Comprehensive analysis of HFE gene in hereditary hemochromatosis and in diseases associated with acquired iron overload

doi:10.4254/wjh.v11.i2.186

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World J Hepatol. Feb 27, 2019; 11(2): 186-198
Published online Feb 27, 2019. doi: 10.4254/wjh.v11.i2.186

Table 1 The single nucleotide polymorphism reference number (rs), the usual single nucleotide polymorphism names (H63DC>G, C282YG>A, IVS2(+4)T>C and IVS4(-44)T>C) and new variation sites

SNPs	Allele/genotype	HH	HCV-IO⁺	HCV-IO^-	HCC HCV-IO⁺	HCC-IO^?	CTL
H63DC>G (rs1799945) [+3511]	C	0.893	0.859	0.864	0.805	0.921	0.825
	G	0.107	0.141	0.136	0.195	0.079	0.175
	GG	0.000	0.042	0.000	0.024	0.000	0.030
	CG	0.214	0.197	0.271	0.341	0.158	0.290
	CC	0.786	0.761	0.729	0.634	0.842	0.680
	HW P value	1.000	1.000	0.580	1.000	1.000	1.000
IVS2(+4)T>C (rs2071303) [+3668]	T	0.857	0.641	0.669	0.585	0.684	0.610
	C	0.143	0.359	0.331	0.415	0.316	0.390
	TT	0.714¹	0.408	0.424	0.390	0.526	0.390
	TC	0.286	0.465	0.492	0.390	0.316	0.440
	CC	0.000	0.127	0.085	0.220	0.158	0.170
	HW P value	0.528	1.000	0.556	0.212	0.295	0.528
G>C (rs807209) [+5197]	G	0.000	0.007	0.017	0.000	0.053	0.035
	C	1.000	0.993	0.983	1.000	0.947	0.965
	GG	0.000	0.000	0.000	0.000	0.000	0.010
	GC	0.000	0.014	0.034	0.000	0.105	0.050
	CC	1.000	0.986	0.966	1.000	0.895	0.940
	HW P value	-	-	1.000	-	1.000	0.103
C282YG>A (rs1800562) [+5473]	G	0.286²	0.979	0.983	0.902	1.000	0.955
	A	0.714²	0.021	0.017	0.098	0.000	0.045
	GG	0.071²	0.958	0.966	0.854	1.000	0.910
	GA	0.429	0.042	0.034	0.098	0.000	0.090
	AA	0.500²	0.000	0.000	0.049	0.000	0.000
	HW P value	1.000	1.000	1.000	0.031	-	1.000
IVS4(–44)T>C (rs1800708) [+5635]	T	1.000	0.880	0.907	0.817	0.842	0.925
	C	0.000	0.120	0.093	0.183	0.158	0.075
	CC	0.000	0.014	0.000	0.024	0.000	0.000
	TC	0.000	0.211	0.186	0.317	0.316	0.150
	TT	1.000	0.775	0.814	0.659	0.684	0.850
	HW P value	1.000	1.000	1.000	1.000	1.000	1.000
New mutation (G>Del) at intron 5 [+5811]	G	1.000	1.000	1.000	1.000	1.000	0.995
	Del	0.000	0.000	0.000	0.000	0.000	0.005
	GG	1.000	1.000	1.000	1.000	1.000	0.990
	G Del	0.000	0.000	0.000	0.000	0.000	0.010
	Del Del	0.000	0.000	0.000	0.000	0.000	0.000
	HW P value	-	-	-	-	-	-

Frequency of single nucleotide polymorphism (SNP) alleles and genotypes observed at the HFE coding region (ordered from 5’ to 3’) in patients with hereditary hemochromatosis (HH), hepatitis C exhibiting (HCV-IO⁺) or not (HCV-IO^-) iron overload, hepatocellular carcinoma and hepatitis C plus iron overload (HCC HCV-IO⁺), hepatocellular carcinoma caused by diverse etiologies other than HCV and without information regarding iron overload (HCC-IO^?), and in healthy control individuals (CTL). The reference SNP numbers (rs) and the position SNP base [ ] are also shown for the previously described HFE variation sites and were assigned according to NCBI (http://www.ncbi.nlm.nih.gov) and Ensembl (http://www.ensembl.org) databases. Significant Fisher’s exact test P values (≤ 0.05) and Hardy-Weinberg equilibrium adherence are shown in table.

¹HH x CTL: TT (P = 0.04; OR = 3.91; 95%CI: 1.14-13.34);

²HH x CTL: G (P < 0.001; OR = 0.01; 95%CI: 0.006-0.05), A (P < 0.001; OR = 53.06; 95%CI: 18.41-152.90), GG (P < 0.001; OR = 0.007; 95%CI: 0.0008-0.065) and AA (P < 0.001; OR = 201.00; 95%CI: 10.44-3.871). The most frequent allele/genotype different of healthy controls. In italics: alleles and genotypes that presented statistically significant values.

Table 2 HFE coding region allele frequency in individuals exhibiting congenital or acquired iron overload and healthy control population

Allele	SNPs sequences	Population frequencies (f)
	SNPs sequences	IO^-				IO⁺								IO^?		Whole
	1-2-3-4-5-6³	CTL		HCV-IO^-		HCV-IO⁺		HCC HCV-IO⁺		HH		TOTAL		HCC-IO^?
	1-2-3-4-5-6³	n = 100	%	n = 59	%	n = 71	%	n = 24	%	n = 28	%	n = 109	%	n = 36	%	n = 304		%
HFE*001⁴	C-T-C-G-T-G	107	0.54	74	0.63	86	0.61	23	0.48	4²	0.14	113	0.52	40	0.56	334	0.55
HFE*001:unofficial:02⁵	C-C-C-G-T-G	28	0.14	12	0.10	15	0.11	3	0.06	1	0.04	19	0.09	4	0.06	63	0.10
HFE*001:unofficial:03⁵	C-T-G-G-T-G	8	0.04	2	0.02	1	0.01	0	0.00	0	0.00	1	0.00	2	0.03	12	0.02
HFE*001:unofficial:04⁵	C-T-C-G-C-G	0	0.00	0	0.00	1	0.01	1	0.02	0	0.00	2	0.01	1	0.01	3	< 0.01
HFE*001:unofficial:05⁵	C-C-C-G-C-G	13	0.07	11	0.09	16	0.11	7¹	0.15	0	0.00	23	0.11	12	0.17	59	0.10
HFE*001:unofficial:06⁵	C-C-G-G-T-Del	1	0.01	0	0.00	0	0.00	0	0.00	0	0.00	0	0.00	0	0.00	1	< 0.01
HFE*002⁴	G-C-C-G-T-G	35	0.17	16	0.13	20	0.14	9¹	0.19	3	0.11	32	0.15	8	0.11	92	0.15
HFE*003⁴	C-T-C-A-T-G	8	0.04	3	0.02	3	0.02	3	0.06	20²	0.71	26	0.12	4	0.06	40	0.06
HFE*004⁴	G-C-C-A-T-G	0	0.00	0	0.00	0	0.00	1	0.02	0	0.00	1	0.00	0	0.00	1	< 0.01
Number of alleles		200		118		142		48		28		218		72		608

Patients with hereditary hemochromatosis (HH), patients with hepatitis C exhibiting (HCV-IO⁺) or not (HCV-IO^-) iron overload, hepatocellular carcinoma (HCC) plus HCV-IO⁺, HCC caused by diverse etiologies other than HCV and without information regarding iron overload (HCC-IO^?), and population healthy control individuals (CTL).

¹HCC HCV-IO⁺ x CTL: HFE*001:unofficial:06/HFE*002 (P = 0.02; OR = 14.14; 95%CI: 1.40-142.80);

²HH x CTL: HFE*001 (P < 0.001; OR = 0.14; 95%CI: 0.04-0.43), HFE*003 (P < 0.001; OR = 60.00; 95%CI: 20.31-177.20), HFE*001/HFE*003 (P = 0.03; OR = 7.20; 95%CI: 1.40-36.85), HFE*003/HFE*003 (P < 0.001; OR = 174.20; 95%CI: 8.92-400.00);

³ Order of base changes for each single nucleotide polymorphism (SNP) observed, encompassing H63DC>G; IVS2(+4)T>C; rs807209G>C; C282YG>A; IVS4(-44)T>C; new deletionG>DEL (5’ to 3’);

⁴Alleles recognized by ImMunoGeneTics information system – IMGT;

⁵Alleles in validation process.

Table 3 Linkage disequilibrium between HLA-B alleles and HFE coding region H63DC>G single nucleotide polymorphism alleles

	Observed frequency		Expected frequency		Standardized value of disequilibrium(D’)		Standardized value of correlation(r²)	QUI²value	P value of QUI²
*HLA-B*	HFE H63DC>G
*HLA-B*	C	G	C	G	C	G
07	16	2	14.83	3.17	0.3683	-0.3683	0.0029	0.5728	0.4492
08	12	1	10.71	2.29	0.5626	-0.5626	0.0047	0.9396	0.3324
13	3	1	3.30	0.70	-0.0899	0.0899	0.0008	0.1547	0.6941
14	10	0	8.24	1.76	1.0000	-1.0000	0.0113	2.2471	0.1339
15	17	0	14.01	2.99	1.0000	-1.0000	0.0199	3.9669	0.0464
18	10	0	8.24	1.76	1.0000	-1.0000	0.0113	2.2471	0.1339
27	2	2	3.30	0.70	-0.3933	0.3933	0.0149	2.9586	0.0854
35	17	4	17.31	3.69	-0.0177	0.0177	0.0002	0.0345	0.8526
37	1	2	2.47	0.53	-0.5955	0.5955	0.0254	5.0617	0.0245
38	3	0	2.47	0.53	1.0000	-1.0000	0.0033	0.6500	0.4201
39	4	2	4.94	1.06	-0.1911	0.1911	0.0053	1.0582	0.3036
40	3	0	2.47	0.53	1.0000	-1.0000	0.0033	0.6500	0.4201
41	3	0	2.47	0.53	1.0000	-1.0000	0.0033	0.6500	0.4201
42	1	0	0.82	0.18	1.0000	-1.0000	0.0011	0.2145	0.6433
44	8	11	15.66	3.34	-0.4891	0.4891	0.1183¹	23.5443	< 0.00001
45	6	0	4.94	1.06	1.0000	-1.0000	0.0066	1.3203	0.2505
48	2	0	1.65	0.35	1.0000	-1.0000	0.0022	0.4312	0.5114
49	8	0	6.59	1.41	1.0000	-1.0000	0.0089	1.7788	0.1823
50	2	0	1.65	0.35	1.0000	-1.0000	0.0022	0.4312	0.5114
51	9	5	11.54	2.46	-0.2199	0.2199	0.0172	3.4137	0.0647
52	7	0	5.77	1.23	1.0000	-1.0000	0.0078	1.5484	0.2134
53	5	0	4.12	0.88	1.0000	-1.0000	0.0055	1.0946	0.2955
55	2	0	1.65	0.35	1.0000	-1.0000	0.0022	0.4312	0.5114
56	0	1	0.82	0.18	-1.0000	1.0000	0.0237	4.7094	0.0300
57	8	2	8.24	1.76	-0.0293	0.0293	0.0002	0.0423	0.8371
58		2	4.94	1.06	-0.1911	0.1911	0.0053	1.0582	0.3036
67	1	0	0.82	0.18	1.0000	-1.0000	0.0011	0.2145	0.6433

¹The higher value of correlation. Identification of single nucleotide polymorphisms and most frequent allele according to NCBI (http://www. ncbi.nlm.nih.gov) and Ensembl (http://www.ensembl.org): rs1799945 (H63DC>G). Shaded cells are showing significant LD values.

Table 4 Linkage disequilibrium between HLA-B alleles and HFE coding region IVS2(+4)T>C single nucleotide polymorphism alleles

	Observed frequency		Expected frequency		Standardized value of disequilibrium(D’)		Standardized value of correlation(r²)	QUI²value	P value of QUI²
*HLA-B*	HFE IVS2(+4)T>C
*HLA-B*	T	C	T	C	T	C
07	13	5	10.98	7.02	0.2877	-0.2877	0.0052	1.0471	0.3062
08	8	5	7.93	5.07	0.0138	-0.0138	0.0000	0.0017	0.9672
13	4	0	2.44	1.56	1.0000	-1.0000	0.0130	2.6096	0.1062
14	4	6	6.10	3.90	-0.3443	0.3443	0.0098	1.9513	0.1624
15	11	6	10.37	6.63	0.0950	-0.0950	0.0005	0.1073	0.7433
18	8	2	6.10	3.90	0.4872	-0.4872	0.0080	1.5973	0.2063
27	1	3	2.44	1.56	-0.5902	0.5902	0.0111	2.2235	0.1359
35	17	4	12.81	8.19	0.5116	-0.5116	0.0196	3.9264	0.0475
37	0	3	1.83	1.17	-1.0000	1.0000	0.0238	4.7638	0.0291
38	2	1	1.83	1.17	0.1453	-0.1453	0.0002	0.0411	0.8393
39	1	5	3.66	2.34	-0.7268	0.7268	0.0256	5.1103	0.0238
40	3	0	1.83	1.17	1.0000	-1.0000	0.0097	1.9472	0.1629
41	2	1	1.83	1.17	0.1453	-0.1453	0.0002	0.0411	0.8393
42	1	0	0.61	0.39	1.0000	-1.0000	0.0032	0.6426	0.4228
44	6	13	11.59	7.41	-0.4823	0.4823	0.0382¹	7.6388	0.0057
45	3	3	3.66	2.34	-0.1803	0.1803	0.0016	0.3146	0.5749
48	2	0	1.22	0.78	1.0000	-1.0000	0.0065	1.2916	0.2558
49	8	0	4.88	3.12	1.0000	-1.0000	0.0266	5.3279	0.0210
50	2	0	1.22	0.78	1.0000	-1.0000	0.0065	1.2916	0.2558
51	10	4	8.54	5.46	0.2674	-0.2674	0.0034	0.6882	0.4068
52	3	4	4.27	2.73	-0.2974	0.2974	0.0050	1.0037	0.3164
53	5	0	3.05	1.95	1.0000	-1.0000	0.0164	3.2787	0.0702
55	0	2	1.22	0.78	-1.0000	1.0000	0.0158	3.1598	0.0755
56	1	0	0.61	0.39	1.0000	-1.0000	0.0032	0.6426	0.4228
57	4	6	6.10	3.90	-0.3443	0.3443	0.0098	1.9513	0.1624
58	1	5	3.66	2.34	-0.7268	0.7268	0.0256	5.1103	0.0238
67	1	0	0.61	0.39	1.0000	-1.0000	0.0032	0.6426	0.4228

¹The higher value of correlation. Identification of single nucleotide polymorphisms and most frequent allele according to NCBI (http://www. ncbi.nlm.nih.gov) and Ensembl (http://www.ensembl.org): rs2071303 (IVS2(+4)T>C). Shaded cells are showing significant LD values.

Citation: de Campos WN, Massaro JD, Cançado ELR, Wiezel CEV, Simões AL, Teixeira AC, Souza FF, Mendes-Junior CT, Martinelli ALC, Donadi EA. Comprehensive analysis of HFE gene in hereditary hemochromatosis and in diseases associated with acquired iron overload. World J Hepatol 2019; 11(2): 186-198
URL: https://www.wjgnet.com/1948-5182/full/v11/i2/186.htm
DOI: https://dx.doi.org/10.4254/wjh.v11.i2.186