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HLA-A and -B alleles and haplotypes in hemochromatosis probands with HFEC282Y homozygosity in central Alabama
© Barton and Acton; licensee BioMed Central Ltd. 2002
Received: 2 August 2002
Accepted: 7 October 2002
Published: 7 October 2002
We wanted to quantify HLA-A and -B allele and haplotype frequencies in Alabama hemochromatosis probands with HFE C282Y homozygosity and controls, and to compare results to those in other populations.
Alleles were detected using DNA-based typing (probands) and microlymphocytotoxicity (controls).
Alleles were determined in 139 probands (1,321 controls) and haplotypes in 118 probands (605 controls). In probands, A*03 positivity was 0.7482 (0.2739 controls; p =< 0.0001; odds ratio (OR) 7.9); positivity for B*07, B*14, and B*56 was also increased. In probands, haplotypes A*03-B*07 and A*03-B*14 were more frequent (p < 0.0001, respectively; OR = 12.3 and 11.1, respectively). The haplotypes A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*35, A*03-B*44, A*03-B*47, and A*03-B*57 were also significantly more frequent in probands. 37.3% of probands were HLA-haploidentical with other proband(s).
A*03 and A*03-B*07 frequencies are increased in Alabama probands, as in other hemochromatosis cohorts. Increased absolute frequencies of A*03-B*35 have been reported only in the present Alabama probands and in hemochromatosis patients in Italy. Increased absolute frequencies of A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*44, A*03-B*47, and A*03-B*57 in hemochromatosis cohorts have not been reported previously.
Hemochromatosis is common among northwestern European peoples and their descendants. This disorder is typically associated with homozygosity for the C282Y mutation of the HFE gene (exon 2, nt 845 G→A) on Ch6p . C282Y lies within an ancestral haplotype which includes the human leukocyte antigen (HLA) haplotype A*03-B*07 [2–5]. The ancestral haplotype is the predominant hemochromatosis-associated haplotype in many northwestern European countries, including Ireland , Brittany , Denmark [7, 8], Sweden , and Germany [10, 11]. This is attributed to the origin of the C282Y mutation on an A*03-B*07 haplotype in northwestern Europe and its early dissemination by Vikings [3, 12]. Modification of the ancestral chromosome by recombination and admixture as a result of geographic migration explains the occurrence of chromosomes bearing C282Y in association with different HLA haplotypes [2, 4, 8, 13–16]. Thus some non-ancestral haplotypes also occur with significantly increased frequencies in hemochromatosis patients in various countries in Europe and in descendants of Europeans [5, 16].
In North America, phenotype frequencies of HLA alleles in persons with hemochromatosis and in control populations have been reported from Canada, Utah, and Minnesota [17–19]. HLA haplotype frequencies for hemochromatosis patients and control subjects in North America have been reported only from Utah . The purpose of the present work was to quantify and analyze the frequencies of HLA-A and -B alleles and haplotypes in hemochromatosis probands with C282Y homozygosity in central Alabama, and to compare the present results to those reported in other populations.
Subjects and Methods
Selection of subjects
The performance of this work was approved by the Institutional Review Boards of Brookwood Medical Center and the University of Alabama at Birmingham. A presumptive diagnosis of hemochromatosis was established using an elevated transferrin saturation criterion; each proband was subsequently evaluated for iron overload and its complications [21–23]. All probands in the present study were white adults (> 18 years of age). Probands were included who had: a) diagnosis of hemochromatosis in routine medical care during the interval 1997 – 2001; b) C282Y homozygosity; c) available HLA-A and -B typing; and d) residence in central Alabama. No patient declined to undergo HFE mutation analysis after it was determined that he/she had a hemochromatosis phenotype. There were A and B typing data in 139 probands. Haplotypes could not be determined in 21 probands due to similarities in alleles of probands and family members, or due to unavailability of family members for analysis. Thus, there were haplotype data on 118 probands.
Data from 1,321 apparently normal, unrelated white adult subjects from Alabama who had undergone A and B phenotype analysis as part of paternity testing were used to estimate allele and gene frequencies [; R.T. Acton, unpublished observations]. A and B haplotypes were determined in 605 unrelated white subjects from Alabama (children and their mothers and/or putative fathers) who had undergone testing to establish paternity.
Serum iron concentration, transferrin saturation, and serum ferritin concentration were measured using automated clinical methods. Sections of liver biopsy specimens were stained using hematoxylin and eosin, Masson's trichrome, and Perls' Prussian blue techniques; intrahepatocytic iron was graded according to the method of Scheuer et al. .
HFE mutation analysis was performed as previously described . A and B alleles were detected using low-resolution DNA-based typing (PCR/sequence-specific oligonucleotide probe) in probands . Control subjects were tested using the microdroplet lymphocytotoxicity test ; subjects were evaluated using antisera that detected allele assignments described in the 9th International Histocompatibility Workshop . Because the levels of resolution of the DNA-based and serological typing methods we used are similar, alleles detected by these respective methods provide concordant allele assignments, with the exception of B*70 and B*71 that were not detected by serological methods. HFE mutation analysis and HLA typing of family members were performed to permit assignment of Ch6p haplotypes. In each proband in whom a single A or B allele was detected by DNA-based typing, we verified the allele(s) and set phase to ascertain haplotypes of the proband using HFE and HLA analyses of appropriate family members. For the present analysis, all haplotypes were defined only by A and B alleles, and the ancestral haplotype was defined as a hemochromatosis-associated Ch6p bearing A*03-B*07 and HFE C282Y.
For most comparisons, recent tabulations of A and B allele associations in 21 case-control studies from thirteen countries and A and B haplotype analyses in persons with hemochromatosis and control subjects in eight countries or regions were used . We also made computerized and manual searches to identify estimates of the prevalence of C282Y homozygosity in hemochromatosis cases in various countries or regions for which A and B haplotype data were also available.
A data set that included HLA types in 139 probands and haplotypes in 118 probands was available. Absolute or "uncorrected" values of A and B phenotype frequencies in probands, respective frequencies of A and B genes, A and B haplotype frequencies, and occurrence of two-haplotype combinations were calculated after enumeration of the raw data. Some previously reported hemochromatosis-associated HLA broad specificities are designated herein as corresponding splits (A*09 = A*23 and A*24; B*05 = B*51 and B*52; and B*12 = B*44 and B*45, respectively) . A computer spreadsheet (Excel 2000, Microsoft Corp., Redmond, WA) and a statistical program (GB-Stat, v. 8.0 2000, Dynamic Microsystems, Inc., Silver Spring, MD) were used to perform the present analyses. Frequency values were compared using chi-square analysis or one-tail Fisher's exact test, as appropriate. A value of p < 0.05 was defined as significant, and these values were expressed to four significant figures. Odds ratios (OR) were calculated as previously described . Bonferroni's correction for multiple tests was not performed because many of the HLA associations with hemochromatosis reported herein have been described elsewhere.
There were 87 men ages 51 ± 4 years (mean ± 1 S.D.) and 52 women ages 50 ± 5 years. Iron overload was detected using serum ferritin concentration, hepatic iron index, or quantitative phlebotomy in 135 probands; three women and one man had no evidence of iron overload. Twenty-six probands (20 men, 6 women) had hepatic cirrhosis demonstrated by hepatic biopsy. Eighteen probands (12 men, 6 women) had diabetes mellitus. Thirteen men had hypogonadotrophic hypogonadism. Cardiomyopathy attributable to iron overload was not diagnosed in any proband.
Phenotype frequencies of HLA-A and -B alleles
Phenotype Frequencies of HLA-A Alleles in Alabama Subjects.1
Frequency in 139 Hemochromatosis Probands
Frequency in Control Subjects (n)
Twenty-five B alleles were detected in 139 probands (Table 2) [Additional file 1]. Thirty-four B alleles were detected in control subjects. The most frequent B alleles in probands were B*07 (0.4748), B*08 (0.1655), B*14 (0.1942), and B*44 (0.2590). The frequencies of B*07, B*14, and B*56 were greater in probands than those in the control subjects (p < 0.0001, OR = 2.6; p < 0.0001, OR = 3.5; and p = 0.0325, OR = 3.8, respectively). B*08 and B*35 occurred with significantly lower frequencies in probands than in control subjects (Table 2) [Additional file 1]. Because arthropathy is common in persons with hemochromatosis , we compared the frequencies of B*27 in probands and control subjects; the difference was not significant (Table 2) [Additional file 1].
Frequencies of HLA-A and -B alleles
Gene frequencies corresponding to A*01 and A*02 were significantly lower in probands than in control subjects (p = 0.0014, OR = 0.5 and p < 0.0001, OR = 0.5, respectively). A*03 was significantly more frequent in probands than in control subjects (p < 0.0001, OR = 6.1). Some probands were homozygous for A alleles by DNA-based typing and family studies: A*01 (n = 2), A*02 (n = 7), A*03 (n = 29), A*11 (n = 1), A*24 (n = 1), and A*24 (n = 1). The B*07 and B*14 gene frequencies were significantly greater in probands than in control subjects (p < 0.0001, OR = 2.5 and p < 0.0001, OR = 3.2, respectively). In addition, the B*56 allele was more frequent in probands (p = 0.0330, OR = 3.8). The B*35 allele was significantly less frequent in probands than in control subjects (p = 0.0159, OR = 0.4). Some probands were homozygous for B alleles by DNA-based typing and family studies: B*07 (n = 13), B*08 (n = 3), B*37 (n = 1), B*44 (n = 2), and B*51 (n = 1).
HLA-A and -B haplotypes
Seventy-two different haplotypes were detected in 118 probands and 133 haplotypes were detected in control subjects. Twenty-three haplotypes detected in probands were not observed in control subjects (Table 3) [Additional file 2].
The most frequent haplotypes in probands were A*01-B*08 (frequency 0.0720); A*02-B*44 (0.0508); A*03-B*07 (0.2966); and A*03-B*14 (0.0847). A*03-B*07 and A*03-B*14 were significantly more frequent in probands than in control subjects (p < 0.0001, respectively; OR = 12.3 and 11.1, respectively) (Table 3) [Additional file 2]. Fifty-eight probands (48.2%) inherited the ancestral haplotype defined as A*03-B*07, HFE C282Y; 46 were heterozygous and 12 were homozygous for the haplotype.
Other haplotypes were also significantly more frequent in probands than in control subjects: A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*35, A*03-B*44, A*03-B*47, and A*03-B*57 (Table 3) [Additional file 2]. The combined frequencies of these ten haplotypes in probands was 0.1441 and in control subjects was 0.0033 (p < 0.0001). The frequencies of haplotypes which included B*07 or B*14 without A*03 were not significantly different in probands and control subjects (Table 3) [Additional file 2]. Homozygosity for these haplotypes was observed in some probands: A*01-B*08 (n = 1); A*02-B*07 (n = 1); A*02-B*44 (n = 1); and A*03-B*07 (n = 12).
HLA Haploidentical Alabama Hemochromatosis Probands.1
Observed Frequency of Probands (no. of probands)
Comparison of Alabama hemochromatosis probands with persons with hemochromatosis in other locations
HLA-A and -B alleles
We compared the present results with data in a previously published tabulation of A and B allele associations in 21 case-control studies from 13 countries or regions in Europe, Australia, and North America . This tabulation yielded a mean A*03 phenotype frequency of 0.75 (range 0.53 – 0.83) in hemochromatosis patients and 0.25 (range 0.19 – 0.31) in control subjects . In Alabama subjects, therefore, the A*03 phenotype frequencies in probands (0.7482) and control subjects (0.2739) were similar to the corresponding mean values previously tabulated . However, the OR for hemochromatosis associated with A*03 in Alabama probands (7.9) was somewhat greater than the corresponding mean value of aggregate data from the tabulation (OR = 6.6; range 3.8 – 15.1; 95% confidence interval 5.7 – 7.6) .
HLA-A and -B haplotypes
We compared the present results with data in a previously published tabulation of A and B haplotypes which occurred with significantly greater frequency in hemochromatosis patients than in corresponding control patients; data were available from Germany, Denmark, Sweden, Brittany, Portugal, Italy, Australia, and Utah (Table 5) [Additional file 3] . Frequencies of the A*03-B*07 haplotype were increased in all hemochromatosis patient groups. The frequencies of the A*03-B*14 haplotype were significantly increased in persons with hemochromatosis in Brittany, Sweden, Utah, and Alabama (Table 5) [Additional file 3] . A significantly increased absolute frequency of the haplotype A*03-B*35 occurred in Alabama probands and in hemochromatosis patients in Italy . A significantly increased frequency of the haplotype A*03-B*15 was observed in the present Alabama hemochromatosis probands; a relative increase in this haplotype was detected in hemochromatosis cohorts in Brittany and Utah [2, 20]. A significantly increased frequency of the haplotype A*03-B*44 was observed in the present Alabama hemochromatosis probands, whereas a relative increase in this haplotype was reported in hemochromatosis cohorts in Sweden, Brittany, and Utah only after "correction" of the data for the preponderance of other haplotypes (Table 5) [Additional file 3] . The increased frequencies of the A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*27, A*03-B*47, and A*03-B*57 haplotypes observed in Alabama probands in the present study were not reported in persons with hemochromatosis in the seven other countries for which data were available (Table 5) [Additional file 3] .
A*03 positivity was detected in more than 74% of Alabama C282Y homozygous hemochromatosis probands in the present study. Similarly, the frequency of A*03 positivity was significantly increased in Alabama hemochromatosis probands diagnosed before the discovery of HFE. These observations are consistent with and extend the findings of 21 previously reported case-controlled studies from thirteen countries which demonstrate the significantly increased prevalence of A*03 in persons with hemochromatosis . The alleles B*07 and B*14 were also more common in the present Alabama probands and in Alabama probands diagnosed before discovery of HFE than in corresponding control subjects . The present analysis demonstrates that this is attributable largely to the association of B*07 and B*14 with A*03, consistent with observations in persons with hemochromatosis patients from many locations, including Ireland , Brittany [2, 32–34], Denmark [7, 8], Sweden [9, 35, 36], Germany [10, 11, 37, 38], Portugal [30, 39], Italy [2, 40], and Utah .
The frequency of the ancestral haplotype defined by A*03-B*07 in the present Alabama probands is greater than that reported in persons with hemochromatosis reported from most other areas. It is possible that our method of selection of subjects for the present study could partly account for this. We selected only probands who had a hemochromatosis phenotype and C282Y homozygosity. Across other studies of HLA haplotypes in subjects with hemochromatosis, criteria for definition of hemochromatosis phenotypes differed. Some studies included probands, whereas others included probands and all family members with hemochromatosis; some required demonstration of segregation with HLA haplotypes, and others did not [33–43]. None used HFE mutation analysis as an inclusion criterion as we required in the present study. In several countries in northwestern Europe, however, the percentage of C282Y homozygotes in hemochromatosis case series is greater than 90% [33–35, 37, 38]. In Queensland, a frequency of C282Y homozygosity of 100% was reported among patients identified by phenotype criteria . Thus, the selection criterion of C282Y homozygosity in the present study nonetheless resulted in a group of hemochromatosis probands the HFE genotypes of which are similar to those of hemochromatosis patients of northwestern European descent in other studies.
The absolute frequencies of haplotypes A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*35, A*03-B*44, A*03-B*47, and A*03-B*57 (in addition to A*03-B*07 and A*03-B*14 haplotypes) were significantly greater in Alabama probands than in control subjects. A significantly increased absolute frequency of the haplotype A*03-B*35 has also been reported in hemochromatosis patients in Italy . The present observations regarding this haplotype may be attributable to the large subgroup of persons of Italian and Sicilian descent in central Alabama . A significantly increased frequency of the haplotype A*03-B*15 was observed in the present Alabama hemochromatosis probands, whereas a relative increase in this haplotype was detected in hemochromatosis cohorts in Brittany and Utah only after "correction" of the data for the preponderance of other haplotypes [2, 20]. Similarly, a significantly increased frequency of the haplotype A*03-B*44 was observed in the present Alabama hemochromatosis probands, whereas a relative increase in this haplotype was detected in hemochromatosis cohorts in Sweden, Brittany, and Utah after "correction" of the data for the preponderance of other haplotypes [2, 8, 19]. The absolute frequency of the haplotype A*03-B*47 was increased in central Alabama hemochromatosis probands, whereas a "corrected" frequency of A*03-B*47 was increased in hemochromatosis patients from Denmark . The other aforementioned haplotypes (except A*03-B*07 and A*03-B*14) have not been reported to occur with increased frequency in any hemochromatosis cohort from locations other than Alabama. Thus, we observed a greater number of haplotypes which were significantly increased in frequency among the present Alabama hemochromatosis probands than have been reported in other hemochromatosis populations, including a cohort in Utah . This could be attributed to a greater degree of genetic heterogeneity among whites in Alabama, consistent with previous reports of genetic characteristics of persons with hemochromatosis in this geographic area [23, 45]. Alternatively, we had greater power to achieve statistical significance in the present analyses than did some other studies. Nonetheless, the percentage of the present probands who were HLA-haploidentical with at least one other proband indicates that the haplotypes among hemochromatosis patients in central Alabama are more restricted than those in the general population [46, 47].
In Alabama subjects with hemochromatosis, the A*03-B*07 haplotype is not invariably associated with inheritance of C282Y. The frequency of the A*03-B*07 haplotype was significantly increased in Alabama hemochromatosis probands without C282Y , some of whom had the common HFE missense mutation H63D . A*03-B*07 haplotypes associated with H63D have also been described in Alabama subjects with primary antibody deficiency . Some Alabama subjects with hemochromatosis have an A*03-B*07 haplotype which includes the novel HFE missense mutation I105T . Thus, a variety of HFE missense mutations occur in association with A*03-B*07 haplotypes in white Alabamians.
A*03 and A*03-B*07 frequencies are increased in Alabama probands, like other hemochromatosis cohorts. Increased absolute frequencies of the haplotype A*03-B*35 have been reported only in the present Alabama probands and in hemochromatosis patients in Italy. Increased absolute frequencies of A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*44, A*03-B*47, and A*03-B*57 were detected in the present cohort of Alabama hemochromatosis probands, but these haplotypes have not been reported to occur with increased absolute frequency in other hemochromatosis populations. Modification of the ancestral chromosome by recombination and admixture as a result of geographic migration could explain the previously undescribed occurrence of HLA haplotypes that occur in association with C282Y. These results could also be explained by the greater degree of genetic heterogeneity in white Alabamians than in other populations, and by the larger numbers of probands and control subjects and greater statistical power to demonstrate significant differences in the present study than in some similar previous studies. A variety of HFE missense mutations occur in association with A*03-B*07 haplotypes in white Alabamians.
This work was supported in part by Southern Iron Disorders Center.
- Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo Jr R, Ellis MC, Fullan A, et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996, 13: 399-408.View ArticlePubMedGoogle Scholar
- Simon M, Le Mignon L, Fauchet R, Yaouanq J, David V, Edan G, Bourel M: A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLA-A locus and characters required to define a homozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet. 1987, 41: 89-105.PubMedPubMed CentralGoogle Scholar
- Fairbanks VF: Hemochromatosis: population genetics. In: Hemochromatosis. Genetics, Pathophysiology, Diagnosis, and Treatment. Edited by: Barton JC, Edwards CQ. 2000, Cambridge, Cambridge University Press, 42-50.View ArticleGoogle Scholar
- Jazwinska EC: The ancestral haplotype in hemochromatosis. In: Hemochromatosis. Genetics, Pathophysiology, Diagnosis, and Treatment. Edited by: Barton JC, Edwards CQ. 2000, Cambridge, Cambridge University Press, 91-99.View ArticleGoogle Scholar
- Porto G, de Sousa M: Variation in hemochromatosis prevalence and genotype in national groups. In: Hemochromatosis. Genetics, Pathophysiology, Diagnosis, and Treatment. Edited by: Barton JC, Edwards CQ. 2000, Cambridge, Cambridge University Press, 51-62.View ArticleGoogle Scholar
- Murphy S, Curran MD, McDougall N, Callender ME, O'Brien CJ, Middleton D: High incidence of the Cys 282 Tyr mutation in the HFE gene in the Irish population – implications for haemochromatosis. Tissue Antigens. 1998, 52: 484-488.View ArticlePubMedGoogle Scholar
- Milman N, Graudal N, Nielsen LS, Fenger K: HLA determinants in 70 Danish patients with idiopathic haemochromatosis. Clin Genet. 1988, 33: 286-292.View ArticlePubMedGoogle Scholar
- Powell LW, Bassett ML, Axelsen E, Ferluga J, Halliday JW: Is all hereditary hemochromatosis HLA-associated?. Ann N Y Acad Sci. 1988, 526: 23-33.View ArticlePubMedGoogle Scholar
- Ritter B, Säfwenberg J, Olsson KS: HLA as a marker of the hemochromatosis gene in Sweden. Hum Genet. 1984, 68: 62-66.View ArticlePubMedGoogle Scholar
- Walz H, Rose M, Klein B, Wichmann V: Vaterschaftswahrscheinlichkeit und Vaterschaftsausschluβ chance im HLA-system. Dtsc Gesund-Wes. 1981, 36: 1576-1579.Google Scholar
- Knau B, Röβner M, Schmidt U: Idiopathische hämochromatose: assoziation mit antigenen des HLA-systems. Med Klin. 1991, 86: 503-507.Google Scholar
- Raha-Chowdhury R, Gruen J: Localization, allelic heterogeneity, and origins of the hemochromatosis gene. In: Hemochromatosis. Genetics, Pathophysiology, Diagnosis, and Treatment. Edited by: Barton JC, Edwards CQ. 2000, Cambridge, Cambridge University Press, 75-90.View ArticleGoogle Scholar
- Ajioka RS, Jorde LB, Gruen JR, Yu P, Dimitrova D, Barrow J, Radisky E, Edwards CQ, Griffen LM, Kushner JP: Haplotype analysis of hemochromatosis: evaluation of different linkage-disequilibrium approaches and evolution of disease chromosomes. Am J Hum Genet. 1997, 60: 1439-1447.View ArticlePubMedPubMed CentralGoogle Scholar
- Gaudieri S, Leelayuwat C, Tay GK, Townsend DC, Dawkins RL: The major histocompatibility complex (MHC) contains conserved polymorphic genomic sequences that are shuffled by recombination to form ethnic-specific haplotypes. J Mol Evol. 1997, 45: 17-23.View ArticlePubMedGoogle Scholar
- Malfroy L, Roth MP, Carrington M, Borot N, Volz A, Ziegler A, Coppin H: Heterogeneity in rates of recombination in the 6-Mb region telomeric to the human major histocompatibility complex. Genomics. 1997, 43: 226-231. 10.1006/geno.1997.4800.View ArticlePubMedGoogle Scholar
- Yaouanq J: Human leukocyte antigen (HLA) association and typing in hemochromatosis. In: Hemochromatosis. Genetics, Pathophysiology, Diagnosis, and Treatment. Edited by: Barton JC, Edwards CQ. 2000, Cambridge, Cambridge University Press, 63-74.View ArticleGoogle Scholar
- Lloyd DA, Adams P, Sinclair NR, Stiller CR, Valberg LS: Histocompatibility antigens as markers of abnormal iron metabolism in idiopathic hemochromatosis. Can Med Assoc J. 1978, 119: 1051-1056.PubMedPubMed CentralGoogle Scholar
- Edwards CQ, Dadone MM, Skolnick MH, Kushner JP: Hereditary haemochromatosis. Clin Haematol. 1982, 11: 411-435.PubMedGoogle Scholar
- Le Sage GD, Baldus WP, Fairbanks VF, Baggenstoss AH, McCall JT, Moore SB, Taswell HF, Gordon H: Hemochromatosis: genetic or alcohol induced?. Gastroenterology. 1983, 84: 1471-1477.Google Scholar
- Bulaj Z, Griffen LM, Jorde LB, Edwards CQ, Kushner JP: Clinical and biochemical abnormalities in people heterozygous for hemochromatosis. N Engl J Med. 1996, 335: 1799-1805. 10.1056/NEJM199612123352403.View ArticlePubMedGoogle Scholar
- Barton JC, Harmon L, Rivers C, Acton RT: Hemochromatosis: association of severity of iron overload with genetic markers. Blood Cells Mol Dis. 1996, 22: 195-204. 10.1006/bcmd.1996.0100.View ArticlePubMedGoogle Scholar
- Witte DL, Crosby WH, Edwards CQ, Fairbanks VF, Mitros FA: Hereditary hemochromatosis. Clin Chim Acta. 1996, 245: 139-200. 10.1016/0009-8981(95)06212-2.View ArticlePubMedGoogle Scholar
- Barton JC, Shih WWH, Sawada-Hirai R, Acton RT, Harman L, Rivers C, Rothenberg BE: Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis. Blood Cells Mol Dis. 1997, 23: 135-145. 10.1006/bcmd.1997.0129.View ArticlePubMedGoogle Scholar
- Scheuer PJ, Williams R, Muir AR: Hepatic pathology in relatives of patients with hemochromatosis. J Pathol Bact. 1962, 84: 53-63.View ArticleGoogle Scholar
- Murphy CC, Acton RT, Barger BO, Go RC, Kirk KA, Reitnauer PJ, Roseman JM: Population genetic analysis of insulin dependent diabetes mellitus using HLA allele frequencies. Clin Genet. 1983, 23: 405-414.View ArticlePubMedGoogle Scholar
- Albert ED, Baur MP, Mayr WR: Histocompatibility Testing 1984. Berlin, Springer-Verlag. 1984Google Scholar
- Woolf B: On estimating the relation between blood groups and disease. Ann Hum Genet. 1955, 19: 251-253.View ArticlePubMedGoogle Scholar
- Rull M, Schumacher HR: The arthropathy of hemochromatosis. In : Hemochromatosis. Genetics, Pathophysiology, Diagnosis, and Treatment. Edited by: Barton JC, Edwards CQ. 2000, Cambridge, Cambridge University Press, 258-267.View ArticleGoogle Scholar
- Piperno A, Fargion S, Panaiotopoulos N, Del Nino E, Taddei MT, Fiorelli G: Idiopathic hemochromatosis and HLA antigens in Italy: Is A3 BW35 HLA haplotype a marker for idiopathic haemochromatosis gene in North East regions?. J Clin Pathol. 1986, 39: 125-128.View ArticlePubMedPubMed CentralGoogle Scholar
- Porto G, Martins da Silva B, Vicente C, de Sousa M: Idiopathic haemochromatosis in North Portugal: association with haplotype A3, B7. J Clin Pathol. 1989, 42: 667-668.View ArticlePubMedPubMed CentralGoogle Scholar
- Summers KM, Tam KS, Halliday JW, Powell LW: HLA determinants in an Australian population of hemochromatosis patients and their families. Am J Hum Genet. 1989, 45: 41-48.PubMedPubMed CentralGoogle Scholar
- Simon M, Yaouanq J, Fauchet R, Le Gall J-Y, Brissot P, Bourel M: Genetics of hemochromatosis: HLA association and mode of inheritance. Ann N Y Acad Sci. 1988, 526: 11-22.View ArticlePubMedGoogle Scholar
- Jouanolle AM, Yaouanq J, Blayau M, Perichon M, Fauchet R, Font MP, Le Gall J-Y, David V: HLA class I gene polymorphism in genetic hemochromatosis. Hum Genet. 1990, 85: 279-282.View ArticlePubMedGoogle Scholar
- Brissot P, Moirand R, Jouanolle AM, Le Gall J-Y, Deugnier Y, David V: A genotypic study of 207 unrelated probands diagnosed as 'genetic hemochromatosis' on 'classical' phenotypic criteria. In: International Symposium: Iron in Biology and Medicine, St. Malo. 1997Google Scholar
- Cardoso EM, Stal P, Hagen K, Cabeda JM, Esin S, de Sousa M, Hultcrantz R: HFE mutations in patients with hereditary haemochromatosis in Sweden. J Intern Med. 1998, 243: 203-208. 10.1046/j.1365-2796.1998.00270.x.View ArticlePubMedGoogle Scholar
- Olsson KS, Ritter B, Sandberg L, Raha-Chowdhury R, Gruen J, Worwood M: The ancestral haplotype in patients with genetic hemochromatosis from Central and Western Sweden. In: International Symposium: Iron in Biology and Medicine, St. Malo. 1997Google Scholar
- Nielsen P, Carpinteiro S, Fischer R, Cabeda JM, Porto G, Gabbe EE: Prevalence of the C282Y and H63D mutations in the HFE gene in patients with hereditary haemochromatosis and in control subjects from Northern Germany. Br J Haematol. 1998, 103: 842-845. 10.1046/j.1365-2141.1998.01037.x.View ArticlePubMedGoogle Scholar
- Gottschalk R, Seidl C, Loffler T, Seifried E, Hoelzer D, Kaltwasser JP: HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic haemochromatosis. Tissue Antigens. 1998, 51: 270-275.View ArticlePubMedGoogle Scholar
- Porto G, Alves H, Rodrigues P, Cabeda JM, Portal C, Ruivo A, Justica B, Wolff R, De Sousa M: Major histocompatibility complex class I associations in iron overload: evidence for a new link between the HFE H63D mutation, HLA-A29 and non-classical forms of hemochromatosis. Immunogenetics. 1997, 47: 404-410. 10.1007/s002510050376.View ArticleGoogle Scholar
- Carella M, D'Ambrosio L, Totaro A, Grifa A, Valentino MA, Piperno A, Girelli D, Roetto A, Franco B, Gasparini P, et al: Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet. 1997, 60: 828-832.PubMedPubMed CentralGoogle Scholar
- Bernard PS, Ajioka RS, Kushner JP, Wittwer CT: Homogeneous multiplex genotyping of hemochromatosis mutations with fluorescent hybridization probes. Am J Pathol. 1998, 153: 1055-161.View ArticlePubMedPubMed CentralGoogle Scholar
- Jazwinska EC, Cullen LM, Busfield F, Pyper WR, Webb SI, Powell LW, Morris CP, Walsh TP: Haemochromatosis and HLA-H. Nat Genet. 1996, 14: 249-251.View ArticlePubMedGoogle Scholar
- Jeffrey G, Rossi E, Chin C: HLA-H genotyping of a western Australian genetic hemochromatosis population. In: International Symposium: Iron in Biology and Medicine, St. Malo. 1997Google Scholar
- Barton JC JC, Acton RT: Transferrin saturation phenotype and HFE genotype screening for hemochromatosis and primary iron overload: predictions from a model based on national, racial, and ethnic group composition in central Alabama. Genet Test. 2000, 4: 199-206. 10.1089/10906570050114911.View ArticlePubMedGoogle Scholar
- Acton RT, Barton JC: HFE genotype frequencies in consecutive reference laboratory specimens: comparisons among referral sources and association with initial diagnosis. Genet Test. 2001, 5: 299-306. 10.1089/109065701753617426.View ArticlePubMedGoogle Scholar
- Zachary AA, Steinberg AG: Statistical analysis and applications of HLA population data. In: Manual of Clinical Laboratory Immunology. Edited by: Rose NR, de Macario EC, Folds JD, Lane HC, Nakamura RM. 1997, Washington, ASM Press, 1132-1140.Google Scholar
- Gjertson DW, Lee S-H: HLA-A/B and -DRB1/DQB1 allele-level haplotype frequencies. In: HLA 1998. Edited by: Gjertson DW, Terasaki PI. 1998, Lenexa, American Society for Histocompatibility and Immunogenetics, 365-450.Google Scholar
- Barton JC, Acton RT, Bertoli LF: Hemochromatosis and primary antibody deficiency: occurrence in the same individual and frequency of common HFE mutations among common variable immunodeficiency and IgG subclass deficiency index cases. Blood. 2000, 96: 4b-Google Scholar
- Barton JC, Sawada-Hirai R, Rothenberg BE, Acton RT: Two novel missense HFE mutations (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. Blood Cells Mol Dis. 1999, 25: 147-155. 10.1006/bcmd.1999.0240.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/3/9/prepub
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