C282Y

9 (0.34%)

Total, n

1,342

1,271

2,613

**Table 2.** Hematological Iron Status Markers in Men and Women in the Entire Series
Variable	Men	Women	P-value*	P-value**
Values are arithmetic mean ± standard deviation. Student’s t-test for unpaired values, two-tailed probability, significance level with Bonferroni’s correction P < 0.01. *Mann-Whitney rank sum test, two-tailed probability. IQR: interquartile range.
Hemoglobin, g/L	158 ± 11.4 (n = 1,336)	141 ± 10.7 (n = 1,265)	< 0.0001	< 0.0001
S-iron, µmol/L	20.5 ± 6.5 (n = 900)	17.8 ± 6.2 (n = 916)	< 0.0001	< 0.0001
S-transferrin, µmol/L	31.4 ± 4.8 (n = 900)	31.1 ± 4.8 (n = 916)	0.09	0.04
S-transferrin saturation, %	33.3 ± 11.9 (n = 900)	29.5 ± 11.5 (n = 916)	< 0.0001	< 0.0001
S-ferritin, µg/L, median (IQR)	128 (80 - 198)	50 (27 - 86)		< 0.0001

Table 2. Hematological Iron Status Markers in Men and Women in the Entire Series

Variable

Men

Women

P-value*

P-value**

Values are arithmetic mean ± standard deviation. *Student’s t-test for unpaired values, two-tailed probability, significance level with Bonferroni’s correction P < 0.01. **Mann-Whitney rank sum test, two-tailed probability. IQR: interquartile range.

Hemoglobin, g/L

158 ± 11.4 (n = 1,336)

141 ± 10.7 (n = 1,265)

< 0.0001

S-iron, µmol/L

20.5 ± 6.5 (n = 900)

17.8 ± 6.2 (n = 916)

< 0.0001

S-transferrin, µmol/L

31.4 ± 4.8 (n = 900)

31.1 ± 4.8 (n = 916)

0.09

0.04

S-transferrin saturation, %

33.3 ± 11.9 (n = 900)

29.5 ± 11.5 (n = 916)

< 0.0001

S-ferritin, µg/L, median (IQR)

128 (80 - 198)

50 (27 - 86)

< 0.0001

**Table 3.** Hematological Iron Status Markers in Men, Non-Blood Donors, According to *HFE* Genotypes
HFE genotype	Hemoglobin, g/L	S-iron, µmol/L	S-transferrin, µmol/L	S-transferrin saturation, %	S-ferritin, µg/L, median (IQR)
Values are arithmetic mean ± standard deviation. Significance level P < 0.05. ANOVA: analysis of variance; IQR: interquartile range; wt: wildtype.
1. wt/wt	158 ± 11.3 (n = 669)	19.7 ± 5.9	31.7 ± 4.8	31.8 ± 10.5 (n = 441)	134 (87 - 200) (n = 666)
2. H63D/wt	159 ± 11.1 (n = 205)	21.5 ± 7.0	30.9 ± 5.0	35.9 ± 12.7 (n = 135)	140 (90 - 229) (n = 204)
3. C282Y/wt	159 ± 10.7 (n = 78)	21.2 ± 6.8	29.5 ± 4.4	36.9 ± 13.3 (n = 52)	145 (87 - 205) (n = 77)
4. H63D/H63D	158 ± 13.7 (n = 18)	23.8 ± 6.1	29.2 ± 4.0	41.5 ± 12.8 (n = 12)	185 (136 - 230) (n = 18)
5. C282Y/H63D	159 ± 9.7 (n = 11)	24.8 ± 7.7	27.8 ± 4.0	45.8 ± 17.1 (n = 10)	209 (115 - 264) (n = 11)
6. C282Y/C282Y	166 ± 13.4 (n = 3)	17; 38	25; 23	34; 83 (n = 2)	1,240 (671 - 3,010) (n = 3) 481; 1,240; 3,600 µg/L
Kruskal-Wallis test, P-value	0.4	0.0006	0.0001	0.0005	0.004
One-way ANOVA F-test, P-value	0.4	0.001	< 0.001	< 0.001	< 0.001

Table 3. Hematological Iron Status Markers in Men, Non-Blood Donors, According to HFE Genotypes

HFE genotype

Hemoglobin, g/L

S-iron, µmol/L

S-transferrin, µmol/L

S-transferrin saturation, %

S-ferritin, µg/L, median (IQR)

Values are arithmetic mean ± standard deviation. Significance level P < 0.05. ANOVA: analysis of variance; IQR: interquartile range; wt: wildtype.

1. wt/wt

158 ± 11.3 (n = 669)

19.7 ± 5.9

31.7 ± 4.8

31.8 ± 10.5 (n = 441)

134 (87 - 200) (n = 666)

2. H63D/wt

159 ± 11.1 (n = 205)

21.5 ± 7.0

30.9 ± 5.0

35.9 ± 12.7 (n = 135)

140 (90 - 229) (n = 204)

3. C282Y/wt

159 ± 10.7 (n = 78)

21.2 ± 6.8

29.5 ± 4.4

36.9 ± 13.3 (n = 52)

145 (87 - 205) (n = 77)

4. H63D/H63D

158 ± 13.7 (n = 18)

23.8 ± 6.1

29.2 ± 4.0

41.5 ± 12.8 (n = 12)

185 (136 - 230) (n = 18)

5. C282Y/H63D

159 ± 9.7 (n = 11)

24.8 ± 7.7

27.8 ± 4.0

45.8 ± 17.1 (n = 10)

209 (115 - 264) (n = 11)

6. C282Y/C282Y

166 ± 13.4 (n = 3)

17; 38

25; 23

34; 83 (n = 2)

1,240 (671 - 3,010) (n = 3) 481; 1,240; 3,600 µg/L

Kruskal-Wallis test, P-value

0.4

0.0006

0.0001

0.0005

0.004

One-way ANOVA F-test, P-value

0.4

0.001

< 0.001

**Table 4.** Differences Between Iron Status Markers in Men, Non-Blood Donors, According to *HFE* Genotypes
HFE genotype	S-iron	S-transferrin	S-transferrin saturation	S-ferritin
Values used for calculation of significances are shown in Table 3. Student’s t-test for unpaired values, two-tailed probability. Significance level with Bonferroni’s correction P < 0.005.
wt/wt vs. H63D/wt	0.0001	0.08	< 0.0001	0.1
wt/wt vs. C282Y/wt	0.009	0.0001	< 0.0001	0.5
wt/wt vs. C282Y/H63D	0.001	0.0023	< 0.0001	0.2
wt/wt vs. H63D/H63D	0.0004	0.5	< 0.0001	0.024
wt/wt vs. C282Y/C282Y	0.066	0.020	0.0003	< 0.0001
H63D/wt vs. C282Y/wt	1.0	0.019	0.2	0.8
C282Y/wt vs. C282Y/H63D	0.4	0.2	0.06	0.4
C282Y/H63D vs. H63D/H63D	1.0	0.06	0.01	0.7
H63D/H63D vs. C282Y/C282Y	0.7	0.08	0.3	< 0.0001

Table 4. Differences Between Iron Status Markers in Men, Non-Blood Donors, According to HFE Genotypes

HFE genotype

S-iron

S-transferrin

S-transferrin saturation

S-ferritin

P-values

Values used for calculation of significances are shown in Table 3. Student’s t-test for unpaired values, two-tailed probability. Significance level with Bonferroni’s correction P < 0.005.

wt/wt vs. H63D/wt

0.0001

0.08

< 0.0001

0.1

wt/wt vs. C282Y/wt

0.009

0.0001

< 0.0001

0.5

wt/wt vs. C282Y/H63D

0.001

0.0023

< 0.0001

0.2

wt/wt vs. H63D/H63D

0.0004

0.5

< 0.0001

0.024

wt/wt vs. C282Y/C282Y

0.066

0.020

0.0003

< 0.0001

H63D/wt vs. C282Y/wt

1.0

0.019

0.2

0.8

C282Y/wt vs. C282Y/H63D

0.4

0.2

0.06

0.4

C282Y/H63D vs. H63D/H63D

1.0

0.06

0.01

0.7

H63D/H63D vs. C282Y/C282Y

0.7

0.08

0.3

< 0.0001

**Table 5.** Frequencies of High Transferrin Saturation Values in Various *HFE* Genotype Groups and Their Relationship With High Serum Ferritin Values in Men and Women, Non-Blood Donors
HFE genotype	Men, non-blood donors, n	Transferrin saturation > 50%, n (%)	S-ferritin > 300 µg/L, n	Women, non-blood donors, n	Transferrin saturation > 45%, n (%)	S-ferritin > 200 µg/L, n
1. wt/wt	441	24 (5.4%)	5/24	517	36 (7.0%)	1/36
2. H63D/wt	135	15 (11.1%)	3/15	175	11 (6.3%)	1/11
3. C282Y/wt	52	7 (13.5%)	3/7	79	9 (11.4%)	0/9
4. H63D/H63D	12	2 (16.7%)	0/2	11	4 (36.4%)	0/4
5. C282Y/H63D	10	3 (30.0%)	0/3	12	2 (16.7%)	0/2
6. C282Y/C282Y	2	1 (50.0%)	1/1	1	1 (100.0%)	0/1
Chi-squared test, P-value		0.0010	0.5		< 0.0001	0.2
Chi-squared test for trend, P-value		< 0.0001	0.8		0.0015	0.7

Table 5. Frequencies of High Transferrin Saturation Values in Various HFE Genotype Groups and Their Relationship With High Serum Ferritin Values in Men and Women, Non-Blood Donors

HFE genotype

Men, non-blood donors, n

Transferrin saturation > 50%, n (%)

S-ferritin > 300 µg/L, n

Women, non-blood donors, n

Transferrin saturation > 45%, n (%)

S-ferritin > 200 µg/L, n

1. wt/wt

441

24 (5.4%)

5/24

517

36 (7.0%)

1/36

2. H63D/wt

135

15 (11.1%)

3/15

175

11 (6.3%)

1/11

3. C282Y/wt

7 (13.5%)

3/7

9 (11.4%)

0/9

4. H63D/H63D

2 (16.7%)

0/2

4 (36.4%)

0/4

5. C282Y/H63D

3 (30.0%)

0/3

2 (16.7%)

0/2

6. C282Y/C282Y

1 (50.0%)

1/1

1 (100.0%)

0/1

Chi-squared test, P-value

0.0010

0.5

< 0.0001

0.2

Chi-squared test for trend, P-value

< 0.0001

0.8

0.0015

0.7

**Table 6.** Hematological Iron Status Markers in Women, Non-Blood Donors, According to *HFE* Genotypes
HFE genotype	Hemoglobin, g/L	S-iron, µmol/L	S-transferrin, µmol/L	S-transferrin saturation, %	S-ferritin, µg/L, median (IQR)
Values are arithmetic mean ± standard deviation. Significance level P < 0.05. ^aAll four were premenopausal. ANOVA: analysis of variance; IQR: interquartile range; wt: wildtype.
1. wt/wt	141 ± 10.4 (n = 713)	17.5 ± 5.8	31.3 ± 5.0	28.7 ± 10.7 (n = 517)	54 (29 - 92) (n = 710)
2. H63D/wt	142 ± 11.2 (n = 248)	17.6 ± 5.7	30.9 ± 4.4	29.4 ± 10.9 (n = 175)	53 (28 - 86) (n = 247)
3. C282Y/wt	143 ± 11.7 (n = 104)	18.3 ± 7.6	29.2 ± 4.4	32.0 ± 13.2 (n = 79)	43 (21 - 71) (n = 102)
4. H63D/H63D	136 ± 10.6 (n = 14)	19.2 ± 12.6	28.0 ± 3.7	34.9 ± 22.5 (n = 11)	42 (31 - 94) (n = 14)
5. C282Y/H63D	146 ± 9.7 (n = 17)	19.3 ± 7.4	28.5 ± 2.9	34.4 ± 14.0 (n = 12)	28 (23 - 111) (n = 17)
6. C282Y/C282Y	144 ± 12.2 (n = 4)	27	23	59^a (n = 1)	57 (28 - 95) (n = 4). ^a14, 41, 73, and 116 µg/L
Kruskal-Wallis test, P-value	0.2	0.5	0.0002	0.050	0.3
One-way ANOVA F-test, P-value	0.1	0.4	< 0.001	0.003	0.2

Table 6. Hematological Iron Status Markers in Women, Non-Blood Donors, According to HFE Genotypes

HFE genotype

Hemoglobin, g/L

S-iron, µmol/L

S-transferrin, µmol/L

S-transferrin saturation, %

S-ferritin, µg/L, median (IQR)

Values are arithmetic mean ± standard deviation. Significance level P < 0.05. ^aAll four were premenopausal. ANOVA: analysis of variance; IQR: interquartile range; wt: wildtype.

1. wt/wt

141 ± 10.4 (n = 713)

17.5 ± 5.8

31.3 ± 5.0

28.7 ± 10.7 (n = 517)

54 (29 - 92) (n = 710)

2. H63D/wt

142 ± 11.2 (n = 248)

17.6 ± 5.7

30.9 ± 4.4

29.4 ± 10.9 (n = 175)

53 (28 - 86) (n = 247)

3. C282Y/wt

143 ± 11.7 (n = 104)

18.3 ± 7.6

29.2 ± 4.4

32.0 ± 13.2 (n = 79)

43 (21 - 71) (n = 102)

4. H63D/H63D

136 ± 10.6 (n = 14)

19.2 ± 12.6

28.0 ± 3.7

34.9 ± 22.5 (n = 11)

42 (31 - 94) (n = 14)

5. C282Y/H63D

146 ± 9.7 (n = 17)

19.3 ± 7.4

28.5 ± 2.9

34.4 ± 14.0 (n = 12)

28 (23 - 111) (n = 17)

6. C282Y/C282Y

144 ± 12.2 (n = 4)

59^a (n = 1)

57 (28 - 95) (n = 4). ^a14, 41, 73, and 116 µg/L

Kruskal-Wallis test, P-value

0.2

0.5

0.0002

0.050

0.3

One-way ANOVA F-test, P-value

0.1

0.4

< 0.001

0.003

0.2

**Table 7.** Differences Between Iron Status Markers in Women, Non-Blood Donors, According to *HFE* Genotypes
HFE genotype	S-iron	S-transferrin	S-transferrin saturation	S-ferritin
Values used for calculation of significances are shown in Table 6. Student’s t-test for unpaired values, two-tailed probability. Significance level with Bonferroni’s correction P < 0.005. wt: wildtype.
wt/wt vs. H63D/wt	0.8	0.3	0.5	0.8
wt/wt vs. C282Y/wt	0.3	0.0004	0.015	0.015
wt/wt vs. C282Y/H63D	0.3	0.054	0.07	0.5
wt/wt vs. H63D/H63D	0.4	0.03	0.07	0.4
wt/wt vs. C282Y/C282Y				0.9
H63D/wt vs. C282Y/wt	0.4	0.0050	0.1	0.041
C282Y/wt vs. C282Y/H63D	0.7	0.6	0.6	0.7
C282Y/H63D vs. H63D/H63D	0.9	0.7	0.9	0.3
H63D/H63D vs. C282Y/C282Y				0.6

Table 7. Differences Between Iron Status Markers in Women, Non-Blood Donors, According to HFE Genotypes

HFE genotype

S-iron

S-transferrin

S-transferrin saturation

S-ferritin

P-values

Values used for calculation of significances are shown in Table 6. Student’s t-test for unpaired values, two-tailed probability. Significance level with Bonferroni’s correction P < 0.005. wt: wildtype.

wt/wt vs. H63D/wt

0.8

0.3

0.5

0.8

wt/wt vs. C282Y/wt

0.3

0.0004

0.015

wt/wt vs. C282Y/H63D

0.3

0.054

0.07

0.5

wt/wt vs. H63D/H63D

0.4

0.03

0.07

0.4

wt/wt vs. C282Y/C282Y

0.9

H63D/wt vs. C282Y/wt

0.4

0.0050

0.1

0.041

C282Y/wt vs. C282Y/H63D

0.7

0.6

0.7

C282Y/H63D vs. H63D/H63D

0.9

0.7

0.9

0.3

H63D/H63D vs. C282Y/C282Y

0.6