Analysis of linkage between the major histocompatibility system and juvenile, insulin-dependent diabetes in multiplex families. Reanalysis of data.

Linkage analysis between the major histocompatibility system (HLA) and juvenile, insulin-dependent diabetes, assuming an autosomal recessive mode and 50% penetrance was performed on 21 juvenile, insulin-dependent diabetic multiplex families (two or more diabetics per sibship) with phenotypically normal parents. The total lod score was the highest (3.98) at a recombination fraction of 13%. For a penetrance of 100%, the highest total lod score was 2.92 at a recombination fraction of 18%. These results are compatible with the existence of linkage between an autosomal recessive diabetic gene with 50% penetrance and the HLA in some of the families studied. Our ascertainment strategy would be expected to increase the likelihood of selecting for genetically homogenous diabetes and against sporadic forms of the disease. Thus, our findings may apply only to a small proportion of all cases of juvenile, insulin-dependent diabetes.

Linkage analysis between the major histocompatibility system and insulin-dependent diabetes in families with patients in two consecutive generations.

We have histocompatibility (HLA) genotyped 28 families with insulin-dependent diabetics in two or more consecutive generations, usually parent and child. This strategy of ascertainment was used to maximize the likelihood of obtaining a homogeneous type of disease within a family, and an autosomal dominant mode of inheritance. 76 diabetics and 169 nondiabetics were studied in these families. The frequencies of the antigens Dw3 and Dw4, and the genotype Dw3/Dw4 among the diabetics are 59, 68, and 30%, respectively, as compared with 15, 12, and 2% in normal controls, and 43, 41, and 10% in the nondiabetic relatives of the diabetics. Dw2 is present in only one diabetic (4%), as compared with 18% in normal controls and 17% in nondiabetic relatives.HLA haplotype concordance was analyzed for sib pairs in relation to the haplotype shared by the affected parent/child pair, and for the diabetic sib pairs within each sibship. The results failed to reveal deviations in the expected HLA haplotype assortment. Assuming an autosomal dominant mode and several penetrance levels, linkage analysis between the HLA and diabetes was performed. The total lod score is 0.37 for a recombination fraction of 0.29 at 50% penetrance. Although the linkage and concordance analysis results are inconclusive, they seem to be different from those reported by us for families with normal parents and two or more diabetic sibs. Because ascertainment biases may have influenced these results in an unquantifiable manner, it is not certain whether the two types of families are genetically different. However, the marked difference in the lod scores for the 50% penetrant autosomal recessive model between the two types of families is compatible with a genetic dissimilarity between them. The high frequency of the Dw3 and Dw4 antigens, the Dw3/Dw4 genotype, and the decreased frequency of Dw2, however, indicate the existence of two or more important diabetic genetic factors associated with the D region of the HLA in these families.

Empirical risk for insulin-dependent diabetes (IDD) in sibs. Further definition of genetic heterogeneity.

We have studied the effect of age at diagnosis in the proband and parental status [normal versus non-insulin-dependent diabetes (NIDD)] on the cumulative risk to age 40 (CR40) for insulin-dependent diabetes (IDD) in sibs of IDD probands in 493 families. We found a significantly increased cumulative risk to age 40 fro IDD in sibs of probands with disease diagnosed before age 10 (8.5 +/- 2.0%) as compared with that in sibs of probands with disease diagnosed after age 10 (4.6 +/- 0.8%) (X2 = 7.6, P = 0.006). Within the family subset with probands of earlier IDD onset (before age 10) we also found an increased CR40 for IDD in the sibs of the probands in families with an NIDD parent (with NIDD parent: CR40 = 7..5 +/- 2.0%, X2 = 12.8, P less than 0.0005). These data are compatible with the theory of heterogeneity (genetic and/or environmental) of IDD and a possible relationship between IDD and NIDD.

On the genetic heterogeneity of juvenile hyperglycemia.

We have briefly discussed immunogenetic studies of families with hyperglycemia which suggest the existence of at least four types of the disease: a) juvenile, insulin-dependent, ketosis prone diabetes determined by an autosomal recessive gene with 50% penetrance and in linkage with the HLA; b) juvenile, insulin-dependent, ketosis prone diabetes probably determined by an autosomal dominant gene; c) unidentified types of juvenile, insulin-dependent diabetes whose pathogenesis may be related to the HLA associations reported; and d) maturity onset type of hyperglycemia in the young, probably determined by an autosomal dominant gene. There are probably other forms of juvenile hyperglycemia. Some may depend on genes unrelated to the HLA, others may be mostly or totally environmental, rather than genetic.

HLA-Dw antigens in unrelated juvenile, insulin-dependent diabetics.

Forty-one unrelated juvenile, insulin-dependent diabetics have been HLA tissue typed for A, B and Dw anitgens and compared with a normal control population. We have found statistically significant increases in the frequencies of B8, B18, and Dw3, and significant decrements in the frequencies of B7, B12 and Dw2. The log-linear modeling technique was used to study the association of JIDD with Dw3 and B8 antigens. We confirmed that the B8 excess seen in diabetics is secondary to the excess of Dw3. The decrements of B7, B12 and Dw2 could reflect an association of these antigens with a protective factor for the disease, or could be due to an artifact. The latter possibility was excluded for B7 and Dw2 by adjusting for the excess antigen frequencies. These findings suggest that the associations between the HLA and diabetes are compatible with the existence of genes which are concerned with the pathogenesis of the disease and are closely associated with the D locus of the major histocompatibility system.

Comparison of a radioimmunoassay and a microbiological assay for measurement of serum vancomycin concentrations.

A newly developed radioimmunoassay was used to measure the concentration of vancomycin in 137 specimens of serum from patients being treated with this antibiotic. Of these sera, 84 were also analyzed with a microbiological assay technique for vancomycin. Duplicate determinations were done with each of the techniques. Individual values and averaged values for both methods were used for statistical analyses. The correlation coefficients between all possible combinations of radioimmunoassay and microbiological assay results for the 84 sera were greater than or equal to 0.99 (P less than 0.01). Values for the regression coefficients of radioimmunoassay results on microbiological assay results ranged from 0.98 +/- 0.01 to 1.03 +/- 0.01. The mean percent deviation of radioimmunoassay versus microbiological assay results was -1.56 +/- 0.60. A one-way analysis of variance demonstrated that the use of different standard curves for each batch of specimens assayed by microbiological assay did not significantly influence the results (P = 0.07). The microbiological assay and the radioimmunoassay for measurement of serum vancomycin levels yielded essentially identical results.