HLA-DR and -DQ gene polymorphism in Latvian patients with insulin-dependent diabetes mellitus

Abstract: Latvian insulin-dependent diabetes mellitus (IDDM) patients ( n =101) and healthy controls ( n = 111) were analyzed for HLA-DR and DQ polymorphism. DR3-DQ2 and DR4-DQ8 were positively associated and DR15-DQ6, DR13-DQ6, DR1-DQ5 and DQ7 negatively associated with the disease. The incidence of LDDM in Latvia is very low (6.5 per 100,000) compared to Sweden (24.4 per 100,000), even though Latvia is close to Sweden. The reasons for the decreased incidence are not clear. When the negatively associated DQ were taken together in the healthy controls, more than 75% of the healthy controls were positive for one of the four negatively associated DQ molecules. The excess frequency of the negatively associated DQ molecules in the general population could explain the lower incidence of IDDM in Latvia. Association of HLA-DR and DQ genes with autoantibody markers shows DR3, but not DQ2, to be increased in GAD65 antibody-positive compared to antibody-negative patients. This association was not observed with ICA512 antibodies.     

HLA-DR2 in two sibships with insulin-dependent diabetes mellitus.

We report two families selected from 124 genotyped Caucasian insulin-dependent diabetes mellitus (IDDM) families because of unusual features. In both families, all offspring are affected and four out of six bear the allele HLA-DR2 which is an uncommon phenotype among diabetic patients. Onset before the age of 1 year in all the patients of one family, association with optic atrophy in the other, and the existence of pairs of affected sibs of different HLA types in both, are infrequent findings and support the evidence of heterogeneity in IDDM.     

TNFB gene polymorphism in insulin-dependent diabetes mellitus: association with HLA-DR alleles

A polymorphism of the TNF-β gene can be detected by restriction digestion of a PCR product with NcoI. In this study we look at the risk associated with this polymorphism in a study of 69 insulin-dependent diabetes patients and 119 healthy controls. The risk was further characterized by comparison to the HLA type of the individual, since the TNF polymorphism is in linkage disequilibrium with HLA genes.     

HLA microsatellite associations with insulin-dependent diabetes mellitus in Singaporean Chinese.

Singaporean Chinese with insulin-dependent diabetes mellitus (IDDM) have previously been shown to be associated with the DRB1*0301 haplotype and the joint occurrence of DRB1*0301/*0901 and DRB1*0301/*04. The present study extended previous HLA associations by investigating the HLA region using four microsatellites (TNFa, D6S273, TAP1, DQCARII). Seventy-five IDDM patients and 80 healthy controls were studied. TNFa*3 (RR = 2.26), TNFa*12 (RR = 3.30), TAP1*9 (RR = 2.55) showed increased frequencies while TNFa*11 (RR = 0.29), TAP1*4 (RR = 0.50) showed decreased frequencies in patients compared to controls. Linkage analysis suggested that the positive associations of TNFa*3 and TAP1*9 were secondary to that of DRB1*0301. However, TNFa*12 appeared to provide additional risks to IDDM besides the DRB1*0301 haplotype, whereas TNFa*11 and TAP1*4 conferred an independent protective effect against IDDM. Our findings reinforce the notion that susceptibility to and protection against IDDM may include TNF region. In the present study, TNFa*12 seemed to be the primary association in the DRB1*0405 haplotype and may play an independent role in the pathogenesis of IDDM through TNF-alpha function.     

HLA-DP, -DQ and -DR RFLP types in South Indian insulin-dependent diabetes mellitus patients

Abstract: : The frequencies of HLA-DP, DQ and DR RFLP types are compared between insulin-dependent diabetes mellitus (IDDM) patients and healthy controls in the South Indian population. There are no significant differences in the frequencies of any of the DPA.DPB haplotypes, when allowance is made for multiple comparisons. The individual frequencies of two novel alleles, designated "DPA*B" and "DPB*B", however, are significantly higher in controls than in patients, suggesting that these alleles are protective against IDDM. A negative association with DRwl5 (DR2).Dwl2 is also observed. The positive association with DPw3/6 RFLPs previously observed in White Australians is not present in South Indians. This difference may be due either to undetected heterogeneity within allelic classes or to different linkage disequilibrium patterns between the populations.     

HLA-DR and -DQ antigens in malnutrition-related diabetes mellitus in Ethiopians: a clue to its etiology?

Thirty Ethiopian malnutrition-related diabetes mellitus (MRDM) patients were HLA typed and their HLA antigen frequencies were compared to those of 31 previously typed insulin-dependent diabetes mellitus (IDDM) patients and to 84 controls from the same ethnic background. In comparison to controls, a striking association between MRDM and HLA-DR3 (X2 = 15.15, p = 0.0001) was observed, whereas the frequency of HLA-DR4 was non-significantly increased (RR = 1.72). The frequency of DR2, DQw1, and DQw6 was decreased among MRDM. In comparison to IDDM that is associated with both DR3 and DR4 in this population, MRDM showed no significant differences in HLA class II antigens frequencies. Therefore, the genetic basis of susceptibility to MRDM and IDMM in Ethiopia is at least partially identical.     

A new HLA-DR2 extended haplotype is involved in insulin-dependent diabetes mellitus susceptibility

To ascertain why HLA-DR2 seems to confer only a moderate resistance to insulin-dependent diabetes mellitus (IDDM) in the high-incidence population of Sardinia, Italy, 32 families having one individual affected with IDDM (the proband) and 31 families without IDDM history were randomly selected from the same geographical area and serologically and molecularly HLA typed. The 64 haplotypes of the probands were then compared with the 122 haplotypes determined in the parents from the control families. Two haplotypes were found to have the highest percentage in the general population (12.3% and 7.3%, respectively). The first is the already described "Sardinian" extended haplotype A30, Cw5, B18, 3F130, DR3, DRw52, DQw2 (39.0% in IDDM patients). The second is an extended haplotype that has not been identified before (A2, Cw7, B17, 3F31, DR2, DQw1), and, due to the DR2 allele, we expected it to be decreased in IDDM. However, a stratified analysis performed by removing the DR3 and DR4 haplotypes showed that the frequency of this haplotype is significantly increased in IDDM patients. A peculiar feature of this haplotype is its DQw1 allele, which is DQB1*0502 and has serine in position 57 of the DQ beta chain. The absence of an aspartic acid in this position seems to confer susceptibility to IDDM and not resistance. The fact that DQB1*0502 was present in 75% of the Sardinian DR2 haplotypes may explain why, in Sardinia, DR2 is not providing the commonly recognized resistance to IDDM.     

Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to Insulin-dependent diabetes mellitus (IDDM)

Abstract: Previous studies have indicated that certain alleles of HLA-DR and -DQ genes were strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM), and the role of DQ molecule in IDDM has been suggested. To further clarify the association of DQ alleles with IDDM, we determined the nucleotide sequences of full-length cDNA from 13 DQA1 alleles and 14 DQB1 alleles. The sequencing analysis revealed sequence polymorphisms outside the hypervariable region of DQ genes. We then analyzed the DQA1 and DQB1 polymorphisms along with that of DRB genes in 86 B-lymphoblastoid cell lines (B-LCLs) from various ethnic groups and in healthy unrelated Japanese and Norwegian individuals. The allelic and haplotypic distributions in each population revealed the characteristic haplotypic formation in the HLA class II region. HLA genes in 139 Japanese and 100 Norwegian IDDM patients were analyzed. DQB1*0301 was negatively associated with IDDM in both ethnic groups, irrespective of associated DRB1 and DQA1 alleles. In DQB1*0302 positive populations, which represented a positive association with IDDM in both ethnic groups, DRB1*0401, *0404, *0802 haplotypes increased in the patients, whereas DRB1*0406 haplotype decreased. Considering about the hierarchy in DRB1 alleles with IDDM susceptibility (DRB1*0401>*0404>*0403 in Norwegian and DRB1*0802>*0403>*0406 in Japanese), the genetic predisposition to IDDM is suggested to be defined by the combination of DR-associated susceptibility and DQ-associated susceptibility and by the DQ-associated resistance which is a dominant genetic trait.     

HLA-DR and -DQ polymorphism in Cameroon

Stress-inducible MICA (MHC class I chain-related A) is known to bind to NKG2D, which is one of the natural killer (NK) cell receptors, and plays a role in immune surveillance. We have reported that a MICA-MICB null haplotype is in linkage disequilibrium with HLA-B*4801 in the Japanese population. In the haplotype, an approximately 100-kb deletion, including the entire MICA gene, was observed and MICB possessed a premature stop codon. In this study, a multiplex polymerase chain reaction (PCR) method was developed for detecting the MICA deletion. MICB alleles were typed by PCR-single-strand conformation polymorphism (SSCP) method and direct sequencing. The frequency of the MICA-MICB null haplotype was 3.7% on the average, and was strongly associated with HLA-B48 in seven East Asian populations. It was presumed that the stop codon of MICB gene generated after the large-scale deletion. The wide distribution of the null haplotype at polymorphic frequencies suggests that the haplotype has been conservatively maintained because of some selective advantage.     

Microalbuminuria in long-term insulin-dependent diabetes mellitus. Prevalence and clinical characteristics in a normotensive population

Albumin excretion rate was determined by radioimmunoassay in overnight urine from 102 normotensive patients with insulin-dependent diabetes mellitus of more than 10 year's duration. Based on two samples, 16 patients (16%) exhibited microalbuminuria, defined as a mean excretion rate greater than 20 micrograms/min. Microalbuminuric patients were significantly younger at onset of diabetes but did not differ from normoalbuminuric patients concerning age or duration of diabetes. Nonetheless, diastolic and mean arterial blood pressures were significantly higher in the microalbuminuric group. The existing glycemic control, assessed by glycosylated hemoglobin (HbA1c) was better in normoalbuminurics, but not significantly so. The albumin excretion rate in microalbuminuric patients correlated significantly (p less than 0.01) to diastolic (r = 0.69) and to mean arterial blood pressure (r = 0.69), but did not correlate to HbA1c. Thus, it is concluded that even normotensive patients with signs of early diabetic nephropathy, i.e. microalbuminuria, exhibit small, but significant increases in blood pressure.     

Immunotherapy of insulin-dependent diabetes mellitus

Type 1 diabetes mellitus is caused by the T cell mediated autoimmune destruction of insulin-producing beta cells of the islets of Langerhans within the pancreas. Current immunotherapy strategies are aimed at directly inactivating the autoreactive T cells and/or inducing T cells with regulatory capabilities. At the preclinical level, several strategies that employ TCR antagonists -- including monoclonal antibodies, autoantigen-specific peptides and soluble TCR ligands -- are showing promise and being developed for clinical application. Several of these approaches employing monoclonal antibodies against the TCR-CD3 complex or soluble peptide antigens are producing favorable results in the clinic.     

Coping styles in youths with insulin-dependent diabetes mellitus

The relationships between two coping styles (i.e., use of personal and interpersonal resources; ventilation and avoidance) and two health outcomes (i.e., adherence and metabolic control) were evaluated in 135 youths with insulin-dependent diabetes mellitus (IDDM). Individual characteristics (i.e., age, duration of illness) and contextual variables (i.e., stress, family relations) were used to predict coping styles. Poor adherence to treatment, older adolescent age, and long duration of IDDM were correlated with ventilation and avoidance coping. Youths with short duration of IDDM were more likely to cope through the use of personal and interpersonal resources, although this strategy was not associated with health outcomes. A multiple regression analysis indicated that high ventilation and avoidance coping was predicted by high stress, low family cohesion, and older adolescent age. In addition, the interaction between family adaptability and duration of IDDM significantly predicted ventilation and avoidance coping.     

HLA-DR and -DQ alleles in Italian patients with melanoma

Abstract: Controversial data have been reported about HLA alleles and susceptibility to melanoma. Our investigation was undertaken to analyze the relationship between HLA alleles distribution in patients with melanoma and susceptibility to the tumor, in order to study the possible correlation between HLA class II DQA1, DQB1 and DRB1 genes involved in immune recognition, and melanoma, usually considered a highly immunogenic tumor. We therefore typed by means of PCR-SSP (sequence-specific primers) 53 Italian patients and 53 healthy random controls coming from the same geographic area. We observed a decrease of all haplotypes bearing DQB1*0301, DQB1*0302 and DQB1*0303 alleles but not of haplotype DRB1*11;DQA1*0501;DQB1*0301. Our results seem to support the hypothesis of a protective role of some DQ3-bearing haplotypic combinations in melanoma.     

Quality of life in adults with insulin-dependent diabetes mellitus

Conventional measures of psychiatric or medical morbidity do not adequately reflect the consequences of chronic illness. Quality of life refers to a more comprehensive assessment of the impact of illness. Uncomplicated insulin-dependent diabetes is usually associated with mild reported reduction in quality of life. Increased depressive and anxiety disorders have been reported in individuals with insulin-dependent diabetes mellitus, particularly in association with more severe medical complications and low social support. The potential benefits of intensive treatment approaches must be weighed against adverse effects on the quality of life.     

Pediatrics residents' attitudes about insulin-dependent diabetes mellitus and children with diabetes

Nationwide, pediatricians provide a substantial portion of the health care of children with diabetes. Their beliefs and attitudes about diabetes and children with the illness have an important influence on their treatment decisions. The attitudes and beliefs of a 1988 sample of pediatrics residents were compared with data from a 1987 national survey of practicing pediatricians' beliefs and attitudes about children with insulin-dependent diabetes mellitus and about the disease itself. Pediatrics residents in their second and third years of training were considerably more negative about diabetes and diabetic children than were either the members of the national sample of practicing pediatricians or the residents' first-year colleagues.     

Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus

We randomly assigned 46 patients (mean age, 11.7 years; range, 4.5 to 32.8) with newly diagnosed insulin-dependent diabetes mellitus within two weeks of beginning insulin to receive either corticosteroids for 10 weeks plus daily azathioprine for one year or no immunosuppressive therapy. Half the 20 immunosuppressed patients completing the one-year trial had satisfactory metabolic outcomes (hemoglobin A1c less than 6.8 percent; stimulated peak C peptide greater than 0.5 nmol per liter; insulin dose less than 0.4 U per kilogram of body weight per day) as compared with only 15 percent of the controls. Three of 20 immunosuppressed patients, but no controls, were insulin independent at one year. Two of these continue to receive azathioprine without insulin after more than 27 months of follow-up. The response to immunosuppression correlated with older age, better initial metabolic status, and lymphopenia (less than 1800 lymphocytes per cubic millimeter) resulting from immunosuppression. The side effects of azathioprine included vomiting in one patient and mild hair loss in several others. Prednisone use resulted in a transient cushingoid appearance, weight gain, and hyperglycemia. The growth rate remained normal in all patients. We conclude that early immunosuppression with short-term use of corticosteroids plus daily azathioprine can improve metabolic control in some patients with insulin-dependent diabetes mellitus, but results from this unblinded study are preliminary and require further confirmation and long-term follow-up.     

Immunogenetics of insulin-dependent diabetes mellitus in humans

Diabetes mellitus is the second most prevalent chronic disease in children in the U.S. It is associated with severe manifestations which include blindness and circulation deficiencies as well as markedly increased risk of death. The etiology of diabetes mellitus remains a mystery although both genetic and environmental factors have been implicated. The geneticist is confronted with a number of obstacles in his attempts to unravel this problem, including differences in the definition of affected individuals. This matter was certainly clarified by the separation of noninsulin-dependent diabetes (NIDDM) and insulin-dependent diabetes mellitus (IDDM) into two separate disease entities. Twin studies, however, show that IDDM cannot be entirely due to genetic causes as concordance is no more than about 50%. Although the disease is then clearly not inherited per se, the "susceptibility" to diabetes seems almost surely inherited and, provided this susceptibility, the disease can be brought on by environmental factors. Until the underlying mechanism causing IDDM is completely ascertained, we have to rely on genetic markers to approach the study of the inheritance thereof. Since, in the early 1970s, research by Nerup's and Cudworth's groups revealed associations between the HLA-B locus and IDDM, the HLA markers are considered the classical genetic markers for IDDM susceptibility. In this paper, we review the nature of the genetic susceptibility to IDDM and the possible environmental factors which can bring on the disease.