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

doi:10.4254/wjh.v11.i2.186

Advanced Search

BPG is committed to discovery and dissemination of knowledge

Home / Archive / Volume 11, Issue 2

This Article

Academic Content and Language Evaluation of This Article

CrossCheck and Google Search of This Article

Academic Rules and Norms of This Article

Supplementary Materials of This Article

Citation of this article

Corresponding Author of This Article

Research Domain of This Article

Article-Type of This Article

Open-Access Policy of This Article

Times Cited Counts in Google of This Article

Number of Hits and Downloads for This Article

Total Article Views (9705)

All Articles published online

The chart showing PDF series, WORD series, HTML series, Figures (1-3) series, Tables (1-4) series.

Item

Count

PDF

449

WORD

201

HTML

5479

Figures (1-3)

365

Tables (1-4)

301

Sum=6795

Publishing Process of This Article

The chart showing Browse series, Download series.

Item

Count

Browse

977

Download

1933

Sum=2910

Feb 27, 2019 (publication date) through Nov 21, 2024

Times Cited of This Article

Times Cited (2)

Journal Information of This Article

Publication Name

World Journal of Hepatology

ISSN

1948-5182

Publisher of This Article

Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Case Control Study

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