Original Article
Analysis of HLA-DQ Genotypes and Susceptibility in Insulin-Dependent Diabetes Mellitus
N Engl J Med 1990; 322:1836-1841June 28, 1990
- Abstract
- Abstract
There is evidence that certain alleles at the HLA-DQ locus are correlated with susceptibility to insulin-dependent diabetes mellitus (IDDM) and in particular that DQ beta-chain alleles containing aspartic acid at position 57 are protective. The availability of a large group of patients with IDDM enabled us to assess the role of HLA-DQ alleles in susceptibility to the disease in order to confirm and extend recent observations derived from studies of smaller numbers of patients. Using allele-specific oligonucleotide probes and the polymerase chain reaction, we studied 266 unrelated patients with IDDM and 203 unrelated normal subjects for eight HLA-DQ beta-chain alleles.
Two major findings emerged from these studies. First, the presence of an HLA-DQw1.2 allele was protective. Only 6 of the 266 patients with IDDM (2.3 percent) were positive for HLA-DQw1.2, as compared with 74 of the 203 normal subjects (36.4 percent; P<0.001). Thus, persons with the HLA-DQw1.2 allele, which is one of the polymorphic forms of the beta chain of the HLA-DQ molecule, rarely had IDDM, no matter which other HLA-DQ beta-chain allele they inherited ("dominant protection"). Second, the presence of the HLA-DQw8 allele increased the risk of IDDM. The relative risk of IDDM was 5.6 in persons homozygous for HLA-DQw8, and it was similar in persons with the HLA-DQw1.1/DQw8 or HLA-DQw2/DQw8 haplotype ("dominant susceptibility"). However, the relative risk of IDDM in persons who had the HLA-DQw1.2/DQw8 haplotype was 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8.
We conclude that the presence of the HLA Class II antigen DQw1.2 is strongly protective against the development of IDDM, and that complete HLA-DQ typing is necessary for accurate assessment of susceptibility to IDDM. (N Engl J Med 1990; 322:1836–41.)
Media in This Article
Table 1
HLA-DQ Gene Frequencies in Normal Subjects and Patients with IDDM.Table 2
Relation of the Presence or Absence of Aspartic Acid to the Risk of IDDM in Normal Subjects and Patients with IDDM, as Determined by HLA-DQ Beta-Chain Analysis.Article Activity
- Article
AMONG whites, the HLA-DR3 and HLA-DR4 alleles confer increased susceptibility to insulin-dependent diabetes mellitus (IDDM),1 2 3 4 5 6 but there is growing evidence that the alleles at the DQ rather than the DR locus are more intimately associated with this increased susceptibility.7 8 9 Both the HLA-DQ and the HLA-DR molecules are heterodimers made up of an alpha chain (34 kd) and a beta chain (29 kd). The chains are noncovalently associated, and both subunits are intrinsic membrane proteins. Most of the variability is found in the outer domains of these Class II molecules, and the regions of polymorphism are probably linked to disease susceptibility. Since the D region of the HLA complex encodes many polymorphic molecules (DP, DQ, and DR), DQ typing by serologic techniques is complicated and incomplete, and analysis of restriction-fragment–length polymorphism on a large scale is cumbersome. However, the introduction of analysis with allele-specific oligonucleotides10 , 11 makes such studies feasible. Using allele-specific oligonucleotides, several investigators have reported that the absence of an aspartic acid at position 57 of the DQ beta chain provides an excellent marker for IDDM.12 13 14 In their original study of 39 patients with IDDM, Todd et al. found no patient who was homozygous and only 3 patients who were heterozygous for aspartic acid at position 57 of the HLA-DQ beta chain, suggesting that the presence of a single aspartic acid at this position was protective.13 In a more recent study of 27 families with multiple cases of IDDM, Morel et al. found only one patient who was heterozygous for aspartic acid at position 57 of the DQ beta chain.15 These results suggest that genetic susceptibility to IDDM is dominant in its HLA association and that a single aspartic acid at position 57 of the DQ beta chain confers allele-specific protection.15 The fact that analysis for aspartic acid does not entirely account for susceptibility to disease is evident from studies in nonwhites. For example, certain haplotypes in Japanese persons may encode aspartic acid at position 57 of the DQ beta chain, yet these haplotypes are positively associated with IDDM.9
The use of oligonucleotide probes to assess susceptibility to disease is attractive as a rapid, inexpensive tool that can be used to screen a large number of people, particularly relatives of patients with IDDM. Such an approach requires the use of control subjects and large numbers of patients with IDDM. Since we had a large, well-defined group of patients with IDDM in our clinic who had undergone HLA typing for other studies, we tested all our white patients for most of the HLA-DQ beta-chain alleles that can be identified by allele-specific oligonucleotide analysis. Specifically, we hoped to confirm and extend previous studies12 13 14 15 to determine whether this DNA-based test could be implemented on a wide scale.
Using allele-specific oligonucleotide probes and the polymerase chain reaction, we analyzed nearly 300 randomly selected whites with IDDM and more than 200 unrelated normal subjects. For nearly all the subjects, HLA typing was performed independently. We confirm the association with IDDM of DQ beta-chain alleles that do not contain aspartic acid at position 57. However, in contrast with other reports, we found that a single DQ beta-chain allele containing aspartic acid was not protective for IDDM. We conclude that accurate assessment of susceptibility to IDDM requires complete HLA-DQ typing, not simply analysis of the HLA-DQ beta chain for aspartic acid at position 57.
Methods
Patient Population
Two hundred eighty-four unrelated white patients with IDDM as defined by the criteria of the National Diabetes Data Group were studied. The patients were recruited by radio announcements; to be included in the study, they were required to have an unaffected sibling under 18 years of age. The diagnosis of IDDM in each patient was confirmed by a single nurse practitioner, and a blood sample was obtained. The mean age of the 284 patients at the time of onset of their diabetes was 9.3 years (range, 6 to 34), and the mean duration of diabetes was 7.2 years (range, 4 to 14). There were 144 female patients and 140 male patients. Thirteen of these had a first-degree relative with IDDM, and in these cases only the oldest sibling was studied.
The control population consisted of 203 randomly selected normal whites (101 women and 102 men; mean age, 22 years; range, 19 to 35). None had a family history of IDDM, and each described himself or herself as nondiabetic, but blood glucose was not measured in these subjects. With only a few exceptions, all subjects were typed for HLA-A, B, and C by the microcytotoxicity method of the National Institutes of Health. The serum samples for typing were prepared locally or obtained in exchange from other investigators. HLA-DR typing was performed on B lymphocytes obtained from peripheral blood with use of similar cytotoxicity methods with prolonged incubation.
DNA Extraction and Polymerase Chain Reaction
DNA was extracted from fresh or frozen peripheral-blood lymphocytes by standard techniques.12 13 14 15 The first domain of the DQ beta-chain gene was amplified from genomic DNA with use of the polymerase chain reaction.16 , 17 The primers used were DQL (5′–GATTTCGTGTACCAGTTTAAGGGC-3′) and DQR (5′–CTGGTAGTTGTGTCTGCACAC-3′), which have a product of approximately 270 base pairs. The amplification was carried out for 40 cycles with 1 μg of genomic DNA and 0.5 U of thermostable Taq polymerase (Perkin–Elmer–Cetus, Norwalk, Conn.). In addition, two DQ alpha-chain primers, DQAL (5′–GGTGTAAACTTGTACCAGTCTTAC-3′) and DQAR (5′–AGCAGCGGTAGAGTTGGAGCGTTT-3′), were used to amplify the DNA of patients typed as HLA-DQw2, in order to distinguish between persons with the HLA-DR3DQw2 and those with the HLA-DR7DQw2 haplotype.
Dot-Blot Analysis Using Allele-Specific Oligonucleotides
DNA was blotted onto MSI Magnagraph nylon membrane (MSI, Westboro, Mass.), baked for one hour at 80°C, and prehybridized for 30 minutes at 42°C (6× SSC [1× SSC is 0.15 M sodium chloride and 0.015 M sodium citrate], 0.5 percent sodium dodecyl sulfate, 5× Denhardt's solution, and 100 μg of denatured salmon-sperm DNA per milliliter). The filters were incubated in the same solution overnight at 42°C with oligonucleotide probes designed to distinguish between specific alleles at the DQ beta-chain locus (allele-specific oligonucleotide probes 5′–3′: DQw1.1, GGCGGCCTGTTGCCGAG; DQw1.2, GGCGGCCTGATGCCGAG; DQw1.AZH, GGCGGCCTAGCGCCGAG; DQw2, GCTGGGGCTGCCTGCCG; DQw7 (formerly DQw3.1), GGCCGCCTGACGCCGAG; DQw8 (formerly DQw3.2), GGCCGCCTGCCGCCGAG; DQw4, GGCGGCTCGACGCCGAG; and DQw1.12, GGCGGCCTGACGCCGAG). Most of these sequences were derived from Todd et al.12 , 13 A control oligonucleotide (5′–3′ CGCTTCGACAGCGACGT) designed from a conserved region among DQ alleles (amino acids 39 to 44 in the DQβ1 domain) was used as an amplification control in order to demonstrate the presence of a DQ beta-chain product even when an allele was not detectable with any of the probes used (i.e., DQ blank). All filters, except those probed with the DQw4 oligonucleotide, were then washed in a tetramethyl-ammonium chloride solution (500 g of tetramethyl-ammonium chloride [pH 8.0], 5.6 ml of 0.5 M EDTA [pH 8.0], and 7 ml of 20 percent sodium dodecyl sulfate, with distilled water added to a total of 1400 ml) for 25 minutes at room temperature and then at varying temperatures (depending on the oligonucleotide) for an additional 25 minutes. Filters probed with the DQw4 oligonucleotide were washed in 1 × SSC for 25 minutes at 42°C. These procedures removed any probe that had one or more mismatches with the target sequence.
The persons with the HLA-DR7DQw2 haplotype were distinguished from those with the HLA-DR3DQw2 haplotype in an analysis of the DQ alpha-chain gene using an oligonucleotide probe, DQ alpha-7 (5′–CTGTTCCACAGACTTAG-3′), which recognizes the difference between the DQ alpha chains but not the DQ beta chains of these two alleles. This latter distinction is crucial, because HLA-DR3DQw2 is a well-known susceptibility marker in IDDM, whereas HLA-DR7DQw2 is not, even though both haplotypes have an alanine at position 57 of their DQ beta chain.
In some instances, it was essential to know the DR assignment by serologic typing in order to assign the haplotype (i.e., HLA-DR4DQw7 vs. HLA-DR5DQw7). In other circumstances, additional polymerase chain reactions were performed to assign haplotypes unambiguously (i.e., HLA-DR3DQw2 vs. HLA-DR7DQw2). In general, these results demonstrated that accurate HLA-DR/DQ typing could be accomplished by allele-specific oligonucleotide screening on a widespread basis.
For technical reasons, either poor amplification of the sequence or the apparent detection of three alleles, 15 patients were excluded. Three other patients were excluded because it was impossible to determine whether they had the HLA-DR7/DR7 or the HLA-DR3/DR7 haplotype on the basis of available serologic and DNA typing data. This distinction was important in the further analysis of these data.
Statistical Analysis
Gene frequencies (Table 1Table 1
HLA-DQ Gene Frequencies in Normal Subjects and Patients with IDDM.) were calculated from the frequencies with which the alleles were observed with use of the formula g = 1 – the square root of (1–f), in which g is the gene frequency and f the observed allele frequency. Since only unrelated persons were studied, no distinction was made between homozygosity for a particular allele and the presence of a DQ beta-chain allele that could not be identified (a "blank"). The significance of the differences in allele frequencies was determined by chi-square analysis with Yates' correction. Odds ratios were calculated by the method of Woolf with use of the formula (a × d)/(b × c) and by convention were expressed as relative risks. When one element of the equation was zero, the relative risk was calculated with the formula of Haldane: [(2a + l)(2nd + l)]/[(2b + l)(2c + 1)].Results
Correlation of Allele-Specific Oligonucleotide Analysis of DQ with Serologically Determined HLA-DR Typing
With only a few exceptions, the results of the allele-specific oligonucleotide analysis agreed with those of HLA-DR serologic typing. The distribution of the various alleles in the normal subjects (Table 1) was comparable with that in another group of normal white subjects,12 except that we found a higher frequency of some HLA-DQ alleles (DQw1.1 and DQw1.2) and a lower frequency of HLA-DQw4. The somewhat higher frequency of DQw1.1 and DQw1.2 probably occurred because we did not distinguish DQw1.1 from DQw1.19 (both of which contain valine at position 57) and DQw1.2 from DQw1.18 or DQw9 (all of which contain aspartic acid at position 57). The results in our normal subjects differed somewhat from those reported by Morel et al.,15 perhaps as a result of the presence of HLA-DQ blank alleles in our control group. However, when we calculated the expected allele frequencies on the basis of our results, using the gene frequencies given in Table 1, we found that they closely matched the frequencies observed, indicating that our population was in Hardy-Weinberg equilibrium.
Positive and Negative Associations of HLA-DQ Alleles with IDDM
Table 1 shows the HLA-DQ gene frequencies in the patients with IDDM. The protective effect of HLA-DQw1.2 was striking, because only 6 of 447 alleles that could be typed (1.1 percent according to the formula described in Methods; P<0.001) from the 266 patients with IDDM contained DQw1.2, and none of the patients were homozygous. In contrast, the gene frequency of HLA-DQw1.2 in the normal subjects was 20.3 percent (74 of 310 alleles). These findings confirm and extend the well-known protective role of HLA-DR2 (linked to DQw1.2) in IDDM.3 , 15 , 16 The frequencies of the other two DQ alleles associated with HLA-DR2, DQw1.12 and DQw1.AZH, were too low in our study to be of particular interest. In addition, our data confirm the known positive association of DQw8 with IDDM (35.7 percent in IDDM vs. 10.1 percent in normal subjects; P<0.001).
The Protective Value of Aspartic Acid at Position 57 of the HLA-DQ Beta Chain
Table 2Table 2
Relation of the Presence or Absence of Aspartic Acid to the Risk of IDDM in Normal Subjects and Patients with IDDM, as Determined by HLA-DQ Beta-Chain Analysis. shows the results of the analysis for DQ beta-chain alleles containing aspartic acid in the normal subjects and the patients with IDDM. Two hundred three of the patients with IDDM (76.3 percent) had no alleles containing aspartic acid at position 57, as compared with 96 percent described by Morel et al.15 Among the normal subjects, 41.9 percent had this haplotype. Fifty-seven of the patients with IDDM (21.4 percent) had one aspartic acid-containing allele, as compared with 33.0 percent of the normal subjects. This approach provides a powerful test of susceptibility, because when the 4 patients with a haplotype containing two unidentified HLA-DQ beta-chain alleles were excluded, 260 of the remaining 262 patients with IDDM (99.2 percent) had at least one allele that did not contain aspartic acid (relative risk, 41.9; P<0.001). Less than 1 percent of the patients with IDDM (2 of 266) had an aspartic acid at position 57 on both DQ beta-chain alleles, as compared with 24.1 percent of the normal subjects (49 of 203) (protective value, 1; relative risk, 41.7).Assessment of Risk in IDDM by Complete Allele-Specific HLA-DQ Typing
Table 3Table 3
Frequencies of the HLA-DQ Haplotypes in Normal Subjects and Patients with IDDM. shows the frequencies of the HLA-DQ haplotypes in the normal subjects and the patients with IDDM. The table is arranged according to relative risk, from low to high, and three arbitrary subdivisions are identified. The frequency of some combinations of haplotypes was so low in either the normal subjects or the patients with IDDM that their placements in this table are obviously tentative. First, 11 haplotypes were "protective," with relative risks of IDDM ranging from 0.013 to 0.38. This group represents 109 of the 203 normal subjects (53.7 percent), but only 13 of the 266 patients with IDDM (4.9 percent). The protective role of HLA-DQw1.2 is evident. The middle group in Table 3 contains haplotypes for which the relative risk of IDDM was close to 1 (relative risk, 1.07 to 1.53). Here the normal subjects and the patients with IDDM are represented nearly equally, with HLA-DQw2 the predominant allele in both groups. The haplotypes shown at the bottom of Table 3 are associated with a significant risk for the development of IDDM (relative risk, 2.18 to 5.99). These haplotypes were found in only 32 of the 203 normal subjects (15.8 percent) but in 157 of the 266 patients with IDDM (59.0 percent). The predominant haplotype in this group was HLA-DQw8.Finally, as an extension to Table 3, Table 4Table 4
Relative Risks Associated with Common HLA-DQ Haplotypes in Patients with IDDM.* shows the relative risks associated with the most common HLA-DQ haplotypes. The infrequent combinations of alleles have been eliminated in order to show the most important findings more clearly. Two major conclusions may be drawn. First, HLA-DQw1.2 had a profound protective effect in combination with any other DQ beta-chain allele. Second, HLA-DQw8 was the dominant susceptibility allele in IDDM (except when it was combined with HLA-DQw1.2).Discussion
This study documents that allele-specific oligonucleotide analysis of HLA-DQ haplotypes provides an important means of assessing disease susceptibility in IDDM. The size of the control and patient groups, the availability of complete, independently performed HLA typing, and the analysis of both alpha-chain and beta-chain genes, when indicated, permit conclusions to be drawn with confidence.
The degree of protection provided by the HLA-DQw1.2 allele in both the heterozygous and the homozygous states was remarkable, because only 6 of 266 patients with IDDM (2.3 percent) were positive for this allele, as compared with 74 of 203 normal subjects (36.4 percent). Among the normal subjects, 74 of the 116 persons (63.8 percent) who had alleles containing aspartic acid at position 57 were positive for HLA-DQw1.2. Although the allele's protective effect has been reported previously,18 , 19 it has seldom been so high.
Unlike many previous investigators, we did not find that HLA-DQw2 was associated with IDDM except when it was paired with HLA-DQw8. For example, persons with the HLA-DQw2/DQw2 haplotype had a relative risk of only 1.35, a value that takes into account the known protective effect of HLA-DR7/DQw2. Such a neutral association of HLA-DQw2 with IDDM is surprising, because persons with the HLA-DQw2/DQw2 (HLA-DR3/3) haplotype have long been known to have increased susceptibility to the disease.19 Moreover, both DQw2 and DQw8 have an alanine at position 57 of the DQ beta chain, but only DQw8 carries a high risk, whereas DQw2 appears to be neutral. The apparently increased frequency of the HLA-DQw2/DQw8 (HLA-DR3/4) haplotype in the patients with IDDM could possibly be due to transcomplementation.20
HLA-DQw8 was the allele most responsible for the apparently dominant pattern of susceptibility to IDDM in our patients. The highest assignments of relative risk (Tables 3 and 4) were among the haplotypes containing at least one HLA-DQw8 allele. The relative risks among the HLA-DQw8/DQw8 homozygotes (5.62) and the HLA-DQw2/DQw8 heterozygotes (5.99) were particularly dramatic. One possible explanation for the increased frequency of DQw8 alleles in the patients with IDDM is that the antigen-binding pocket or the region of T-cell interaction21 , 22 of a DQw8 molecule may have higher affinity for a relevant antigen in diabetes or be more conducive to interaction with the T-cell receptor of the responding T cell (either helper or suppressor).
The only situation in which a DQw8 allele did not act as a dominant susceptibility allele occurred in heterozygous persons with the HLA-DQw1.2/DQw8 haplotype (relative risk, 0.37), in whom the protective value of the DQw1.2 allele (containing aspartic acid) completely overrode the susceptibility effect of the DQw8 allele. Moreover, HLA-DQw1.2 had a profound protective effect in combination with any other allele, as is shown clearly in Table 3, where the relative risk of all haplotypes containing DQw1.2 is less than 0.5. No other aspartic acid-containing allele conferred such protection unless it was present in the homozygous state. When we examined complete haplotypes (Tables 3 and 4), HLA-DQw7 appeared to be neutral or positively associated with IDDM (relative risk, >1) unless it was combined with another aspartic acid-bearing allele. Interestingly, HLA-DQw1.1 appeared to be protective in the homozygous state, like DQw7 (Table 4), even though it has a valine at position 57 of the DQ beta chain, not an aspartic acid. In addition, the presence by itself of one of the other DQ beta-chain alleles containing aspartic acid (DQw 1.12 or DQw4) conferred no protection against diabetes, although these alleles did not appear often in our study subjects. Thus, with only a small decrease in the number of persons heterozygous for alleles coding for aspartic acid at position 57, this analysis argues against the theory that protection against or resistance to IDDM is conferred by the DQ beta-chain alleles DQw1.12, DQw7, or DQw4 (all aspartic acid-bearing) as has been suggested by both Todd et al.12 , 13 and Morel et al.15 Furthermore, it is well known that HLA-DQ and HLA-DR are strongly linked. That is, any person with the HLA-DQw1.2 allele by definition has DR2. In contrast, not all DR2-positive persons have the DQw1.2 allele; they may have DQw1.AZH or DQw1.12. Since we found no protection associated with HLA-DQw1.12, protection was probably not due to a DR effect. We therefore conclude that there is a profound protective effect associated only with the aspartic acid-bearing allele DQw1.2 and not with any of the other aspartic acid-bearing alleles (DQw1.12, DQw4, and DQw7).
Todd et al.12 proposed originally that an aspartic acid at position 57 of a DQ beta chain determines a critical function of the DQ molecule in IDDM. This residue, along with other polymorphisms in DQ molecules, undoubtedly has a major effect on the relations of structure and function that are operative at the level of antigen presentation. That is, the structural configuration of the DQ molecule determines which antigens can bind to it and how tightly they are bound, as well as the nature of the T-cell response that is elicited (help or suppression), which ultimately leads to the autoimmune destruction of the pancreatic islet cells in IDDM. These investigators concluded that complete susceptibility to IDDM required that a person have two DQ beta-chain alleles not containing aspartic acid. The apparent requirement in IDDM for two DQ beta-chain alleles neither of which contains aspartic acid at position 57 can be explained by a simple recessive model of the disease. Our data, in contrast, do not support such a model; instead, a dominant pattern of inheritance explains our findings better. That is, in some persons only one allele not bearing aspartic acid is needed to promote disease susceptibility (particularly if that allele is HLA-DQw8); conversely, the presence of only one aspartic acid-bearing allele (except HLA-DQw1.2) is insufficient to confer protection.
It is apparent that the mere analysis of DQ beta chains for aspartic acid at position 57 is insufficient for assessment of the risk of IDDM. There are two major exceptions that diminish the usefulness of such typing for aspartic acid by itself as a test of the risk for IDDM. First, persons with the HLA-DR7/DQw2 haplotype, which is known to be negatively associated with IDDM (yet does not bear an aspartic acid at position 57 of the DQ beta chain), would be placed in the wrong risk category. This is important, since this haplotype is found in more than 10 percent of whites. When DQ alpha-chain analysis is performed on all DQw2-positive persons, however, considerably more information is gained. With both pieces of information, only those rare persons with the HLA-DQw2/DQw2 and HLA-DR7 haplotype as determined by DQ alpha-chain typing would need further analysis, because the polymerase-chain-reaction test would have difficulty distinguishing a person with the HLA-DR3/DR7 (DQw2/DQw2) haplotype from one with the HLA-DR7/DR7 (or DQw2/DQw2) haplotype. The second major exception that diminishes the usefulness of aspartic acid typing as the sole test is that persons with HLA-DQw7 would be considered to have a protective allele and therefore not to be at risk for IDDM. Our data refute this notion, because 81 percent of the diabetic patients heterozygous for aspartic acid had an aspartic acid-positive DQw7 allele (Table 3). Thus, these two examples (persons with the DR7 and DQw7 alleles, respectively) show that a simple DQ beta-chain analysis for aspartic acid at position 57 is insufficient to assess genetic risk in IDDM.
From these studies, however, it is clear that accurate DQ genotyping can be accomplished by dot-blot analysis using allele-specific oligonucleotides and that this analysis provides information of value in assessments of disease susceptibility for IDDM. Although the region of the DQ beta chain surrounding codon 57 is an ideal site for use in the design of oligonucleotides that can distinguish most of the known DQ alleles, the presence or absence of an aspartic acid at position 57 does not by itself correlate strongly with the risk for IDDM. To be optimal, this system of typing must involve alpha-chain typing for HLA-DR, HLA-DQ, or both. Nonetheless, taken together, these methods provide a powerful and efficient tool for the accurate assessment of the association of Class II genotypes with certain autoimmune diseases.
Note added in proof: Since this paper was submitted, two other, similar studies have been published.23 , 24
Supported by grants (188117 and 1881226) from the Juvenile Diabetes Foundation, a grant (A1–23271) from the National Institutes of Health, and grants from the John Hartford Foundation and the Greenwall Foundation, which provided funds for the development of the Dallas Diabetes Registry. Dr. Capra holds the Edwin L. Cox Distinguished Chair in Immunology and Genetics at the University of Texas Southwestern Medical Center.
We are indebted to the staff of our Diabetes Clinic, especially Marilyn Alford, M.S.N., for assistance in collecting these blood samples; to Dr. Ted Ball for helpful discussions; and to Drs. Roger Unger and Daniel Foster for constant encouragement and help in organizing the Diabetes Center.
Source Information
From the Departments of Microbiology and Internal Medicine, the Center for Diabetes Research and the Graduate Program in Immunology, the University of Texas Southwestern Medical Center, Dallas (J.M.B., P.S., J.D.C.); Gene-Screen, Dallas (T.W., R.G.); and the Department of Microbiology and Immunology, School of Medicine, the University of Louisville, Ky. (M.H.). Address reprint requests to Dr. Capra at the Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235.
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