HLA determinants in 70 Danish patients with idiopathic haemochromatosis

HLA-A, -B, -C and -DR antigens were determined in 70 unrelated Danish patients with idiopathic haemochromatosis. The frequencies of HLA-A and -B antigens compared to 1967 normal control subjects and the relative risk values (RR) were: A3, 80.0% vs. 26.9% (P less than 0.0001), RR = 10.9; B7, 60.0% vs. 26.8% (P less than 0.0001), RR = 4.1; B14, 10.0% vs. 4.5% (P = 0.03), RR = 2.4; B47, 4.3% vs. 0.5% (P less than 0.0001), RR = 9.7; A3, B7, 51.4% vs. 12.2% (P less than 0.0001), RR = 7.6; A3, B14, 10.0% vs. 1.4% (P less than 0.0001), RR = 7.7; A3, B47, 4.3% vs. 0.5% (P less than 0.0001), RR = 9.7. Six patients (8.6%) possessed none of these four typical antigens. There was no association between disease and the frequencies of HLA-C and HLA-DR antigens. The pattern of HLA-antigens associated with haemochromatosis in Denmark shows similarities to those reported both in Germany, being HLA-A3, B7 dominated, and in Brittany, Great Britain and Central Sweden, being HLA-A3, B14 dominated.     

HLA antigens in Hungarian patients with idiopathic haemochromatosis.

Thirteen unrelated patients with idiopathic haemochromatosis (eight men, five women) were studied. The diagnosis was based on clinical, biological, and histochemical findings. HLA typing was performed in all 13 and in all of their available first degree relatives (n = 31). HLA A3 was present in nine of 13 probands (69.2% compared with 18.8% in the group of 53 healthy blood donors and 22.4% in a selected Hungarian population (n = 1910). HLA B7 was present in five of 13 probands (38.4% compared with 11.3% and 14.6%). An A3B7 antigen association was found in five of 13 patients. The A3B7 haplotype was found in three, A2B12 and A2B38 haplotypes were found twice in 10 genotyped probands. Pedigree studies showed that there was one unaffected homozygote, 24 heterozygotes, and six non-carriers. Extended family and population studies are necessary to establish the prevalence of the gene in Hungary and an association with haplotypes other than A3B7.     

Idiopathic haemochromatosis and HLA antigens in Italy: is A3 Bw35 HLA haplotype a marker for idiopathic haemochromatosis gene in north east regions?

Thirty two unrelated Italian subjects with idiopathic haemochromatosis were studied. HLA-A3 was present in 26 of them (81% v 22% in controls; p less than 0.001) and HLA B7 in eight (28% v 9%; p less than 0.01). There was no important association between idiopathic haemochromatosis and HLA B14. Subdividing the patients on the basis of their regional origin a noticeably higher prevalence of HLA Bw35 in patients with idiopathic haemochromatosis from north eastern Italy was found than in those from Lombardy, or in the controls; there were no differences in the incidence of HLA A3 and B7 between patients with idiopathic haemochromatosis from different areas. A high prevalence of A3, Bw35, and A3, B7 haplotypes was found in our patients with idiopathic haemochromatosis. A3, Bw35 could be the haplotype most commonly linked to the idiopathic haemochromatosis gene in north eastern Italy.     

Differential ferrioxamine test in idiopathic haemochromatosis and transfusional haemosiderosis

The differential ferrioxamine test measures the amount of body iron as ferrioxamine (Fv) chelated by a standard dose of desferrioxamine.Five patients with untreated, uncomplicated idiopathic haemochromatosis and one with transfusion haemosiderosis gave Fv in the range 1,948 to 2,462 mug./kg. (normal 110 to 500). One case of transfusion haemochromatosis with haemolytic anaemia and renal failure gave an Fv value of 8,019 mug./kg. Four patients with idiopathic haemochromatosis after therapeutic venesection gave Fv values of 212 to 885 mug./kg. One relative with a value for Fv of 776 mug./kg. was shown to have early cirrhosis by liver biopsy. Serial Fv measurement after venesection in this patient provided a preliminary assessment of the relationship between Fv values and available iron stores up to about 2,000 mg. iron. This relationship applies only when red cell survival is normal. Approximate figures for the range of available storage iron in 31 healthy men are deduced, namely, 200 mg. to 1,000 mg. (3 to 14 mg./kg.).The test should prove useful in the diagnosis of iron overload, in the screening of relatives for early haemochromatosis, and in the management of iron storage diseases.     

HLA genetic determinants in familial MS

Fourteen multiplex MS families, 9 single-case MS families and 11 normal families from the Grampian region of North-East Scotland were studied. The prevalence rate of MS for individuals in multiplex families was calculated at 809/100,000; 4.5 times the prevalence rate for the general population in this region. The distribution of shared haplotypes in 12 affected and 19 unaffected sib-pair comparisons did not differ significantly from that expected by chance. Furthermore there was no evidence that homozygosity of a particular HLA gene was required for increased susceptibility to the disease. HLA-B7, C4A3, C4B1, BfS, HLA-DR2, HLA-DQw1 was the commonest haplotype accounting for 18.9% and 24.2% of parental haplotypes from multiplex and single-case families, respectively, compared with 2.3% of parental haplotypes from control families (p less than 0.05 and p less than 0.01, respectively). No significant differences were observed in the frequencies of complement gene polymorphisms (Factor B and C4). The data suggests that a MS susceptibility gene exists, in the HLA complex, and is in closest linkage disequilibrium with the HLA-D region; although other factors, environmental and/or independent genetic loci, may have an important influence.     

Idiopathic haemochromatosis in the Australian population: HLA linkage and recessivity

Studies of 73 unrelated patients and 19 families with idiopathic haemochromatosis are reported. The unrelated patients showed a highly significant association between the disease and HLA-A3. There was a less strong association with HLA-B7 and HLA-DRw2 attributed to the linkage disequilibrium between HLA-A3, B7, and DRw2. Lod scores and haplotytype analysis of the families indicated a recessive mode of inheritance for an idiopathic haemochromatosis susceptibility factor in close linkage with the HLA region. These results, for Australian caucasoid patients, are not in total agreement with those reported in studies of other populations.     

HLA antigens in idiopathic thrombocytopenic purpura

The lymphocytes of 52 patients with the clinical diagnosis of idiopathic thrombocytopenic purpura (ITP) were typed for the HLA-A,-B and-C antigens, and of 27 of those patients also for the DR antigens. ITP proved not to be significantly associated with any of the HLA-A,-B,-C or-DR antigens tested for. On the platelets of 35 of these 52 patients, autoantibodies were detected in the direct immunofluorescence test. In these 35 patients with autoimmune thrombocytopenia (AITP), an increased frequency of HLA-Bw38 was found (14.3% versus 2.6% in controls). The frequency of none of the HLA antigens was significantly increased in the group of 17 ITP patients without demonstrable autoantibodies. The difference in association with HLA-Bw38 between AITP and ITP without demonstrable autoantibodies was not significant.     

HLA-antigens in idiopathic haemochromatosis (i.h.). preliminary report

Striking differences could be observed when the HLA-antigens of 11 unrelated idiopathic haemochromatosis (i.h.) patients were compared with healthy controls. Besides the increase of the antigens A3, A11 and B7 and the decrease of A2, the large number of homozygous antigens at the A or/and at the B locus was found to be the most interesting result. Taking the latter finding into account, the possible existence of a recessive "disease-susceptibility gene" closely linked to the major histocompatibility system, playing a basic role in the etiology of i.h. was assumed.     

Heredity of idiopathic haemochromatosis: A study of 106 families

More than 80 % of the first degree relatives of 106 patients with iron overload - 97 with idiopathic haemochrornatosis (I.H.) and nine with haemosiderosis secondary to alcohol induced liver disease (A.H.) - were examined. Physical examination and measurement of plasma iron level and UIBC were done in all subjects; relatives who presented with some anomaly were submitted to a desferrioxamine test and, if the latter showed a high urinary iron output, to a liver biopsy. While absent in relatives of A.H. patients, iron overload was present in 78 out of 499 relatives of I.H. patients: 29 major and 49 minor forms. The major forms involved the sibships almost exclusively. The genetic analysis showed much evidence in favour of a recessive or rather intermediate form of inheritance, with heterozygous developing minor forms. However, other modes of transmission, especially poly-genic (probably oligogenic), cannot be totally excluded. Data from recent studies showing a strong correlation between I.H. and certain HLA antigens do not conflict with the above conclusions.     

An HLA study in 74 Danish haemochromatosis patients and in 21 of their families

HLA-A and -B alleles in 74 Danish patients and 21 homozygous relatives with idiopathic haemochromatosis (IH) were compared with those in a sample of 1719 chromosomes from healthy Danish control subjects. The following alleles occurred with higher frequencies in IH compared to controls: A3: 53.6% vs. 15.1% (Pc less than 0.001); B7: 33.1% vs. 15.6% (Pc less than 0.001); B14: 6.9% vs. 3.0% (Pc greater than 0.05); B38: 5% vs. 0.9% (Pc greater than 0.05); B47: 4.0% vs. 0.4% (Pc greater than 0.05). Pedigree analyses disclosed 19 different haplotypes in IH subjects, compared to 286 haplotypes in controls. The following haplotypes occurred with higher frequency in IH compared to controls: A3,B5: 10.3% vs. 0.3% (Pc less than 0.001); A3,B7: 25.6% vs. 6.6% (Pc = 0.001); A3,B14: 3.4% vs. 0.6% (Pc greater than 0.05); A3,B47: 6.9% vs. 0.2% (Pc greater than 0.05). The major IH marker HLA-A3 was found in 56% of the haplotypes. The patterns of HLA-alleles associated with IH in Denmark show similarities to those in Central Europe, Australia, USA and Canada, being A3,B7 dominated and those in Central Sweden, England and Ireland, being A3,B14 dominated.     

The molecular basis for the association between HLA-A3 and idiopathic haemochromatosis

An association was found between idiopathic haemochromatosis and a 6.2-kb Bgl I genomic DNA fragment. This fragment constitutes a class I sequence which correlates with HLA-B3. The Bgl I fragment could represent a sequence in linkage disequilibrium with the haemochromatosis gene.     

HLA and immunoglobulin polymorphisms in idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is an idiopathic heart muscle disorder. The presence of circulating cardiac antibodies and the association with HLA-DR4 are consistent with autoimmune pathogenesis in a subset of patients. Sixty-eight DCM patients and 277 controls were typed for IgG heavy-chain constant region (Gm) and kappa light-chain (Km) allotypes. All patients and 210 of the 277 controls were HLA-DR typed. The Gm (1, 3, 17; 23; 5*, 21, 28) phenotype was overrepresented in DCM compared with controls (25% vs 13%, p = 0.0139, pc = NS, RR = 2.23). The frequency of this phenotype was higher in patients with younger age at onset, shorter symptom duration, and among those who were positive for cardiac as well as for non-organ-specific autoantibodies than in controls. A higher frequency of the Gm (1, +/- 2, 3, 17; +/- 23; 5*, 21, 28) heterozygous phenotypes was also found in DCM compared to controls (40.91% vs 26.89%; p = 0.02, pc = 0.04, RR = 1.88). The finding of Gm heterozygosity in DCM was associated with serum positivity for cardiac antibodies. A higher proportion of DCM patients were positive for both the Gm (1, 3, 17; 23; 5*, 21, 28) phenotype and HLA-DR4 compared to normals (3/68 vs 0/210; p = 0.04, RR = 22.50).(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA class II associations with idiopathic nephrotic syndrome in children

Abstract: The occasional familial occurrence of idiopathic nephrotic syndrome (NS) points to a genetic predisposition. Reports on associations with certain HLA class II antigens support this hypothesis. In order to define the immunogenetic background of NS more precisely, HLA class II allele frequencies in 161 children with NS were studied by restriction fragment length polymorphism (RFLP) typing. The patient cohorts consisted of 87 children from Southwest-France and 74 from Southwest-Germany. The control group consisted of 118 French and 101 German unrelated individuals from the same geographical areas. HLA alleles were defined in patients with steroid-sensitive (SS) and steroid-resistant (SR) NS and in controls. RFLP typing revealed that the previously reported association between SSNS and HLA-DR7 is confined to the RFLP split 7.1 (DRB1*07) with a combined relative risk (RRcomb) of 6.2. HLA-DQB typing showed an increased frequency of the allele DQB2b (DQB1*0201) (RRcomb = 7.8). HLA-DQA typing showed an association of SSNS with DQA3 (DQA1*0201,0301,0302) (RRcomb = 4.1). The highest RR (16.5) for SSNS was found in German patients who carried the two DRB1 specificities 17.1 (DRB1*0301) and 7.1 (DRB1*07). All associations were stronger in SS patients with frequent relapses or steroid dependency than in non- or infrequent relapsers. SR patients exhibited no significant associations with HLA class II alleles.     

HLA typing in 67 Italian patients with idiopathic hemochromatosis and their relatives

The frequency of HLA A3 and B7 antigens was significantly higher in 67 unrelated patients with idiopathic hemochromatosis (IH) than in 700 controls (62.7% vs 22.5%, p less than 10(-8) and 26.9% vs 9.3%, p less than 10(-3), respectively). A3 B7, A3 B35 and A3 B5 were significantly more frequent in 72 haplotypes linked to IH gene than in 278 control haplotypes. The prevalence of B35 and A3 B35 was significantly higher in IH patients from North-Eastern Italy than from other regions (60% vs 21%, p less than .05 and 54.5% vs 8.2%, p less than 0.0001, respectively). All 15 siblings HLA identical to the respective proband were homozygous for IH with variable expression of the disease, whereas minor abnormalities of iron-related indexes were present in 23% of heterozygous relatives. Homozygous-heterozygous mating probably occurred in three of 40 families, accounting for the overt disease in three offspring and in one HLA semi-identical sibling; however, in this last case the possibility of a recombination event cannot be excluded.     

特发性儿童中风患者HLA的相关性研究

目的　探讨与中国北方汉族特发性儿童中风患者相关的HLA抗原及等位基因。方法应用标准微量淋巴细胞毒试验方法及聚合酶链反应 序列特异性探针 (PCR SSO)技术对 43例该病患者进行HLAⅠ类抗原及Ⅱ类等位基因的分型 ,并和 10 7例相匹配的无关健康人进行了对照比较。结果　患者组中HLA B5 1频率为 0 .395 ,而对照组仅为 0 .0 94,相对危险率 (RR)及 χ2 分别为 6 .34和18.94(Pc<0 .0 1)。HLA DRB1 0 80 2频率显著升高 (患者组 0 .2 0 9,对照组 0 .0 2 2 ,RR =11.78,χ2 =13 .5 0 ,Pc=0 .0 0 38)。此外还见到DQA1 0 40 1和DQB1 0 40 2频率也升高 ,校正P值后两组差异仍有显著性 ,二者均与DRB1 0 80 2连锁在同一单倍型中。结论　中国北方汉族特发性儿童中风的发生与HLA B5 1,DRB1 0 80 2显著相关。     

Neonatal haemochromatosis

Four cases of neonatal haemochromatosis presenting as fulminant hepatic failure in the newborn were diagnosed by autopsy. In all four cases the diagnosis was made by histochemical demonstration of excessive iron deposition in hepatocytes and extrahepatic parenchymal cells, particularly pancreatic acinar epithelium, thyroid follicular epithelium and distal renal tubules. No haemosiderin was detectable in the extrahepatic mononuclear-phagocytic cells of the spleen, lymph nodes and bone marrow. The liver was the most severely affected organ. The hepatic haemosiderosis was associated with massive hepatocellular necrosis of prenatal onset in three patients, one of whom showed formation of regenerative nodules, establishing true congenital cirrhosis. Other inconstant findings included giant cell transformation, diffuse sinusoidal fibrosis with segregation of small groups of hepatocytes and cholestasis with pseudoacinar change of liver cell plates. The fetal liver disease had its onset in the late second trimester of pregnancy and was reflected clinically by severe panhypoproteinaemia with non-immune hydrops; hyperbilirubinaemia and haemorrhagic diatheses were apparent in the newborn. Neonatal haemochromatosis is a metabolic disorder, probably of autosomal recessive inheritance. The site and nature of the basic defect remain uncertain. Pathologists should be aware of this condition and its potential recurrence in subsequent pregnancies.