Risk Of Insulin-dependent Diabetes Mellitus Research Articles

Prevalence of cytoplasmatic islet cell antibodies and insulin autoantibodies is increased in subjects with genetically defined high risk for insulin-dependent diabetes mellitus

The presence of cytoplasmatic islet cell antibodies (ICA) and IgG insulin autoantibodies (IgG-IAA) has been observed in the prediabetic state of type 1 (insulin-dependent) diabetes (IDDM). We therefore analyzed the prevalence of these markers in sera from 1117 healthy HLA-typed first-degree relatives (1 degree Rel) of IDDM patients. ICA was determined by indirect immunofluorescence on cryostat sections of human pancreas. For IgG-IAA measurement a competitive solid-phase ELISA was used. ICA were present in 3.5% of 1 degree Rel vs 0.4% of controls (P less than 0.025). The highest frequencies of ICA were found in individuals of IDDM multiplex families (7.7%) and HLA-DR1,3 (5.4%), -DR1,4 (5.8%), and -DR3,4 (6.7%) positive subjects. We therefore conclude that the prevalence of ICA is increased in 1 degree Rel with high genetic risk for diabetes. IgG-IAA occurred in 9.9% of 1 degree Rel vs 1.4% of controls (P less than 0.01). Like ICA, IgG-IAA were significantly increased in a group of subjects being positive for either HLA-DR1,3 -DR1,4, or -DR3,4 (16.5%, P less than 0.01). In multiplex families, however, prevalence of IgG-IAA was not increased. In contrast to ICA there was an additional influence of age and sex: IgG-IAA were found more often in siblings (mean age, 16.6 years; prevalence, 15.0%) than in parents (mean age, 44.1 years; prevalence, 8.3%) of IDDM patients (P less than 0.01). In brothers the prevalence of IgG-IAA is higher than in other 1 degree Rel. Only a weak association between ICA and IgG-IAA was observed in subjects (n = 810) tested for both antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Definition of IDDM-associated HLA DQ and DX RFLPs by segregation analysis of multiplex sibships

Genetic variation of the DQα and β and of the DXα genes, detectable as RFLP in genomic DNA digests, has been suggested to improve the identification of individuals at high risk for insulin-dependent diabetes mellitus (IDDM). DNA from all members of 32 IDDM multiplex families was digested with six restriction endonucleases and the resulting fragments analyzed in Southern blots for hybridization with labeled cDNA probes for those genes. A computerized segregation analysis procedure was then used to assign fragments to haplotypes. Associations among fragments and between fragments and haplotypes characterized serologically and biochemically for their class II genes and IDDM-carrier status were calculated. The results indicate that the alleles of the DXα polymorphism maintain linkage disequilibrium with those of the DQβ genes responsible for the well-known DQβ3.2-IDDM association, so that IDDM-carrier haplotypes carry disproportionally often both DQβ3.2 and DXα-TaqI-2.2kb. Thus, these RFLPs identify a DR-DQ-DX haplotype in high linkage disequilibrium, rather than the locus or loci that account for their high relative risk. However, four DR4-DQβ3.2 haplotypes that lack DXα-TaqI-2.2kb were encountered, two of which are “affected”. These haplotypes suggest that the identification of the “disease locus” can be facilitated by the study of unusual haplotypes in which distinct IDDM-associated alleles occur separated from their neighbors of the standard genetic configurations.

Anti-sympathetic ganglia antibodies and postural blood pressure in IDDM subjects of varying duration and patients at high risk of developing IDDM.

We examined the sera of 94 subjects with insulin-dependent diabetes mellitus (IDDM) for the presence of complement-fixing sympathetic ganglia (CF-SG) antibodies. In a cross-sectional analysis (duration 0-43 yr), 22% had detectable CF-SG antibodies. Subjects at high risk for IDDM were also studied. Four groups were studied: group 1 (aged 4-64 yr) islet cell antibody-positive (ICA+) prediabetic subjects, 10 of 19 (53%) were CF-SG+; group 2 (aged 6-14 yr) ICA- prediabetic subjects (first-degree relatives of IDDM subjects with either transient hyperglycemia, impaired oral glucose tolerance, and/or first-phase insulin release after intravenous glucose tolerance testing), 4 of 9 (44%) were CF-SG+ (2 of the 4 ICA- CF-SG+ subjects have progressed to IDDM); group 3 (aged 1.5-43 yr) ICA+ IDDM subjects (less than or equal to 1 yr duration) 6 of 10 (60%) were CF-SG+; and group 4 (aged 8-59 yr) ICA- IDDM subjects (less than or equal to 1 yr duration), 2 of 11 (18%) were CF-SG+. All groups had increased CF-SG compared with controls. Postural blood pressure and simultaneous CF-SG antibody measurements were performed in 28 IDDM subjects. The drop in systolic blood pressure was greater in the CF-SG+ subjects (P less than .05), and the frequency of CF-SG was greater in the mean to -2SD group (P less than .03) when data were analyzed within mean +/- 2SD of the normal blood pressure response.

Reduced Risk of IDDM Among Breast-Fed Children: The Colorado IDDM Registry

The hypothesis that breast-feeding can provide protection against the development of insulin-dependent diabetes mellitus (IDDM) and would, therefore, be less common among subjects with IDDM was tested with a retrospective design. Cases (n = 268) were selected from the Colorado IDDM Registry and the Barbara Davis Center for Childhood Diabetes (Denver, CO). Two control groups were recruited, one from physicians' practices throughout Colorado (n = 291) and the second through random-digit dialing from the Denver area (n = 188). Cases were less likely to have been breast-fed than controls after adjustment for birth year, maternal age, maternal education, family income, race, and sex [adjusted odds ratio (OR) = 0.70; 95% confidence interval (CI) = 0.50-0.97]. This finding was consistent for both control groups and by birth-year intervals. A greater decrease in risk of IDDM was seen among subjects who had been breast-fed to an older age (for breast-feeding duration of greater than or equal to 12 mo, adjusted OR = 0.54, 95% CI = 0.27-1.08). The amount of IDDM that might be explained by breast-feeding habits (population percentage attributable risk) ranged from 2 to 26%, varying according to the breast-feeding prevalence reported in other studies. Replication of this work in different populations, controlled for the strong secular trends in breast-feeding habits, is critical before the hypothesis of protection is accepted.

Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study.

One hundred seventy-two members from 27 randomly selected multiple case Caucasian families of patients with insulin-dependent diabetes mellitus (IDDM) were studied at the DNA level to ascertain the reliability of codon 57 of the HLA-DQ beta-chain gene as a disease protection/susceptibility marker. The analysis was carried out by polymerase chain reaction amplification of DNA encoding the first domain of the DQ beta chain and by dot blot analysis of the amplified material with allele-specific oligonucleotide probes. One hundred twenty-three randomly selected healthy Caucasian donors were also tested. The results demonstrated that haplotypes carrying an aspartic acid in position 57 (Asp-57) of their DQ beta chain were significantly increased in frequency among nondiabetic haplotypes (23/38), while non-Asp-57 haplotypes were significantly increased in frequency among diabetic haplotypes (65/69). Ninety-six percent of the diabetic probands in our study were homozygous non-Asp/non-Asp as compared to 19.5% of healthy unrelated controls. This conferred a relative risk of 107 (chi 2 = 54.97; P = 0.00003) for non-Asp-57 homozygous individuals. Even though the inheritance and genetic features of IDDM are complex and are not necessarily fully explained by DQ beta chain polymorphism, this approach is much more sensitive than HLA serolog in assessing risk for IDDM.

Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes Epidemiology Research International Group

Population-based registries of insulin-dependent diabetes mellitus (IDDM) worldwide have reached the critical mass needed to investigate global patterns of the disease. International collaboration of 24 registries from 15 countries resulted in the first set of standardized incidence measures among divergent areas and ethnic groups. The average annual age-adjusted incidence under age 15 yr ranged from 1.7/100,000 person-yr in Hokkaido, Japan, to 29.5/100,000 person-yr in Finland during the years 1978-1980. The geographic differences in IDDM in childhood are rarely seen among chronic diseases. It appears that the risk for IDDM is determined by factor(s) correlated to the average yearly temperature of environment and to the ethnicity of the population at risk.

Geographic Patterns of Childhood Insulin-Dependent Diabetes Mellitus

Population-based registries of insulin-dependent diabetes mellitus (IDDM) worldwide have reached the critical mass needed to investigate global patterns of the disease. International collaboration of 24 registries from 15 countries resulted in the first set of standardized incidence measures among divergent areas and ethnic groups. The average annual age-adjusted incidence under age 15 yr ranged from 1.7/100,000 person-yr in Hokkaido, Japan, to 29.5/100,000 person-yr in Finland during the years 1978–1980. The geographic differences in IDDM in childhood are rarely seen among chronic diseases. It appears that the risk for IDDM is determined by factor(s) correlated to the average yearly temperature of environment and to the ethnicity of the population at risk.

Incidence of IDDM in Montreal by Ethnic Group and by Social Class and Comparisons With Ethnic Groups Living Elsewhere

We examined the incidence of insulin-dependent diabetes mellitus (IDDM) among children aged 0-14 yr in Montreal by social class and by ethnic group from 1971 to 1985. There was a slightly higher risk in wealthier as opposed to poorer classes. This income gradient was more marked in younger than in older children. Children of French extraction had about two-thirds the risk of IDDM of children of other origins, mainly British and other European. This mimics the patterns of risk in Europe, where France is reported to have lower rates than does Britain and Scandinavia. The absolute levels of risks among French Canadian and Jewish Canadian children were about double those reported from France and Israel, respectively. These various results are compatible with the hypothesis that both genetic and environmental factors influence IDDM risk.

HLA-D region RFLPs indicate that susceptibility to insulin-dependent diabetes in South India is located in the HLA-DQ region.

Recently close markers for insulin-dependent diabetes mellitus in Western 'Caucasoid' subjects have been defined from DQ region (both alpha and beta genes) restriction fragment length polymorphisms. In order to define the genetic contribution to insulin-dependent diabetes mellitus in an Indian population we have analysed 58 unrelated Dravidian (South Indian) insulin-dependent diabetic patients and 43 controls. In insulin-dependent diabetes an increased frequency of the Taq 1 DQ beta restriction fragment length polymorphisms designated T2 omega/T6 (relative risk = 10.6), and of homozygotes for Taq 1 DQ alpha 4.6 kb (relative risk = 11), was found in the patients. The highest relative risk for insulin-dependent diabetes mellitus was obtained by comparing patients and control subjects who either (a) co-inherited DQT2 omega/T6 with certain DQ alpha restriction fragment length polymorphisms or (b) were DQ alpha 4.6 kb homozygotes, the combination of (a) and (b) accounting for 55.5% of insulin-dependent diabetes mellitus subjects and none of the controls (relative risk = 101; 95% confidence limits 93-109).

HLA-DR4 in insulin-dependent diabetic parents and their diabetic offspring: a clue to dominant inheritance.

Insulin-dependent diabetes mellitus (IDDM) susceptibility determinants are known to be associated with both HLA-DR3 and -DR4. We monitored the inheritance of HLA-DR alleles in 37 families in which IDDM affected one parent and at least one offspring in order to try to learn more about the modes of inheritance of IDDM determinants. Ninety-seven insulin-dependent diabetics whose parents did not have diabetes and 158 nondiabetics were used as control groups for estimates of DR allele frequencies in the overall diabetic and general populations. The proportion of diabetic parents who transmitted DR4 to diabetic offspring (78%) was significantly higher (P less than 0.001) than the gene frequency of DR4 in the overall diabetic population (43%). The proportion of nondiabetic parents who transmitted DR4 to diabetic offspring (22%) was not significantly different from the gene frequency of DR4 in the nondiabetic population (16%), but it was significantly lower (P less than 0.05) than the gene frequency in the overall IDDM population. These proportions suggest that inheritance of the DR4-associated IDDM susceptibility determinant is not recessive, because in recessive inheritance expression of a trait depends on each parent contributing a susceptibility determinant. The proportions of diabetic and nondiabetic parents who transmitted the DR allele associated with the susceptibility determinant would then equal one another. The transmission of predominantly DR4 from affected parents to affected offspring suggests that susceptibility to IDDM is inherited primarily via a single dose of a potent determinant associated with DR4, as in dominant inheritance. When DR3 was transmitted at all it was usually by the nondiabetic parent. Only 8% of diabetic parents transmitted DR3 but 35% of nondiabetic parents transmitted DR3. The proportion of nondiabetic parents who transmitted DR3 was similar to the gene frequency of DR3 in the overall diabetic population (29%), but it was significantly higher than the gene frequency of DR3 in the nondiabetic population (15%; P less than 0.005). The percentage of diabetic offspring with the genotype DR3DR4 (35%) was identical to the percentage of individuals in the overall IDDM population with this genotype (35%). Numerous population data indicate that the DR3DR4 genotype carries a higher relative risk for IDDM than any other genotype, which suggests synergism between the DR3- and DR4-associated determinants. The family data reported here support this synergism but suggest that the DR4-associated determinant can give substantial susceptibility independent of the DR3-associated determinant and that the DR3-associated determinant is often expressed as enhancing susceptibility in the presence of the dominant DR4- associated determinant.

Susceptibility to IDDM is marked by MHC supratypes rather than individual alleles.

107 patients with insulin-dependent diabetes mellitus (IDDM) were typed for HLA A, B, C-, and DR antigens, and for complement C4A, C4B, and Bf alleles, and the results were compared with those of a combined reference group of 332 appropriately matched healthy subjects. Supratypes (allelic combinations) were identified from the phenotype of each group, and it was shown that the frequency of several supratypes is increased in patients with IDDM, in particular supratypes (A1 Cw7) B8 C4AQ0 C4B1 BfS DR3 (P = 0.0001), (A30 Cw-) B18 C4A3 C4BQ0 BfF1 DR3 (P = 0.0003), (A2 Cw3) B62 C4AR C4B2.9 BfS DR4 (P = 0.0002), and three other supratypes including DR4. It was also shown that increases in the frequency of individual alleles are secondary to increases in supratype frequency. Moreover, supratypes appeared to interact; the presence of two relevant supratypes being particularly important. The absolute risk of IDDM was approximately 0.5 in subjects who were homozygous for B18 C4A3 C4BQ0 BfF1 DR3. We concluded that genetic susceptibility is best recognized by MHC supratypes rather than isolated alleles, and that supratype combinations make the identification of even greater disease risk possible.

Geographic differences in the risk of insulin-dependent diabetes mellitus: the importance of registries.

There are marked geographic differences in the incidence of insulin-dependent diabetes mellitus (IDDM); for example, children in countries such as Finland are over 35 times more likely to develop IDDM than children in Japan. An understanding of the reasons for the geographic differences is likely to be important for understanding and, hopefully, preventing IDDM. There are problems, however, because of the lack of registries with adequate standardization. The major needs for the future studies include (1) to clarify the definition of IDDM for epidemiologic study, (2) to establish a standardized approach for IDDM registries, (3) to use registries to evaluate viral, immunologic, and genetic differences in order to explain differential risks across populations, and (4) to encourage the development of new population-based registries worldwide.

First-degree relatives of patients with type I diabetes mellitus. Islet-cell antibodies and abnormal insulin secretion.

In a prospective study to evaluate the prevalence and predictive potential of circulating islet-cell antibodies, we have screened 1723 "normal" first-degree relatives (parents, siblings, and offspring) of patients with insulin-dependent diabetes mellitus. The prevalence of islet-cell antibodies on initial screening was 0.9 per cent (16 of 1723). Over a maximal follow-up period of two years, insulin-dependent diabetes mellitus developed in 2 of 16 relatives with islet-cell antibodies and in 1 of 1707 without antibodies. In addition, 6 of 12 nondiabetic relatives with islet-cell antibodies had abnormally low insulin responses--below the third percentile in 6 and below the first percentile in 4--on their initial intravenous glucose challenge. Thus, prospective islet-cell antibody screening of high-risk first-degree relatives, in combination with intravenous glucose-tolerance testing, is capable of identifying immunologically abnormal persons with profoundly diminished beta-cell function, who are presumably at increased risk of insulin-dependent diabetes mellitus.

Complement and HLA. Further definition of high-risk haplotypes in insulin-dependent diabetes.

The families of 41 probands with type I (insulin-dependent) diabetes mellitus (IDDM) were typed for HLA-A, HLA-B, and HLA-DR antigens in addition to the complement polymorphisms C2, C4A, C4B, and Bf. All of these loci are encoded on the short arm of human chromosome 6 in a narrow region. Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM. This study confirms those significant risks in addition to confirming increased risk for the null (silent) allele for C4A (C4AQ0) and a rare C4B variant (C4B2.9). The significantly associated antigens (alleles) and risks were: HLA-B8 (RR = 3.1), HLA-DR3 (RR = 5.2), HLA-DR4 (RR = 4.3), and BfF1 (RR = 7.1), in addition to C4AQ0 (RR = 2.8) and C4B2.9 (RR = 12.6). Significantly low risk was associated only with HLA-DR2 (RR = 0.1). In a recent study, we defined five high-risk haplotypes that were determined solely by HLA-B, Bf, and HLA-DR (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4). By inclusion of information from the complement polymorphism, we have defined in greater detail three of these five high-risk haplotypes. One previously identified haplotype (B40-BfS-DR4) showed no complement clustering, while the rare high-risk haplotype (B8-BfS-DR4) was seen only once in this smaller sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome.

An increased incidence of insulin-dependent diabetes mellitus (IDDM) has been reported in patients with congenital rubella syndrome (CRS). Thus, studies of children with CRS would be of great importance in following the development of IDDM in a susceptible population. A total of 242 children with CRS, 30 of whom already have diabetes (mean age, 17.4 +/- 0.3 years) have been evaluated. In this latter group, the frequency of HLA DR3 is significantly increased and that of HLA DR2 significantly decreased. While pancreatic islet cell cytotoxic or surface antibodies (ICSA) are found in 20.2% of the total population of patients with CRS, they are present in 50%-80% of patients with glucose abnormalities. In all but five of the ICSA-positive patients, glucose abnormalities are currently present. In addition, glucose intolerance is found in greater than 50% of the DR3-positive nondiabetic patients with CRS evaluated to date. The data demonstrate that patients with CRS at risk for IDDM have the same genetic and immunologic features seen in classic IDDM, namely the presence of HLA DR3 and the absence of HLA DR2 and the high prevalence of ICSA before decompensation.

Differences in Risk of Insulin-Dependent Diabetes in Offspring of Diabetic Mothers and Diabetic Fathers

One of the best means of determining the risk of insulin-dependent diabetes mellitus in relatives of index cases is to study the offspring of matings between patients with diabetes and persons without the disease. If the affected parents are selected before the birth of any child, the frequency of insulin-dependent diabetes mellitus in the offspring should not be biased by the method of ascertainment. The purpose of this article is to report a new analysis of the data from one such study, which shows differences in the risk for offspring according to the sex of the affected parent, and to consider the implications of this finding for the possible role of heritable factors in insulin-dependent diabetes mellitus. The study identified patients through the medical records of the Joslin Diabetes Center for the period of 1928 to 1939. Eligible patients were those with diagnoses of insulin-dependent diabetes mellitus before the age of 20. Eighty-eight affected men produced 244 offspring, and 99 affected women produced 175 offspring. By age 20, 6.1 ±; 1.8 per cent (mean ±; SE) of the fathers with diabetes had the disease. This risk is similar to that reported for the siblings of patients with diabetes. By contrast, the risk of development of the disease in the offspring of affected mothers was only one-fourth as large (1.3 ±; 0.9 per cent). This is still about five times the cumulative risk found in the general population by age 20. The 4.8 per cent difference in the cumulative risks between the offspring of diabetic women and those of diabetic men is significant (P < 0.05; 95 per cent confidence interval, 2.1–10.8 per cent). Daughters and sons of the fathers with insulin-dependent diabetes mellitus were affected equally (six and five, respectively) and were combined in the analysis. The finding of different risks of diabetes in offspring according to the sex of the affected parent was unexpected. The authors examined studies from other countries and found similar results, i.e., lower rates of diabetes in the offspring of diabetic mothers than in those of affected fathers. The results from several types of studies are summarized in Table 1. Another source of evidence regarding sex differences in the transmission of insulin-dependent diabetes mellitus from parent to child is found in studies of the prevalence

The genetic susceptibility to insulin-dependent diabetes mellitus: combined segregation and linkage analysis.

We report a combined segregation and linkage analysis of a Danish sample of 216 insulin-dependent diabetes mellitus (IDDM) nuclear families: of these 216, twenty multiplex families were haplotyped regarding HLA-DR and -B markers. The analysis was conducted using the computer program COMBIN, which includes a modifier to absorb family resemblance that is additional to the effect of the major locus that is assumed linked to a marker locus, eg, within the HLA region. The initial analysis could clearly reject a dominant major locus but could not discriminate between other models with or without modifier. However, after adding supplementary information on population associations between HLA and IDDM together with the identity-by-descent (IBD) distribution to the analysis, a final model was identified. This invokes an additive major locus, linked to HLA with recombination not significantly different from 0, a disease gene frequency of 0.217, plus a dominant modifier. From this model it can be predicted that about 0.15% of the general population is at 100% risk of IDDM, about 5% is at intermediate risk (approximately 10%), while the remaining population has a risk of 0. The model predicts recurrence risks compatible with empirically estimated values. Particularly strong, positive haplotype associations were found for the DR3,B8, DR3,B18, and DR4,B15 haplotypes, but detailed analyses showed that neither these particular haplotypes nor the DR3 and DR4 haplotypes in general could entirely explain the HLA-associated susceptibility. The DR2 haplotypes showed a strong negative association. The results are discussed in the light of available data on the epidemiology of IDDM in order to provide a framework for further epidemiological studies.

Multivariate analyses of the risk of insulin-dependent diabetes mellitus for siblings of insulin-dependent diabetic patients.

Multivariate models for the risk of insulin-dependent diabetes mellitus for siblings of patients with insulin-dependent diabetes were developed using logistic regression analysis. The individuals studied in this report are full siblings of the insulin-dependent diabetic patients diagnosed at Children's Hospital of Pittsburgh between 1964 and 1982. For all siblings considered together, the sharing of two (but not one) HLA haplotypes, the presence of insulin-dependent diabetes in a parent, and being relatively young at the time the proband in the family was diagnosed were significantly associated with increased risk. On the other hand, B7 + siblings had a significantly decreased risk compared to B7--siblings, indicating the presence of an HLA-linked protective gene for the development of the disease. There was a significant interaction between sharing two HLA haplotypes and maternal age at the time of birth; for non-HLA-identical siblings, risk increased with increased maternal age, but maternal age had little or no effect on the risk for HLA-identical siblings. When non-HLA-identical siblings (0 or 1 HLA haplotypes shared) were analyzed separately, only the presence of insulin-dependent diabetes in one of the parents and increased maternal age at the time of birth of the sibling were found to be significantly associated with increased risk. Both of the totally non-HLA-identical diabetic siblings (neither HLA haplotype shared) in this data set had a parent with insulin-dependent diabetes, indicating that at least one HLA haplotype must be inherited in common with an affected family member for diabetes to develop. For HLA-identical siblings, the significant variables were the age of the sibling when the proband was diagnosed, the possession of B7, and maternal age at the time of birth of the sibling, and all three were negatively associated with risk.

The Pittsburgh insulin-dependent diabetes mellitus (IDDM) study. HLA antigens and haplotypes as risk factors for the development of IDDM in IDDM patients and their siblings

The relationships between HLA antigens, sex, age at diagnosis, season of onset and insulin-dependent diabetes mellitus (IDDM) were studied in a consecutive admissions series of newly-diagnosed IDDM patients at Children's Hospital of Pittsburgh. In agreement with the findings of others, the strongest positive associations between IDDM and HLA antigens were seen with DR3 and DR4 (odds ratios (OR) of 3.5 and 4.4, respectively), while a very strong negative association was observed with DR2 (OR of 0.1). Male patients were significantly more likely than female patients to possess DR3 while female patients were significantly more likely to be DR4 + . No consistent relationships were found between HLA antigens and either age at diagnosis or season of onset. Using a life table approach, the cumulative risk of IDDM by age 24 in HLA-identical siblings of IDDM patients was estimated to be 10.3%. This risk was significantly greater than the risks to either HLA-haploidentical siblings (2.2%) or to HLA-nonidentical siblings (1.0%), whose risks were not significantly different. B7 + HLA-identical siblings of patients appeared to be protected from the effects of HLA-identicality—their cumulative risk by age 24 was estimated to be only 2.3%.

Influence of HLA Types on Carbohydrate Effects of a Low-Estrogen Oral Contraceptive

The lymphocyte HLA types were determined for 13 women, who were then separated into a subgroup of those having a "high" risk for insulin-dependent diabetes mellitus (B8, B15, AW30) and a "low-risk" subgroup (B7, BW35). A 3-hour oral glucose tolerance test was conducted on each woman before starting on oral contraceptives (OC) and then 6 months after using them. Both blood glucose and plasma insulin levels were measured. The OC contained 0.035 mg of ethinylestradiol and 0.4 mg of norethindrone. There was a significantly higher 0.5-hour glucose value in the control test in the "high risk" group. There was a significant elevation of the 1-hour plasma insulin value in the 6-month test for the "high-risk" group. The usefulness of the HLA prescreening of women prior to use of OC needs more study.