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The distribution of HLA class II alleles associated with insulin-dependent diabetes mellitus (Type 1) in the Algerian population is poorly known. We have typed 36 Algerian Type 1 diabetic probands and their families using DQA1 and DQB1 oligonucleotide probes. Fifty-nine parental haplotypes non transmitted to diabetic offspring served as controls. The frequencies of DQA1 and DQB1 alleles and haplotypes and their associations with Type 1 diabetes were, except minor differences, similar to those reported in French. Susceptibility DQA1 (Arg52+) and DQB1 (Asp57-) alleles were significantly increased among patients versus controls (90% vs 53%, RR = 8.4, p < 10(-6), and 94% vs 64%, RR = 9.4, p < 10(-5), respectively). 85% of Type 1 diabetics versus 34% of control haplotypes were either DR3DQw2 or DR4DQw8 susceptibility haplotypes (DQA1 Arg52+, DQB1 Asp57-) (RR = 10.8, p < 10(-7). 75% of the probands vs 14% of the controls (RR = 18, p < 10(-5)) and 73% of affected siblings versus 24% of unaffected siblings (RR = 8.4, p < 0.02) possessed a genotype composed of these two susceptibility haplotypes in the homozygous or heterozygous state. 42% of the probands were DR3DQw2/DR4DQw8, corresponding to Hardy-Weinberg expectations. The lack of excess of heterozygotes could be due to the consanguine families in this sample, as among the patients with consanguine parents the frequency of DR3, 4 heterozygotes was lower (27% vs 48% in non-consanguine patients, NS) and that of DR3 homozygotes increased (45% vs 12%, respectively, p < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to determine which candidates were suitable for immunotherapy among adult insulin dependent diabetic patients of recent onset. A statistical analysis was performed using the results of a multicentre randomized trial of cyclosporine versus placebo after nine months of treatment. When the baseline characteristics of the patients in remission were compared with those not in remission, there was no difference observed either in initial residual beta-cell function (glucagon stimulated C-peptide level), or in immunological markers (T4 and T8 lymphocytes counts, Interleukin 2). The parameters showing the most difference were, in addition to treatment group, the duration of diabetes symptoms and body mass index at inclusion, and the HLA-DR phenotype. This was confirmed using a logistic regression analysis, in which these variables were found to be significantly related to remission. The probability of remission in each individual patient was then calculated using these variables in the mathematical function provided by the logistic model. Ninety eight out of 110 patients were correctly classified using this method. In addition, it must be noted that only subjects adequately treated by cyclosporine were still in complete remission after a one year follow-up. Conversely, it appeared that immunosuppression in subjects having a predicted probability of remission lower than 0.35 using the mathematical function, and being non-DR3, non-DR4 has to be avoided. These results will be useful in optimizing the recruitment of patients in on-going or future trials of immunotherapy in early diabetes.

In order to precise the prevalence and incidence of IDDM in a well characterized population, we have ascertained between 1979 and 1988 all juvenile diabetic patients living in the department of Oran (Wilaya of Oran), Algeria, aged less than 20 years at the date of Dec. 31th 1988 who had onset of the disease before 15 years old. Cross comparisons of the data obtained both by a IDDM registry and a questionnaire sent to the practitioners show an excellent correlation. A total of 173 families was studied, including 155 Simplex Families (SF), and 18 Multiplex Families (MF). The prevalence was 0.27 p. 1000 among children aged less than 15 years. The annual incidence (mean = 4.4 p. 100,000) increased regularly from 1.6 p. 100,000 in 1981 to 8.1 p. 100,000 in 1988. The prevalence of IDDM among siblings was 3.8%. The birth order of index cases (first affected siblings) was lower in MF (3.0 +/- 0.4) than both in index cases of SF (4.0 +/- 0.3; p less than 0.01) and in secondary affected siblings of MF (4.8 +/- 0.05; p less than 0.001). The frequency of 2nd degree consanguineous marriages (between first cousins) was greater among the IDDM families compared with control families: 25% vs 11% (RR = 2.9; p less than 0.001).

The information and counselling of diabetic patients and their families requires for the practitioner to know about some fundamental aspects of diabetes and in particular, to distinguish between the different types of diabetes with different causes, pathogenetic mechanism and modes of inheritance. Recent developments in the fields of immunogenetics have improved the understanding of type I diabetes, an auto-immune disease associated with HLA and made possible the identification of genetically susceptible individuals. The etiology of type II diabetes, by far the most frequent form, remains unknown. In the absence of genetical markers, the screening of predisposed subjects is, however, useful in order to propose preventive measures.

Thirty-one unrelated patients, 15-52 years old, were typed by microlymphocytotoxicity for 27 alleles of the HLA system. In addition, 12 families including 1 or more patient were also analysed. This criteria for diagnosis were those of Sohar et all. (Am. Intern. Med., 1967, 43, 227-253). All patients were of Israelite-Sephardin origin except two (Armenian and French); they were from North-Africa (Tunisia, Morocco and Algeria) and Israël. The results were compared to the antigen frequencies of 3 reference normal populations. The frequencies of the studied alleles do not differ from those of controls, except for HL-A28 and B14 slightly increased when compared to the normal frequencies. The study of 7 families with at least two sibs suffering from FMF shows a random distribution of the genotypes : 2 HLA identical, 6 different and 10 haploidentical diseased sibs. This distribution differs significantly (p less than 0.01) from that expected in the case of a recessive inheritance. These data do not support the hypothesis of a linkage between genes controlling FMF and HLA genes.

A new classification based on physiopathological criteria distinguishes Type I diabetes, observed in patients with stigmata of anti-islet of Langerhans auto-immunity, from Type II diabetes without these autoimmune changes. Type I diabetes is sub-divided into Classes Ia and Ib, Class Ib comprising those cases associated with other auto-immune diseases. Serological analysis of 76 patients with clinical type Ia diabetes and 215 healthy, first degree relatives showed that the distinction between Classes Ia and Ib was not clear-cut and that patients classified clinically Ia were in fact infraclinical Ib subjects. Forty-one per cent of patients with Class Ia diabetes had anti-gastric, anti-adrenal or anti-thyroid antibodies, and 28 p. 100 of their healthy relatives also had the same types of antibodies. Several prospective studies of the families of patients with Type I diabetes have shown that anti-islet of Langerhans antibodies were associated with a high risk of diabetes. Similarly, the presence of these antibodies in patients apparently with Type II diabetes (non-insulin dependent) was associated with an increased risk of developing insulin dependence. These results illustrate the value of immunological investigations in diabetic patients. They may influence the choice of treatment in the future.

One hundred and thirty-three insulin-dependent diabetic (IDD) patients were genotyped for HLA-A, B, C, DR and 123 of them for Bf. The study shows a relationship between these genes and the age of onset of diabetes and emphasizes the possible heterogeneity of the disease. When patients under the age of 0 years at the onset of the disease were compared with those aged 11 to 29 years, a significant excess of HLA-B18 (41% versus 15%, p less than 0.001) and BfF1 (40% versus 21%, P less than 0.05) was observed. The haplotype B18, BfF1 was also more frequent in the first group of patients (haplotype frequency 18% versus 6%, p less than 0.02). The frequency of the whole haplotype Cw5, B18, BfF1, DR3 and of its segment BfF1, DR3, and the strength of the gametic associations between these alleles were much higher in IDD patients than in non-diabetic controls, irrespective of the age of onset of their diabetes. The association between early age of onset of IDD and the B18, BfF1 haplotype independently of DR3 (no association between age and DR3) suggests that a factor influencing the onset of the disease in young children could be under the control of (1) gene (s) in linkage disequilibrium with B18 and/or BfF1.

HLA A and B typing was performed in 86 unrelated obese subjects and in 10 families including at least one parent and one obese sibling. The results in the series of unrelated subjects show no significant difference in antigen frequencies as compared to the control series. However in the 10 families studied, a group of 5 families is characterized by a high penetrance of obesity. In this group, inheritance of obesity seems to be transmitted through a dominant mode, and antigen B 18 appeared 4 times out of 5. The possible existence of a genetic form of obesity is considered in the discussion.

It is now well established that HLA system is involved in the susceptibility to Type 1 diabetes mellitus. In this study we look for a possible effect of the Gm system. A first study (cases-controls) suggests that among individuals who had HLA-DR3 but not HLA-DR4 or HLA-DR4 without HLA-DR3, there is a possible effect of the phenotype Gm3,23,5 or Gm3,-5 in the susceptibility to IDDM. Moreover, we have tested by the sibpair method whether HLA and Gm are transmitted independently from IDDM: an unaffected sib, sharing the same HLA haplotypes than an affected individual, seems to be more often phenotypically different at the Gm loci.

The authors studied HLA tissue groups for 28 specificities in 70 patients with psoriatic arthropathy (44 with pure peripheral arthropathy and 26 with axial involvement, 19 of whom also had peripheral lesions). Four antigens of this system were found with a significantly increased frequency in 70 patients in comparison with a control group of 152 normal subjects. For antigen HLA-B27, the frequency seemed very significantly increased in patients with axial involvement as compared with those without axial troubles (pc less than or equal to 0.0001) and with the controls (pc less than or equal to 0.0001). For antigen HLA-B13, the frequency was significantly increased in patients with axial involvement as compared with the controls (pc less than 0.05). Antigen HLA-Bw17 was present with significantly increased frequency as compared with the controls in the patients with peripheral involvement (pc less than 0.001). For antigen HLA-Bw38 (W16.1), the frequency in patients with or without axial involvement was significantly increased in comparison with the controls (pc less than 0.001). The interpretation of these results is discussed and the association of antigen HLA-B27 with sacro-iliac involvement once again stressed.

49 unrelated subjects suffering from systemic scleroderma were typed for 28 HL-A antigens, without any particular significant association of an antigen with the disease or one of its manifestations being noted. In addition, 13 patients from the same family were genotyped for HL-A. Transmission of the disease through 4 generations does not seem to be linked to a particular haplotype and no pair of sibling HL-A identical patients were seen in the same generation. By contrast, two pairs of sibling patients were HL-A different. Nevertheless, other cases, and in particular familial, will be necessary before an association between the genes of susceptibility to S.S. and a gene in the chromosomal HL-A region may be definitely eliminated.

31 families with at least two psoriatic members, including sometimes three generations (4 families) have been studied looking for HL-A markers. They include 80 affected (45 females, 35 males) and 75 healthy persons. BW 17 has been found present in 58 p. 100 of the unrelated patients, versus 7 p. 100 only in the normal population (p less than 10-9). Relative risk (R.R.) for the people bearing BW 17 is 38.34. Increase of B 13 is slight and non significant. BW 16, BW 37, BW 27 are within normal range. B 12 (R.R. :0.36) seems to have a protecting effect. B 8, B 14 are also decreased. Study of way of genetic transmission favours existence of a dominant gene of susceptibility frequently associated with BW 17 and particularly with haplotype A 1, BW 17. But other genetic or environmental factors may also play a role.

The study of a hundred and fifteen unrelated insulin-dependent diabetes and eight families with at least two insulin-dependent diabetes members made it possible to confirm the higher frequency of HLA-B8 and B18 (p less than 0.001) among patients, producing a RR of 2.24 and 2.47 respectively. The increased B15 frequency did not achieve statistical significance. B18 whose gametic association (delta = 0.0438) was significant only in diabetic patients was often related to Aw19-2 (Aw30 + Aw31). The B8/B18 genotype gave a relative risk (RR = 4.98) which was significantly higher than that of B8, B18 and B15 heterozygotes (1.50, 1.24 and 1.39 respectively). Pairs of diabetic siblings were more frequently HLA identical than would be expected by chance, and distribution of the pairs of affected sibs into the three categories, identical, semi-identical and different, was closer to the recessive model than to the dominant one. The fact that the B8/B18 individuals had a RR slightly higher than the B8 and B18 homozygotes and distinctly higher than the heterozygotes for only one of these genes, favours the hypothesis of two dominant genes, giving the appearance of recessivity. The gene associated with B18 in Southern Europe seems to play the same part as that of the gene associated with B15 in Northern Europe.

Fourteen selected families containing two or more subjects suffering from idiopathic hemochromatosis and 34 unrelated cases have been studied for their HLA markers. A 3 was present in 75% of the unrelated cases vs 26% in the normal population (p less than 10(-8)). The frequencies of B 7 (38% vs 19%) and B 14 (23% vs 9%) were also increased (p lessthan 0,05). Inevitably, in most cases both antigens in the B locus were associated with A 3. Seven of nine affected sib pairs shared both HLA haplotypes, while two shared only one. Significant association between HLA haplotypes and diseases segregation has been demonstrated in family studies. These facts are consistent with the recessive inheritance of a strongly A 3 linked "disease" gene responsible for abnormal iron stores in the heterozygote state. This hypothesis would account for 64% of our present cases. Most of discordances (26%) were females who are physiologically protected, or children under 17 who might later develop the disease. The remaining 10% of disordant cases could be explained by crossing-over between "disease" gene and HLA loci or by an heterogeneity of the disease. This provides a method for screening for high risk subjects and perhaps an opportunity for anticipatory prevention.