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An analysis of HLA-linked genetical factors conferring susceptibility to IDDM is reported. On the basis of population and family studies a recessive mode of inheritance of disease susceptibility provided by an assumption of HLA-B8-linked DS gene was observed. The characteristic component of the immunogenetical background was the high frequency of HLA-B8 (0.208) and the HLA-A1, B8 haplotype (0.134) (linkage disequilibrium D = 0.1031), reminiscent of that found also in other disorders with autoimmune features, such as Graves disease, SLE, etc. Considering the HLA-B8 and IDDM association, the DS gene frequency (pD = 0.25) was estimated and the gametic association between HLA-B8 andu DS gene was calculated. The low value of penetrancy (4.8%) revealed the important role of non-HLA-linked genetical and environmental factors. The HLA-linked genetic factors in question might be responsible for an inclination to several kinds of autoimmune disorders.

Graves' disease is associated with HLA-DR3 in Caucasoids. We have now demonstrated, on the basis of disease-associated MHC haplotypes (A1, Cw3, B8, DR3 and fragments thereof) from 38 families in which more than one member had Graves' disease compared with MHC haplotypes from 56 healthy families, that the risk was highest with the DR locus (relative risk for A1, B8, DR3 = 2.3, for B8, DR3 = 5.3, and for DR3 = 6.8). We further used the sib-pair method to explore linkage of Graves' disease liability to the MHC in 67 affected sib-pairs. The data were consistent with an MHC-linked recessive gene with a frequency of 0.2 to 0.3 and a penetrance of 7.2%; the data, however, accommodated penetrance of up to 16.3%. A recessive model was also consistent with the HLA-B8 genotype distribution in 286 unrelated patients. As the effect of the marker alleles on the course of the disease had been debated several times, we applied a cluster analysis method using 49 clinical and laboratory characteristics, including the HLA-A and HLA-B antigens of 196 patients. Three groups were identified, corresponding to patients with mild disease, Hashitoxicosis and severe (relapsing) disease. The prevalence of HLA-B8 was 8.9%, 21% and 87%, respectively (compared to 18.8% in 380 controls). This suggests the existence of an underlying continuum of genetic liability, apparently related to that for Graves' disease severity, associated with the MHC and mediated through immunoregulatory disturbances.

We have studied the distribution of IgG heavy chain markers (Gm) among 90 Hungarian patients with systemic lupus erythematosus (SLE) (55 of whom were also typed for HLA). This study confirms previously described increases in HLA-B8 and DR3 in this condition. No difference in the distribution of Gm phenotypes was found between patients and 168 controls from the same geographical area. HLA-B8/Gm homozygous individuals were, however, at greater risk for SLE (relative risk = 5.13) compared to B8 + Gm heterozygotes or B8- individuals, irrespective of Gm phenotype. When patients with renal manifestation (n = 40) were compared to those without, the Gm phenotype 3; 5, 13 was found to be significantly increased (chi 2 = 10.36, P less than 0.0001, relative risk (RR) = 4.69). HLA and Gm increased additively the risk for renal manifestations in that for those patients who were both Gm3;5,13+ and HLA-B8+, PR was 110, while it was 21.2 for Gm3;5, 13-/B8+, 7.9 for Gm3;5, 13+/B8- and 1.0 for Gm3;5, 13-/B8- patients. The study suggests that combined HLA and Gm typing can be used to identify SLE patients at high risk for manifesting renal abnormalities.

To relate genetic variation in Graves' disease (GD) susceptibility to polymorphism at MHC loci, clinical and family studies were undertaken in eastern Hungary. Among 1980 relatives of 534 index patients, 2.9% of siblings, 2.7% of offspring, and 3.0% of parents had GD. HLA haplotype combinations in affected sibling pairs were determined in the present data and combined with data in the literature (12 sibling pairs from Farid 1981, 12 from Chan et al. 1980, and 15 from Sasazuki et al. 1983); 43, 23, and 1 affected sibling pairs shared, respectively, 2, 1, and 0 HLA haplotypes. This distribution is inconsistent with simple dominant inheritance, but is consistent with simple recessive inheritance of HLA-related susceptibility over a range of gene frequencies (0.2-0.4). A frequency of 0.3 gives the best fit and is consistent with penetrance of 7.1% for the recessive susceptibility genotype; the data, however, can accommodate penetrance values up to 16%. The distribution of HLA haplotypes in 33 families related disease susceptibility more strongly to DR than to other loci. The distribution of HLA-B8 genotypes in 256 patients was in close agreement with Hardy-Weinberg equilibrium proportions, also favoring recessive inheritance of MHC-related susceptibility. The probability that an individual will be affected with GD can be predicted, based on sex, HLA genotype, and family history. For example, 14.9% of DR3-positive women with an affected first degree relative are likely to be affected. These predictions can be tested as family data accumulate.

A group of 67 juvenile insulin dependent diabetic patients and their 167 healthy first degree blood relatives were HLA-typed. In the patients the frequency of HLA-A9 and B8 antigens was significantly increased as compared to healthy controls, while in the family members only the presence of HLA-B8 was significantly increased. All diabetics carrying HLA-B8 antigen had frequently higher 125I-insulin-antibody complex levels than those lacking the antigen. Prevalence of some autoantibodies to human thyroglobulin, microsomal thyroid and antigastric mucosa antigen were investigated and compared to healthy controls. Increased antibody titres were more frequent in diabetics and their blood relatives than in the healthy controls, and more frequent in those carrying the HLA-B8 antigen than in those lacking it.

For 75 patients with systemic lupus erythematosus (SLE), 39 laboratory and clinical characteristics, including HLA-A, B, C and DR typing, were analysed using a cluster analysis technique. Three groups were identified. Group I (46 patients) was characterized by infrequently severe disease, good response to therapy and infrequent multisystem involvement. Group II (24 patients) was characterized by a severe course of disease (although the tendency to remit after therapy was not unusual), and frequently, renal involvement and pericarditis. Group III (5 patients) was characterized by more severe renal disease. Of the 75 patients studied, 38.7% possessed HLA-DR3, compared to 17.4% of controls. Group I patients did not differ from controls but 80% of Group II patients and 4/5 Group III patients had DR3. Cluster analysis identifies subsets of SLE patients who show marked differences in disease course and severity, correlated with possession of the HLA B8, DR3 phenotype.

We investigated the distribution of HLA and immunoglobulin G heavy chain markers (Gm) in 117 patients with Graves' disease, 62 with ophthalmopathy and 55 without. With Graves' disease per se, there is a closer association with HLA-DR3 than with B8. The opposite was true for Graves' patients with ophthalmopathy (odds ratio for ophthalmopathy associated with B8 was 12.4 and with DR3 was 7.7, both with P less than 0.0005). HLA-DR7 interacts with B8 in modifying the risk for eye disease; using the phenotype B8- DR7- as reference, the odds ratios were 16.7 for B8+ DR7+, 8.7 for B8+ DR7- and 0.26 for B8- DR7+. Thus, DR7 enhanced the risk for ophthalmopathy in the presence of B8+ but had a protective influence in its absence. Although Gm showed no association with eye disease, it modified the risk for ophthalmopathy associated with HLA-B8; the odds ratios were 20.9 for B8+ Gmfb homozygozity (fb+), 15.3 for B8+ fb- and 1.7 for B8- fb+ (B8- fb- = 1.00). We conclude that the genetic factors contributing to Graves' ophthalmopathy are different from those related to liability for Graves' hyperthyroidism.