Racial Variation in Human Leukocyte Frequency in Insulin-Dependent Diabetic Nephropathy1

Barry I. Freedman,2 Mark A. Espeland, Eugene R. Heise, Joni Evans, and Vincent J. Canzanello, in association with the South-Eastern Organ Procurement Foundation

used to correct for multiple comparisons. A compar- B.l. Freedman. Department of Medicine. Section on ison of HLA frequencies in patients with insulin-de- Nephrology. Bowman Gray School of Medicine of pendent diabetes mellitus-induced renal failure Wake Forest University. Winston-Salem. NC demonstrated the presence of racial differences be- MA. Espeland, Department of Public Health Sciences. yond those normally present between the black and Bowman Gray School of Medicine of Wake Forest white populations. Blacks, compared with whites, University. Winston-Salem, NC had increased frequencies of HLA-B62 (odds ratio

ER. Heise, Department of Microbiology/Immunology, (OR) black:white, 6.13:1.97; P < 0.02) and HLA-DR9 Bowman Gray School of Medicine of Wake Forest (OR black:white, 4.82:1.57; P < 0.008) and de- University, Winston-Salem, NC creased frequencies of HLA-A1 (OR white:black, 1.56:0.8; P < 0.008) and HLA-DR3 (OR white:black, Joni Evans, Biostatistics Center, George Washington 4.9:2.82; P< 0.004). These results suggest that differ- University, Washington, DC, ences in HLA frequency may account, in part, for the V.J. Canzanello, Division of Hypertension and Internal observed racial variation in incidence of diabetic Medicine. Mayo Clinic, Rochester, MN nephropathy. In addition, several in positive The South-Eastern Organ Procurement Foundation, and negative association with diabetic nephropathy Richmond, VA were identified within each race. (J. Am. Soc. Nephrol. 1993; 3: 1467-1473) Key Words: HLA. type / diabetic nephropathy. race

Jiabetes meblitus (DM) is the leading cause of ABSTRACT ESRD in the United States, accounting for more than 30% of all patients curnentby beginning renal Black patients with insulin-dependent diabetes mel- replacement therapy (1 ). The incidence of DM-in- litus are at increased risk for the development of duced ESRD increased by 1 1 .8% per year between diabetic nephropathy compared with white patients. 1983 and 1987. faster than that of any other disease To determine if genetic differences associated with (2). Those of African-American ancestry (American the HLA system account for racial variation in insulin- blacks) are at increased risk for developing ESRD due dependent diabetes mellitus-induced nephropa- to both insulin-dependent DM (IDDM) and non-in- thy, serologically defined HIA phenotypes from renal sulin dependent DM (NIDDM) compared with whites. transplant recipients and donors in the South-Eastern Relative risks (bback:white) reported for the develop- Organ Procurement Foundation database from 1982 ment of IDDM-induced renal failure (DMRF) have to 1986 were analyzed. Renal transplant recipients ranged from 1 .62 to 2.96 (3.4). Genetic predisposition. environmental factors, or a (N = 1,531) with insulin-dependent diabetes melli- tus-induced renal failure as the cause of ESRD (pa- combination of both could account for the race-dc- pendent differences in the prevalence of DM and its tients) were compared with 4,506 race-matched, complications. There is an increased risk for the nondiabetic cadaveric kidney donors (controls). development of nephnopathy in diabetic individuals Log-linear models were used to assess the relation- with a family history of nephropathy (5) or with ship between insulin-dependent diabetes mellitus- hypertensive first-degree relatives (6). HLA hapbotype induced renal failure and prevalence of each HLA and genotype associations exist In IDDM, whereas phenotype. Bonferroni adjustments of P values were other HLA alleles exist in negative association and appear to protect from IDDM (7- 1 2). The complex I Received March 17, 1992. Accepted October 19, 1992. HLA associations in IDDM have focused attention on 2 correspondence to Dr. B.I. Freedman, Department of Internal Medicine/Ne- phrology, Bowman Gray School of Medicine of Wake Forest University. Medical HLA-DQ heterodimers in order to account for the cis cenfer Boulevard, Winston-Salem, NC 27 157-1053. and trans influences in IDDM susceptibility (13). 1046-6673/0308-1467$03.00/0 Associations between the HLA system and NIDDM Journal of the American Society of Nephrology Copyright © 1993 by the American Society of Nephrology have not been described (14).

Journal of the American Society of Nephrology 1467 Race, HLA. and Diabetic Nephropathy . .

In this study. we analyzed data from a barge renal was multiplied by the number of comparisons pen- transplant registry: ( 1 ) to determine whether differ- formed (80 for HLA-A and HLA-B analysis and 1 0 for ences existed in the frequency of HLA phenotypes in HLA-DR analysis) to control for the inflation of type patients with DMRF. beyond those normally present I error introduced by the performance of multiple between black and white subjects; (2) to determine comparisons. For those comparisons. unless other- if particular HLA phenotypes, within each racial wise specified, the term “significant” is used to de- group. existed in positive or negative association with scribe a difference associated with a corrected P DMRF; and (3) to estimate the proportion of cases value (P01-) of less than 0.05. Tests for the three-way attributable to. or prevented by. the HLA markers of interactions between DMRF, race, and HLA pheno- hapbotypes associated with DMRF. type, which are associated with hypothesis (2), were performed only for those phenotypes identified as having significant associations with disease. P val- PATIENTS AND METHODS ues for these tests In this limited pool of phenotypes were not corrected via the method of Bonferroni. Patient Information Etiobogic fractions (EF) and preventive fractions The database consisted of all cases of ESRD due to (PF) of the black and white DMRF patient populations diabetic nephropathy. IDDM, or type I diabetes mel- were estimated by the methods of Miettinen (1 8) and bitus (diagnoses are listed on the Medicare ESRD Green (1 9). The EF indicates the proportion of disease form) in the South-Eastern Organ Procurement cases attributable to a marker or other risk factors Foundation (SEOPF) registry who received a cadav- associated with this marker (i.e., an HLA) in positive eric or living related renal transplant between 1982 association (OR > 1 ). The PF indicates the pnoportion and 1 986. Patients who received their renal trans- of reduction in cases among the population. due to plants after the age of 45 yr were excluded to remove the presence on action of the marker or factors asso- subjects with NIDDM-induced renal disease from the ciated with the markers, in negative association (OR analyses. Race-matched, normotensive, nondiabetic <1) with the disease. The formulae used were: cadaveric kidney donors who were entered into the SEOPF registry over the same interval were used as EF = (OR - 1) x h controls. Living rebated donors were excluded from OR the control group to avoid the bias that would have (OR - 1) x been introduced by the inclusion of familial HLA PF = data. OR x (1 - h) + h

whene h is the antigen frequency in cases and OR is Statistical Analyses the odds ratio or relative risk. The statistical methods have been reported previ- ousby ( 1 5). Briefly. odds ratios (OR) were computed RESULTS from the frequency of each HLA-A, HLA-B, and HLA- DR phenotype among the patients versus the con- A total of 1 .53 1 cases of DMRF (transplanted be- trobs, separately for blacks and whites (16). Log-bin- fore age 45) and 4,506 controls were listed in the ear models (1 7) were fitted to data fnom black and SEOPF database, as shown in Table 1 . Black patients white subjects to assess whether a relationship cx- comprised 1 6. 1 % (246 of 1 .53 1) of the total DMRF isted between DMRF and altered frequencies of HLA population contrasted with 83.9% (1 ,285 of 1 .531) phenotypes. Statistical inference was performed by fon white patients. Among the control population, examining partial likelihood ratio statistics generated 1 0.4% (467 of 4,506) were black and 89.6% (4,039 by contrasting the fit of different log-linear models. of 4,506) were white. which allowed interactions between the presence of HLA phenotypes and race to be explicitly parameter- Ized and tested. Analysis of the data involved examination of con- TABLE 1. Racial composition and DMRF status tingency tables (2 x 2 or 2 x 2 x 2) associated with DMRF Cases Controls the following hypotheses: ( 1 ) no differences exist Race between the HLA phenotype frequencies in DMRF N(%) N(%) patients and race-matched controls; and (2) variation In DMRF frequency between the races is not related Black 246(16.1) 467 (10.4) to racial differences in HLA frequency. Bonferroni White 1,285 (83.9) 4,039 (89.6) corrections were applied in assessing relationships Total 1,531 4,506 between phenotypes and disease. The raw P value

1468 Volume 3’ Number 8’ 1993 Freedman et al

TABLE 2. HLA frequencies in white DMPF patients

P Value Odds Ratio HLA Cases (N = I .285) Controls (N = 4,039) EF PF Present (%) Present (%) (Corrected) (95% Confidence Interval)

Antigen Associated With Susceptibility Al 523 (40.7) 1236 (30.6) <0.008 1.56 (1.37-1.77) 0.15 A2 709(55.2) 1967(48.7) <0.008 1.30(1.14-1.47) 0.13 A24 270(21.0) 521(12.9) <0.008 1.80(1.53-2.11) 0.10 B8 583 (45.4) 901 (22.3) <0.008 2.89 (2.53-3.30) 0.14 B18 164(12.8) 323(8.0) <0.008 1.68(1.38-2.05) 0.05 B62 220(17.1) 384(9.5) <0.008 1.97(1.64-2.35) 0.08 DR3 702 (57.3) 868 (21.5) <0.001 4.90 (4.28-5.62) 0.46 DR4 820(66.9) 1115(27.6) <0.001 5.31(4.63-6.09) 0.52 Antigen Associated With Protection All 83(6.5) 469(11.6) <0.008 0.53(0.41-0.67) 0.06 B7 190(14.8) 977(24.2) <0.008 0.54(0.46-0.64) 0.11 Bl4 52 (4.1) 283 (7.0) <0.008 0.56 (0.41-0.76) 0.03 B35 I 16 (9.0) 574 (14.2) <0.008 0.60 (0.49-0.74) 0.25 B5l 64 (5.0) 335 (8.3) <0.05 0.58 (0.44-0.76) 0.03 DR2 67 (5.5) 1018 (25.2) <0.001 0.17 (0.13-0.22) 0.21 DR5 42 (3.4) 574 (14.2) <0.001 0.21 (0.16-0.30) 0.11 DR6 126(10.3) 582(14.4) <0.001 0.68(0.56-0.84) 0.05 DR7 118 (9.6) 864 (21.4) <0.001 0.39 (0.32-0.48) 0.13

TABLE 3. HLA frequencies in black DMRF patients

P Value Odds Ratio HLA Cases (N = 246) Controls (N = 467) EF PF Present (%) Present (%) (Corrected) (95% Confidence Interval)

Antigen Associated With Susceptibility B62 16 (6.5) 5 (1.1) <0.008 6.13 (2.33-17.76) 0.05 DR3 96 (43.4) 100 (21.4) <0.001 2.82 (1.99-3.98) 0.28 DR4 73 (33.0) 50 (10.7) <0.001 4.11 (2.74-6.17) 0.25 DR9 23 (10.4) 11 (2.4) <0.001 4.82 (2.30-10.07) 0.08 Antigen Associated With Protection DR2 35 (15.8) 127 (27.2) <0.008 0.50 (0.33-0.76) 0.39

HLA Phenotype Frequencies in White Patients markers of the largest proportion of cases within the and Controls white population (Indicated by higher EF values as compared with HLA-A and HLA-B). In white DMRF patients compared with white con- trols, the frequencies of HLA-A1 1 . HLA-B7. HLA- HLA Phenotype Frequencies In Black Cases B14, HLA-B35, HLA-B51, HLA-DR2, HLA-DR5, HLA- and Controls DRw6. and HLA-DR7 were significantly decreased, A significant decrease in the frequency of HLA- whereas the frequencies of HLA-A1 . HLA-A2. HLA- DR2 and Increases In HLA-B62, HLA-DR3, HLA- A24, HLA-B8, HLA-B18, HLA-B62, HLA-DR3, and DR4, and HLA-DR9 were observed In black patients HLA-DR4 were increased (Table 2). In the case of with DMRF compared with black controls (Table 3). HLA-A 1 1 . for example. the prevalence In white pa- The HLA-DR3- and HLA-DR4-associated OR and EF tients in the DMRF group was 6.5% (83 of 1,285) values were lower within the black compared with contrasted with an 1 1 .6% prevalence (469 of 4.039) the white population. in white controls. The OR for the presence of DMRF In white individuals with HLA-A1 1 compared with whites without HLA-A1 1 was 0.53 wIth a 95% con- HLA Variation Between Black and White Patients with DMRF fidence interval of 0.41 to 0.67 < 0.008). As expected. HLA-DR3 and HLA-DR4 were most DMRF in black, compared with white patients. is strongly associated with susceptibility and also were associated with a significantly increased frequency

Journal of the American Society of Nephrology 1469 Race, HLA, and Diabetic Nephropathy

TABLE 4. Interracial#{176} HLA frequency differences in DMRF

HLA Population Al B62 DR2 DR3 DR5 DR7 DR9

Black Cases Present N(%) 26 (10.6) 16 (6.5) 35 (15.8) 96 (43.4) 31 (14.0) 47 (21.3) 23 (10.4) Absent N(%) 220 (89.4) 230 (93.5) 186 (84.2) 125 (56.6) 190 (86.0) 174 (78.7) 198 (89.6) Controls PresentN(%) 60(12.9) 5(1.1) 127(27.2) 100(21.4) 101(21.6) 80(17.1) 11(2.4) AbsentN(%) 407(87.1) 462(98.9) 340(72.8) 367(78.6) 366(78.4) 387(82.9) 456(97.6) OddsRatio(95% 0.8 6.13 0.50 2.82 0.59 1.31 4.82 Confidence (0.49-1.31) (2.33-17.76) (0.33-0.76) (1.99-3.98) (0.38-0.92) (0.87-1.95) (2.30-10.07) Interval) White Cases Present N(%) 523 (40.7) 220 (17.1) 67 (5.5) 702 (57.3) 42 (3.4) 118 (9.6) 33 (2.7) AbsentN(%) 762(59.3) 1065(82.9) 1158(94.5) 523(42.7) 1183(96.6) 1107(90.4) 1192(97.3) Controls PresentN(%) 1236(30.6) 384(9.5) 1018(25.2) 868(21.5) 574(14.2) 864(21.4) 70(1.7) AbsentN(%) 2803(69.4) 3655(90.5) 3021(74.8) 3171(78.5) 3465(85.8) 3175(78.6) 3969(98.3) OddsRatio(95% 1.56 1.97 0.17 4.90 0.21 0.39 1.57 Confidence (1.37-1.77) (1.64-2.35) (0. 13-0.22) (4.28-5.62) (0. 16-0.30) (0.32-0.48) (1.03-2.39) Interval) PValue <0.008 <0.02 <0.0001 <0.004 <0.0Q03 <0.0001 <0.008

0 Differences in OP for black compared with white patients.

of HLA-B62 (OR 6.1:2.0), HLA-DR2 (OR 0.50:0.17), different patient populations (32). Population-based HLA-DR5 (OR 0.59:0.21), HLA-DR7 (OR 1.31:0.39), (33) and referred studies (34) reveal that between 8 and HLA-DR9 (OR 4.8: 1 .6) and a significantly de- and 35% of patients with IDDM develop an associated creased frequency of HLA-A1 (OR 0.8: 1 .6) and HLA- nephropathy, for which a familial predisposition DR3 (OR 2.8:4.9) beyond those normally observed clearly exists. It is reported that the HLA-DR/DQ between the races (Table 4). Although HLA-DR2 and serotype associations with IDDM in American blacks HLA-DR5 frequencies are increased in blacks rela- are the same as those in white patients (22,23). This tive to whites, they are decreased in frequency for study may help to explain the different natural his- patients compared with controls within each race. tories of DM (particularly the development of neph- This indicates that the protective effect afforded by ropathy) between the races. Additionally, HLA anal- the presence of HLA-DR2 and HLA-DR5 from DMRF yses within white and black populations may provide is less marked in the black population. insight into which diabetic patients are at risk for this dreaded complication. We were able to confirm the initial report of an DISCUSSION increase in HLA-DR9 frequency in IDDM within the Associations between the HLA system and IDDM, black population (26). The strength of the HLA-DR9 per Se. have been previously documented within di- association in black DMRF patients (OR 4.8) was verse ethnic groups (20-31). This study is the first much greater than that in the white DMRF cohort analysis to describe altered HLA frequencies between (OR 1 .5; P > 0.2). The OR of 4.8 in the black popu- American black and white subjects with diabetic lation was higher than that for either HLA-DR4 or nephropathy. This study involves the largest num- HLA-DR3. Although HLA-DR9 is an uncommon an- bers of IDDM patients with renal failure and race- tigen in the black control group (present in only matched controls of any reported to date. The large 2.4%), more than 10% of blacks affected with DMRF sample size allowed us to detect additional HLA-A possess HLA-DR9. These results can be partially cx- and HLA-B associations that define extended suscep- plained at the DNA bevel because the same HLA-DQ tibibity and protective hapbotypes. heterodimers are involved in both HLA-DR4 and The renal abnormalities occurring before the de- HLA-DR9 haplotypes. This observation supports the vebopment of overt diabetic nephropathy (hyperfiltra- view that gene complementation contributes to tion and microalbuminuria) appear to be uniform in DMRF risk.

1470 Volume 3 ‘ Number 8 ‘ 1993 Freedman et al

HLA-Bw62 was the only HLA class I antigen to be of this model is found in the mouse model of IDDM. associated with DMRF in both races. The OR of 6.13 where an allele near the Thy-l locus (located on the in the black DMRF patients was larger than that for long arm of chromosome 1 1 in humans) is responsi- any antigen. in either race, in our analysis. HLA- ble for the development of insubitis (39). A second Bw62 is one of several antigenic variants of HLA- hypothesis involves genetic susceptibility to certain B15 (others are HLA-Bw63, HLA-Bw75, HLA-Bw76, Infections (i.e.. ), providing a link between the and HLA-Bw77). HLA-B15 has previously been as- environment and genetic predisposition to disease sociated with the development of IDDM in both black (40). Reduced expression of majon histocompatibility and white subjects (22,35). Our analysis demon- complex class I proteins in human IDDM and diabe- strates that the association between HLA-B 1 5 and tes-prone. nonobese diabetic mice has been reported IDDM involves hapbotypes with the HLA-Bw62 allele. (4 1 ). Accordingly. a defective intracellular trans- HLA-Bw62 occurs in gametic association with HLA- porter gene might be involved in the pathogenesis of DR4 and HLA-DR9 in the U.S. black population, both IDDM. The primary importance of class II HLA genes of which are associated with increased IDDM risk. In and particular DQA-DQB heterodimens ( 1 3.42) is con- the North American white population. HLA-Bw62 sistent with the view that peptide presentation plays occurs in gametic association with HLA-DR7 but not a role in the etiology of the autoimmune process. with HLA-DR4 or HLA-DR3. Because HLA-DR7 in Many analyses between disease states and their white subjects was associated with DMRF protection, HLA associations have suffered from basic method- HLA-Bw62 may be secondary to HLA-DR4/DQw3 in obogic flaws. Whenever analysis of a barge antigenic white DMRF patients. system. such as the HLA system, is undertaken, one Mijovic et at. (31) and Dunston et at. (36) have must be certain that correction for multiple compar- reported linkage disequilibrium between HLA-DR3 isons is performed to avoid spurious associations and and HLA-DQw2 in black patients with IDDM and the that barge numbers of patients are included In the absence of disease in blacks with other HLA-DR3 analysis. In addition, it is impenative that the control and HLA-DQw hapbotypes. Because HLA-DR9 is as- subjects be individuals that are matched for racial sociated with HLA-DQw9 in whites and with HLA- background and geographic area of residence. One DQw2 and HLA-DQw3 in blacks (37), it is likely that cannot perform racial comparisons within the HLA the variable patterns of gametic association can cx- system without controlling for the normal racial van- plain the racial differences in susceptibility to DMRF. lation in abbelic frequencies. In this study. the HLA All of the HLA in positive or negative association frequencies in our control group wene representative with DMRF in the white population could represent of those of other U.S. studies (16). hapbotypes exhibiting linkage disequilibrium. HLA- It Is difficult to verify that IDDM is actually the

Al 1 , HLA-B7. HLA-B14, HLA-B35, HLA-B51 , HLA- cause of ESRD in patients from the SEOPF registry. DR2, HLA-DR5. HLA-DRw6, and HLA-DR7 were de- Previous studies have revealed that If the diagnosis creased in white patients with DMRF. suggesting a of diabetic nephropathy is based upon the presence protective effect of certain extended haplotypes. In of IDDM with diabetic retinopathy. neuropathy. pro- healthy white populations, these antigens exist in teinunia, duration of disease for longer than 5 yr. and the following linkage disequilibria: Al l,B35,DR2: the absence of associated risk factors fon other renal All,B51: Al1,B7,DR2; B7,DR2; B35,DR5: and diseases, one would be correct 88% of the time (43). B5 1 ,DR2. In contrast, increased frequencies of HLA- The findings. in both races, that DMRF is associated Al. HLA-A2, HLA-A24. HLA-B8. HLA-B18. HLA- with an increased frequency of HLA-DR3 and HLA- B62. HLA-DR3. and HLA-DR4 are all associated with DR4 and a decreased frequency of HLA-DR2 is con- DMRF in the white patient group. Likewise, these sistent with the literature on IDDM (7-12). These antigens exist in the following linkage disequilibnia: data suggest that the SEOPF cases have DMRF. It A 1 ,B8,DR3; A2,Bw62,DR4; B 1 8,DR3; B8,DR4; and also reveals that at beast one of the genetic compo- Bw62,DR9. nents associated with IDDM must also play a robe in Although nearly 80% of patients with IDDM pos- the development of DMRF. sess HLA-DR3 or HLA-DR4, the relationship between An argument could be made that these HLA asso- their presence and the processes beading to overt DM ciations are characteristic of IDDM per se and not ane not clear. Interestingly. HLA-DR3 and HLA-DR4 DMRF. The optimal control HLA frequencies to de- frequencies were markedly increased in black and termine the cause of DMRF would be from patients white patients with DMRF; however, no racial differ- with a long history of IDDM and without evidence of ences in HLA-DR4 frequency were observed. It has renal Involvement. We are not aware of a database been postulated that an allele at a locus distinct from that contains this information. However, the intent the HLA region Initiates insubitis. and that the HLA of this study was to determine why black patients (or neighboring loci) mediate immunologic destruc- with IDDM develop renal disease more often than do tion of pancreatic beta cells (38). Evidence in support white patients. The most Important findings from

Journal of the American Society of Nephrology 1471 Race. HLA. and Diabetic Nephropathy

our analyses are the differences in HLA frequencies abetics are susceptibility factors for the development that exist between black and white patients with of renal microvascubar or glomerular injury once DMRF. The lack of a nonrenab disease control group either disease process is initiated. does not diminish the importance of the effect of In summary. the different incidence rates of DMRF these HLA on the race-specific risks of developing between black and white populations may be asso- diabetic nephropathy. It is clear that IDDM is not a ciated, in part. with differences in the HLA gene homogeneous disorder. The variable clinical mani- complex located on human chromosome 6. Future festations ranging from a benign course with insulin studies should be directed at precise HLA-DR and replacement to severe vascular involvement with ac- HLA-DQ allele definition by DNA techniques, partic-

celerated atherosclerosis , retinopathy. and renal fail- ularly in HLA-DR9-positive black patients with ure make it important to study uniformly affected DMRF and HLA-DR3-positive black patients with populations. When one examines the previous re- DMRF or HRF. Efforts to determine the biologic sig- ports of HLA associations in IDDM. the marked racial nificance of the various HLA associations in DM and differences in HLA frequencies that we observed for glomerubosclerosis should continue as well. HLA-DR2, HLA-DR3, HLA-DR5. HLA-DR7, and HLA- DR9 are not uniformly present. There are three pos- ACKNOWLEDGMENTS sibbe explanations for this: ( 1 ) the fact that our da- tabase was much larger than that of any other pre- We are indebted to Dr. James Burdick and Mr. Jack Blanton of the vious report: (2) the fact that prior HLA frequencies South-Eastern Organ Procurement Foundation for supplying the were detected serobogicably before the newer HLA-DR data on HLA antigens and Dr. Thomas Peters for his review of the manuscript. We also thank Mrs. Kim Hairston for her secretarial specificities were detected (i.e.. HLA-DR9): and (3) assistance. the important fact that our population is a select group of diabetics who progressed to renal failure requiring replacement therapy. IDDM-induced auto- REFERENCES nomic neuropathy has recently been associated with 1 . U.S. Renal Data System. USRDS 1 99 1 Annual the HLA-DR3/4 hapbotype (44), supporting the con- Data Report. Bethesda, MD: The National Insti- tention that target organ-specific HLA associations tutes of Health, National Institute of Diabetes exist in IDDM. Additional genetic analyses comparing and Digestive and Kidney Diseases: 1991. 2. U.S. Renal Data System. USRDS 1989 Annual IDDM-induced target organ damage. such as neph- Data Report. Bethesda, MD: The National Insti- nopathy. with IDDM populations backing these com- tutes of Health, National Institute of Diabetes plications are clearly needed. and Digestive and Kidney Diseases; 1989. Finally. a potential source of bias in our analysis 3. Cowie CC, Port FK, Wolfe RA, Savage PJ. Moll might be introduced by underestimation of the pres- PP, Hawthorne VM: Disparities in incidence of diabetic end-stage renal disease according to ence of diabetes or renal disease in the transplant race and type of diabetes. N Engl J Med 1989: donor (control) population. This is unlikely to occur 321:1074-1079. in view of the detailed clinical evaluation and rigid 4. Stephens GW, Gillaspy JA, Clyne D, Mejia A, exclusion criteria required for organ donation. In ad- Pollak VE: Racial differences in the incidence of end-stage renal disease in types I and II diabetes dition, only cadaveric (unrelated) donors were evabu- mellitus. Am J Kidney Dis 1990:15:562-567. ated as controls to avoid any potential bias introduced 5. Seaquist ER, Goetz FC, Rich 5, Barbosa J: Fa- by using living related donors. milial clustering of diabetic kidney disease. N Are the findings of this study specific for diabetic Engl J Med 1989:320:1161-1165. 6. Krolewski AS, Canessa M, Warram JH, et at.: nephropathy. or could they be present in other forms Predisposition to hypertension and susceptibil- of renal disease such as gbomerubonephnitis or hyper- ity to renal disease in insulin-dependent diabetes tension? We have previously reported the racial van- mellitus. N Engl J Med 1988:318:140-145. iatlon in HLA frequencies in hypertensive renal fail- 7. Singal DP, Blajchman MA: Histocompatibility (HL-A) antigens, lymphocytotoxic and ure (HRF) ( 1 5). The HLA associated with HRF and tissue antibodies in patients with diabetes mel- DMRF appear to be distinct. HLA-DR3 was associated litus. Diabetes 1973;22:429-432. with HRF in the black population. a group known to 8. Ilonen J, Tiilikainen A, Akerbiom HK, Kaivu- be at increased risk for HRF. HRF is thought to be kangas T, Kouvalaimen K: HLA-DW2 as a an unusual manifestation of hypertension in the marker of resistance against juvenile diabetes meblitus. Tissue Antigens 1 978: 1 1:144-146. white population (excluding renovascular disease 9. Thomsen M, Platz P, Christy M, Nerup J, Ryder and malignant hypertension). Although the physiob- LP, Svejgaard A: HLA-D associated resistance ogy underlying the development of renal failure in and susceptibility to insulin-dependent diabetes IDDM and hypertension appears to be markedly dif- melbitus. Trans Proc 1979;l 1:1307-1308. 10. Farid NR, Sampson L, Noel P. Barnard JM, ferent, it is possible that particular DR3.DQw4 hap- Davis AJ, Hillman DA: HLA-D-related (DRW) lotypes in black hypertensive patients or DR3,DQw2 antigens in juvenile diabetes mellitus. Diabetes haplotypes in black and white insulin-dependent di- 1979:28:552-557.

1472 Volume 3’ Number 8’ 1993 Freedman et al

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23. Omar MAK, Hammond MG, Asmal AC: HLA-A, 5: “Thy- 1 “ linked diabetogenic gene but not B, C and DR antigens in young South African “MHC” linked gene causes Ithe primary destruc- blacks with type I (insulin-dependent) diabetes tion of B cells of the NOD mouse lAbstract]. melbitus. Diabetobogia 1 984;26:20-23. Diabetes 1987;36(suppb l):82A. 24. Ottenhoff THM, Mengistu M, Tadesse G, Dc 40. Rubinstein P, Walker ME, Fedun B, Witt ME, Vries RRP, Converse PJ: HLA-DR and DQ anti- Cooper LZ, Ginsberg-Fellner F: The HLA system gens in insulin-dependent diabetics in Ethiopia. in congenital rubella patients with and without Tissue Antigens 1987:30:193-197. diabetes. Diabetes 1 982;3 1 :1088-1091. 25. Hawkins BR, Lam KSL, Ma JTC, et at: Strong 4 1 . Bell JI, Todd JA: HLA class II sequences infer associations of HLA-DR3/DRw9 heterozygos- mechanisms for major histocompatibility com- ity with early-onset insulin-dependent diabe- plex-associated disease susceptibility. Mob Blob tes melbitus in Chinese. Diabetes 1987;36: Med 1989;6:43-53. 1297-1300. 42. Faustman D, Li X, Lin HY, et at.: Linkage of 26. Fletcher J, Mijovic C, Odugbesan 0, Jenkins D, faulty major histocompatibility complex class I Bradwell AR, Barnett AH: Trans-racial studies to autoimmune diabetes. Science 1991:254: implicate HLA-DQ as a component of genetic 1756-1761. susceptibility to type I (insulin-dependent) dia- 43. Amoah E, Glickman JL, Malchoff CD, Sturgill betes. Diabetobogia 1 988;3 1:864-870. BC, Kaiser DL, Bolton WK: Clinical identifica- 27. Apanicio JMR, Wakisaka A, Takada A, Mat- tion of nondiabetic renal disease in diabetic pa- suura N, Aizawa M: HLA-DQ system and insu- tients with type I and type II disease presenting bin-dependent diabetes meblitus in Japanese: with renal dysfunction. Am J Nephrob 1988;8: Does It contribute to the development of IDDM 204-211. as it does in Caucasians? Immunogenetics 1988; 44. Barzilay J, Warram JH, Rand LI, Pfeifer MA, 28:240-246. Krolewski AS: Risk for cardiovascular auto- 28. Vadhein CM, Zeidler A, Rotter JI, et at.: Differ- nomic neuropathy Is associated with the HLA- ent HLA haplotypes in Mexican Americans with DR3/4 phenotype In type I diabetes meblitus. IDDM. Diabetes Care 1989:12:497-500. Ann Intern Med 1992:116:544-549.

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