HLA haplotypes associated with type 1 diabetes mellitus in north indian children

doi:10.1016/j.humimm.2003.10.013

Human Immunology

Volume 65, Issue 1, January 2004, Pages 47-53

https://doi.org/10.1016/j.humimm.2003.10.013 Get rights and content

Abstract

Human leukocyte antigen (HLA) encoded susceptibility to develop type 1 diabetes mellitus (T1DM) has been investigated in children from North India. The results revealed significantly increased prevalence of HLA-A26, -B8, and -B50 among patients and strong positive association of the disease with DRB1*0301 (82.1% vs 13.9%, χ² = 71.3, odds ratio [OR] = 28.3) and a negative association with DRB1*02 (χ² = 12.2, PF = 38.5). HLA-DQB1*0201 occurred in 96.4% of the patients, whereas the heterodimer DQA1*0501-DQB1*0201 was present in 82.1% of patients (60.7% in single dose and 21.4% in double dose) and revealed significant deviation from the healthy controls (χ² = 74.1, p_c = 6.0E-10). In addition to DRB1*03, positive association was also observed with DRB1*09 (14.3% vs 1.3%, χ² = 13.4) and DRB1*04 (39.3% vs 15.6%, χ² = 8.39). No HLA association was observed in relation to residual pancreatic β-cell function or associated thyroid autoimmunity. Family analysis revealed involvement of multiple DR3+ve haplotypes with T1DM in North Indian children with A26-B8-DRB1*03 (25% vs 3.5%, χ² = 16.9, p = 3.96E-05) and Ax-B50-DRB1*03 (25% vs 0.7%, χ² = 44.7, p = 9.88E-11) being the most frequent haplotypes encountered among patients. The classical Caucasian haplotype A1-B8-DRB1*03 was infrequent (7.2%) among the diabetic children. The study highlights the race specificity of HLA association and disease associated HLA haplotypes in T1DM among North Indian Children.

Introduction

Childhood diabetes is a significant health problem in India and needs an active input in terms of clinical research [1]. Genome wide mapping for predisposing genes has identified several regions of susceptibility, designated as insulin-dependent diabetes mellitus (IDDM1–IDDM18) [2] of which the human leukocyte antigen (HLA) complex in humans is the most significant genetic region that accounts for at least 50% of the overall genetic susceptibility to type 1 diabetes [3]. Many studies have implicated HLA-DQ molecules, especially DQ8 and DQ2, in governing susceptibility to type 1 diabetes mellitus (T1DM), whereas DQ6 is associated with protection 4, 5, 6. Although HLA-DQA1*0301-DQB1*0302 (DQ8) and DQA1*0501-DQB1*0201 (DQ2) have been reported as the major susceptibility alleles in all Caucasian populations studied, DQA1*0301-DQB1*0401(DQ4) and DQA1*0301-DQB1*0303 (DQ9) are the most significant HLA alleles encountered among the Japanese patients. Further, it has been demonstrated that DRB1 molecules play a significant role in the development of type 1 diabetes, either directly or by modifying the effect of DQ molecules 7, 8, 9, 10. The 12^th International Histocompatibility Workshop Study reported increased frequencies of DRB1*03 and DRB1*04 in all populations studied [11]. High resolution analysis revealed that although DRB1*0401,*0402,*0405, and heterozygote *0301/*0401 were the predominant alleles associated with susceptibility to type 1 diabetes in most of the Caucasian 11, 12 and Black populations [13], these are replaced by DRB1*0301/0901 in Chinese [14] and Koreans [15], whereas DRB1*0802/ *0405 predominates amongst the Japanese [12]. On the other hand, HLA-DRB1*15, *0403, *0404, and *0407 have been reported to confer protection against the development of type 1 diabetes in most ethnic groups [11]. Also, the important role played by particular amino acid residues of HLA class II alleles in determining susceptibility of individuals of different populations to type 1 diabetes has been re-evaluated [16].

Diabetes appears to be heterogeneous with respect to its sporadic or familial occurrence, the age at onset, its association with other autoimmune diseases, duration of clinical symptoms before insulin dependency, and the occurrence of clinical remissions. Together with the development of immunologic markers of islet cell autoimmunity, studies of HLA association can provide a genetic basis for understanding mechanisms leading to islet cell destruction, as well as for the identification of subjects at risk of developing type 1 diabetes.

The present study was undertaken to define HLA association with type 1 diabetes in the North Indian children. Inclusion of families (affected siblings and parents) helped us to define the disease associated HLA-A, -B, -DR, and -DQ haplotypes with the disease.

Section snippets

Patients

The study was conducted on a group of 38 unrelated children diagnosed to have type 1 diabetes mellitus according to the diagnostic criteria laid down by the International Expert Committee on Diabetes Mellitus [17]. All patients were < 16 years old and exhibited signs of ketosis/ ketoacidosis. Those with associated thyroid disease (already under treatment) and other autoimmune diseases with chronic renal failure or protein energy malnutrition were excluded from the study. Ethnically, all

Clinical and laboratory parameters

The clinical and laboratory parameters in the 38 type 1 diabetic patients are summarized in Table 1. The disease was observed in similar number of boys and girls, the mean age of disease onset being 6.4 years. Family history of autoimmune disease was recorded in 17.5% of patients. HBA₁C levels ranged between 10 and 15 in about half the patients (48%). None of the patients had normal C-peptide levels. Only one patient had raised TSH levels, which returned to normal after 6 months (treated with

Discussion

The results of the present study reveal that the HLA-DRB1 alleles associated with susceptibility to develop type 1 diabetes in the North Indian children are in the order DRB1*03>DRB1*09>DRB1*04. Other studies conducted in the diabetics from North India and in patients from Eastern India have also reported DRB1*03 as the most significant allele associated with susceptibility to type 1 diabetes 20, 21. Similar results have also been reported in other Asian populations 14, 15, 22 except the

Acknowledgements

The financial support for this study has been provided by the Indian Council of Medical Research, Goverment of India. Technical assistance provided by Mrs. Esther Philip and Mr. Shekhar Neolia is gratefully acknowledged.

References (27)

J.L. Davies et al.
A genome- wide search for human type 1 diabetes susceptibility genes
Nature
(1994)
R. Tisch et al.
Insulin dependent diabetes mellitus
Cell
(1996)
F. Cucca et al.
The distribution of DR4 haplotypes in Sardinia suggests a primary association of type 1 diabetes with DRB1 and DQB1 loci
Hum Immunol
(1995)
Y.S. Park et al.
Contributions of HLA-DR and -DQ molecules determine the susceptibility to insulin dependent diabetes mellitus in Koreans
Hum Immunol
(1998)
R. Rani et al.
Association of MHC class II alleles with insulin dependent diabetes mellitus (IDDM) in patients from North India
Hum Immunol
(1999)
H.C. Lee et al.
Role of HLA class II alleles in Korean patients with IDDM
Diabetes Res Clin Pract
(1996)
H. Izaabel et al.
Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics
Hum Immunol
(1996)
R. Jaini et al.
Heterogeneity of HLA-DRB1*04 and its associated haplotypes in the North Indian population
Hum Immunol
(2002)
T. Maruyama et al.
Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay
Diabetes Res Clin Pract
(1994)
A. Ramachandran et al.
High prevalence of diabetes and impaired glucose tolerance in Indianational urban diabetes survey
Diabetologia
(2001)

E. Thorsby et al.

The HLA associated predisposition to type 1 diabetes and other autoimmune diseases

J Pediatr Endocrinol Metab

(1996)

J.X. She

Susceptibility to type 1 diabetesHLA-DQ and DR revisited

Immunol Today

(1996)

Ronningen KS, Spurkland A, Tait BD, Drummond B, Lopez Larrea C, Baranda FS, Menendez-Diaz MJ, Caillat-Zucman S,...

Cited by (38)

HLA-DRB1* and DQB1* allele and haplotype diversity in eight tribal populations: Global affinities and genetic basis of diseases in South India
2021, Infection, Genetics and Evolution
The distribution of HLA class-II DRB1* and DQB1* alleles/ haplotypes were studied in 438 individuals of 8 Dravidian tribal groups inhabiting the Western Ghats, south India. The HLA typing was performed by PCR-SSP method. In order to identify the 5-locus Ancestral Extended Haplotypes (AEH), the alleles of HLA-A, -B and -C loci were typed for DNAs with predominant 2-locus haplotypes. The analyses have revealed allele HLA-DRB1*15 as the most predominant allele (Lowest / Highest range: Urali, 14.81 / Malasar, 48.94), followed by the alleles DRB1*10 (Katunayakan, 1.85 / Paliyan, 48.21), DRB1*14 (Paliyan 4.46 / Katunayakan, 40.74), DRB1*12 (Mannan, 1.64 / Katunayakan, 20.37) and DRB1*03 (Mannan, 1.64 / Urali, 29.63). The most frequent DQB1* alleles were DQB1*02 (Paliyan 3.57 / Urali, 23.15), DQB1*05 (Katunayakan, 27.77 / Paliyan 84.82) and DQB1*06 (Malasar, 8.51 / Kuruman, 33.51). The most predominant two-locus haplotypes observed were DRB1*15-DQB1*05, DRB1*10-DQB1*05, DRB1*15-DQB1*06 and DRB1*04-DQB1*05. The present study of HLA immunogenetics of south Indian tribes have revealed the presence of globally shared two and 5-locus haplotypes. Many of these haplotypes were implicated in a number of diseases in south India. We observed the presence of ancestral extended haplotypes (AEHs), hitherto not reported in Indian populations such as, A*68-B*35-C*02-DRB1*15:01-DQB1*05:01, A*24-B*57-C*06-DRB1*04:01-DQB1*05:01 and A*24-B*35-C*02-DRB1*15:01-DQB1*05:02. The dendrogram based phylogenetic analyses have revealed the Caucasian affinity of Urali, palaeo-Mediterranean and Indo-European affinity of Malasar tribes. The presence of globally shared susceptible and protective haplotypes reiterated the mosaic immunogenetic fabric of south Indian tribes.
Association of HLA-G 3' untranslated region variants with type 1 diabetes mellitus
2016, Human Immunology
Citation Excerpt :
MHC encompasses many genes actively involved in the coding of several molecules responsible for antigen presentation (HLA-A, -B, -C, -DR, -DQ and -DP) to T lymphocytes or molecules that modulate (HLA-E, F and G) the function of many leukocytes leukocytes [1,2]. HLA class II genes contribute up to 50% of the susceptibility to T1D, especially HLA-DRB1∗03 and ∗04 allele groups [3], and DQA1∗05:01-DQB1∗02:01 and DQA1∗03:01-DQB1∗03:02 allele combinations [4]. A study mapping the MHC region, performed on a large number of families with T1D patients, identified the region of the HLA-G gene as an independent locus for disease susceptibility [5].
Besides the well recognized association of HLA-DRB1 and DQB1 alleles with type 1 diabetes mellitus (T1D), linkage studies have identified a gene region close to the non-classical class I HLA-G gene as an independent susceptibility marker. HLA-G is constitutively expressed in the endocrine compartment of the human pancreas and may play a role in controlling autoimmune responses. We evaluated the genetic diversity of the 3′ untranslated region (3′UTR) of HLA-G, which have been associated with HLA-G mRNA post-transcriptional regulation, in 120 Brazilian T1D patients and in 120 healthy controls. We found the +3001 T allele was observed only in T1D patients. Notably, the +3001 T allele was in linkage disequilibrium with polymorphic sites associated with low production of HLA-G mRNA or soluble HLA-G levels. Moreover, T1D patients showed a low frequency of the HLA-G 3′UTR-17 (14bpINS/+3001T/+3003T/+3010C/+3027C/+3035T/+3142G/+3187A/+3196C). The +3010 CC genotype and the UTR-3 haplotype (14bpDEL/+3001C/+3003T/+3010C/+3027C/+3035C/+3142G/+3187A/+3196C), associated with low and moderate soluble HLA-G expression, respectively, were underrepresented in patients. The decreased expression of HLA-G at the pancreas level should be detrimental in individuals genetically prone to produce less HLA-G.
Family-based association study of HLA class II with type 1 diabetes in Moroccans
2015, Pathologie Biologie
The T1D is a multifactorial disease; with a strong genetic control. The human leukocyte antigen (HLA) system plays a crucial role in the autoimmune process leading to childhood diabetes. About 440,000 of the childhood population of the world (1.8 billion children under 14 years of age), have type 1 diabetes, and each year an additional 70,000 develop this disorder. The objective of this study was to investigate the distribution of HLA class II in Moroccan families of diabetic children to identify susceptibility alleles of the Moroccan population.
We included in this study, Moroccan families who have at least one child with T1D. The age of onset of diabetes was less than 15 years. HLA class II (DRB1* and DQB1*) was carried out by molecular biology techniques (PCR-SSP and PCR-SSO). The FBAT test (family-based association test) was used to highlight the association between T1D and the HLA-DRB1* and -DQB1* polymorphism.
The association of HLA class II (DRB1*, DQB1*) in type 1 diabetes was analyzed in fifty-one Moroccan families, including 90 diabetics. The results revealed that the most susceptible haplotypes are the DRB1*03:01–DQB1*02:01, DRB1*04:05–DQB1*03:02 (Z = 3.674, P = 0.000239; Z = 2.828, P = 0.004678, respectively). And the most protective haplotype is the DRB1*15–DQB1*06.
This is the first family-based association study searching for an association between HLA class II and T1D in a Moroccan population. Despite the different ethnic groups forming Morocco, Moroccan diabetics share the most susceptible and protective HLA haplotypes with other Caucasians populations, specifically the European and Mediterranean populations.
Le diabète de type 1 (DT1) est une maladie multifactorielle avec un important contrôle génétique. Le système HLA joue un rôle primordial dans le processus auto-immun conduisant au DT1. Dans le monde, environ 440 000 enfants (1,8 milliards d’enfants âgés de moins de 14 ans) ont le DT1 et chaque année 70 000 enfants supplémentaires développent ce désordre. L’objectif de ce travail était d’étudier la distribution des molécules HLA de classe II (DRB1*, DQB1*) chez des enfants diabétiques pour identifier les allèles de susceptibilité et de protection vis-à-vis du DT1 chez la population marocaine.
On a inclus dans cette étude des familles marocaines qui ont au moins un enfant atteint DT1. L’âge d’appariation du diabète était inférieur à 15 ans. Le typage HLA classe II (DRB1* et DQB1*) a été réalisé par des techniques de biologie moléculaire (PCR-SSP et PCR-SSO). Le test FBAT (Family-Based Association Test) a été utilisé pour mettre en évidence l’association entre DT1 et le polymorphisme HLA-DRB1* et HLA-DQB1*.
L’association HLA classe II (DRB1*, DQB1*) et le diabète type 1 a été étudiée chez 51 familles marocaines, incluant 90 diabétiques. L’analyse des donnés par FBAT montre que les deux haplotypes associés au DT1 dans la population marocaine sont le DRB1*03:01–DQB1*02:01, DRB1*04:05–DQB1*03:02 (Z = 3,674, P = 0, 000239; Z = 2,828, P = 0, 004678, respectivement). L’haplotype le plus protecteur est DRB1*15–DQB1*06.
Même si la population marocaine est formée de plusieurs groupes ethniques, elle partage les mêmes haplotypes HLA de susceptibilité et de protection vis-à-vis du DT1 avec d’autres populations caucasiennes et plus spécifiquement les populations européenne et méditerranéenne.
The Raikas - A unique combination of high prevalence of type 1 diabetes susceptibility genes and near zero incidence of the disease
2014, Human Immunology
Citation Excerpt :
The HLA Class II haplotypes of the major histocompatibility complex (MHC) region particularly DR3-DQ2 and DR4-DQ8 have been reported to associate with T1D in most Caucasian populations as >80% of the patients carry either of the two haplotypes or both [2,3]. In the Indian population, we have earlier shown a positive association of multiple HLA-DR3-DQ2 haplotypes with T1D [4,5] as well as celiac disease [6] with almost no contribution of the DR4-DQ8 haplotypes. In addition to class II alleles, several HLA class I alleles e.g., HLA-A*01, A*02, A*11, A*24, C*05, B*08, B*18, B*39 and B*50, have been reported to associate with T1D susceptibility either independent of HLA class II or due to their strong linkage disequilibrium with HLA-DRB1-DQA1-DQB1 haplotypes [7–10].
The Raikas, a camel rearing tribal group living in the Thar desert of Rajasthan has been reported with a very low incidence of diabetes. We analysed the frequency distribution of HLA alleles in this community and compared the same with the non-Raika group living in the same geographic location and also that of the healthy North Indian (NI) population. The data revealed an exceptionally high phenotype frequency of HLA-DRB1*03 in this community (53%) as compared to the non-Raika group (27.73%, p = 7.9E-05) and the NI population (14.6%, p = 7.65E06). Further analysis revealed the occurrence of four major DRB1*03 haplotypes in the Raikas: (i) A*26-B*08-DRB1*03 (AH8.2, 11.76%); (ii) A*24-B*08-DRB1*03 (AH8.3, 8.82%); (iii) A*02-B*08-DRB1*03 (3.78%); (iv) A*01-B*08-DRB1*03 (AH8.1v, 0.84%); all of which occurred with a several fold higher frequency in the Raikas than the other two groups. These haplotypes have been reported to be positively associated with T1D in the NI population. The apparent lack of T1D and/or other autoimmune diseases in the Raikas despite the higher occurrence of known disease associated HLA alleles/haplotypes is intriguing and highlights the quintessential role of the environmental factors, food habits and level of physical activity in the manifestation of T1D. Possible influence of other protection conferring genes located on, as yet undefined chromosomal locations cannot be ruled out.
Tumor necrosis factor-associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes
2012, Human Immunology
Citation Excerpt :
On the other hand, TNFa1 confers risk to T1D in the Belgian population [61]. Our previous studies have demonstrated that autoimmune diseases such as celiac disease [62] and T1D [27] in the North Indian population are strongly associated with multiple HLA-DR3–DQ2 haplotypes and that these haplotypes are distinctly different from the classical Caucasian A1–B8–DR3–DQ2 (AH8.1) haplotype at multiple loci [19,20,63]. The Indian autoimmune-favoring haplotypes include B8–DR3 (AH8.2, AH8.1v, and others), B50–DR3 (AH50.2), and B58–DR3 (AH58.1), each with a distinct central MHC complement component of C4A and C4B [20] and factor B [21].
Tumor necrosis factor-α (TNF-α) is an important proinflammatory cytokine involved in the pathogenesis of autoimmune type 1 diabetes (T1D). The TNF gene locus is located in the major histocompatibility complex (MHC) class III region and its genetic polymorphisms have been reported to be associated with T1D. However, it is not clear whether these associations are primary or caused by their linkage disequilibrium with other predisposing genes within the MHC. We have tested 2 TNF-α single nucleotide polymorphisms at positions −308G/A and −238G/A in the 5′ untranslated region and a (GT)n microsatellite TNFa in the North Indian healthy population and T1D patients with known HLA-A–B–DR–DQ haplotypes. The allele frequencies of TNFa5, −308A, and −238G were determined to be significantly increased among patients compared with controls. Although the observed positive association of −238G was caused by its presence on all 3 DR3⁺ groups, namely, B8–DR3–DQ2, B50–DR3–DQ2, and B58–DR3–DQ2 haplotypes associated with T1D in this population, the increase of the −308A allele was caused by its association with the latter 2 haplotypes. On the other hand, TNF −308G occurred on B8–DR3 haplotypes along with −238G and TNFa5 alleles, particularly in T1D patients with late disease onset (at >20 years of age). These results indicate that TNF associations with T1D are caused by their linkage disequilibrium with specific HLA-DR3–DQ2 haplotypes in the Indian population. Because polymorphisms in the promoter region regulate TNF expression levels (e.g., −308A), they retain crucial immunological significance in the development of T1D and its management.
Autoimmune-associated HLA-B8-DR3 haplotypes in Asian Indians are unique in C4 complement gene copy numbers and HSP-2 1267A/G
2008, Human Immunology
Citation Excerpt :
In the Asian Indian population, HLA-B8-DR3 is more commonly associated with A26 instead of A1 and represents a conserved haplotype referred to as AH8.2 [15]. The AH8.2 and other B8-DR3 haplotypes favor autoimmunity and related conditions in Asian Indians, including rheumatic heart disease [16], Graves' disease [17], type 1 diabetes [18,19], and celiac disease [20]. Our previous studies showed that the AH8.2 in Asian Indians share only B8 and DR3 with the Caucasian AH8.1, but differ at several gene loci across the major histocompatibility complex (MHC) [15].
The classical AH8.1 (HLA-A1-B8-DR3-DQ2) is the most common Caucasian haplotype, associated with several autoimmune diseases, immunologic hyperreactivity and rapid progression to the acquired immunodeficiency syndrome. However, in Asian Indians, there are multiple unique B8-DR3 haplotypes that are associated with autoimmunity and differ significantly from the common Caucasian AH8.1. The Indian HLA-A1-B8-DR3 is therefore referred to as an AH8.1 variant. The aims of this study were to compare C4A and C4B copy numbers and to identify alleles in HSP70-2 and LTA in these haplotypes. The Indian B8-DR3 haplotypes differ from the Caucasian AH8.1 at C4A and HSP70-2 loci. The Indian B8-DR3 haplotypes have 1 copy each at C4A and C4B, while the Caucasian AH8.1 has 1 copy at C4B but no C4A gene. Moreover, the Indian and Caucasian B8-DR3 haplotypes had HSP70-2 1267 ^*A, and *G alleles, respectively. By contrast, the LTA 252 *G allele occurred both in the Indian and Caucasian haplotypes. The Indian haplotypes also contained Bf*F and TNF-308*G that were different from the Caucasian equivalents Bf*S and TNF-308*A. These differences and previous studies support the hypothesis that B8-DR3-DQ2 haplotypes in Asian Indian population might have originated independently of Caucasian AH8.1 selectively through recombination and mutations. Because autoimmune disease associations are shared among these otherwise diverse haplotypes, these data strongly suggest that some shared component(s) of all these associated haplotypes may be playing a key role in such associations.

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HLA haplotypes associated with type 1 diabetes mellitus in north indian children

Abstract

Introduction

Section snippets

Patients

Clinical and laboratory parameters

Discussion

Acknowledgements

Nature

Cell

Hum Immunol

Hum Immunol

Hum Immunol

Diabetes Res Clin Pract

Hum Immunol

Hum Immunol

Diabetes Res Clin Pract

High prevalence of diabetes and impaired glucose tolerance in Indianational urban diabetes survey

Diabetologia

The HLA associated predisposition to type 1 diabetes and other autoimmune diseases

J Pediatr Endocrinol Metab

Susceptibility to type 1 diabetesHLA-DQ and DR revisited

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