Association of HLA class II alleles with different subgroups of diabetes mellitus in Eastern India identify different associations with IDDM and malnutrition‐related diabetes

Abstract

Genetic studies of Malnutrition related diabetes are few. We have analyzed HLA class II gene polymorphism in different types of diabetes mellitus patients from Cuttack in Eastern India. Patients with insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and malnutrition-related diabetes mellitus (MRDM), which is subdivided into protein-deficient diabetes mellitus (PDDM) and fibrocalculous pancreatic diabetes (FCPD), were studied and their associations with autoantibody markers. IDDM and PDDM were associated with DR3 and DQ2 but not DR4 and DQ8. FCPD was positively associated with DQ9 (A*0201-B*0303). The association of DQ9 with FCPD suggests differences in the genetic background for susceptibility between IDDM and MRDM in the Cuttack population. There is no association seen between HLA-DR-DQ and NIDDM patients from Eastern India. Clinical classification of diabetes into IDDM, NIDDM and MRDM does not identify the underlying pathological mechanisms. Presence of autoantibodies to IDDM autoantigens in clinical MRDM and NIDDM identifies the slow-onset form of IDDM. Due to the absence of autoantibody assays for diagnosis of IDDM in India, slow onset IDDM is not diagnosed and the patients are classified as NIDDM or MRDM. Our study demonstrates that the presence of GAD65 antibody and DR3-DQ2 positivity in MRDM and NIDDM patients in Eastern India would suggest the presence of slow-onset IDDM. Our data would indicate alternatively that MRDM can coexist with IDDM in these patients and malnutrition could be one of the reasons for the slower onset in IDDM-prone individuals.

Genetic susceptibility to fibrocalculous pancreatic diabetes in Bangladeshi subjects: a family study

“…6 Other case-control studies have also reported associations between the HLA and FCPD but not with the same HLA-DQB1 allele. 8,9 For example in eastern Indian subjects from Cuttack an association was found between FCPD and HLA-DQ9 (A* 0201-B*0303); this was different to that found in T1DM and protein deficiency diabetes mellitus. 8 Despite these reported HLA associations there is little evidence to support FCPD being an autoimmune disease.…”

“…8,9 For example in eastern Indian subjects from Cuttack an association was found between FCPD and HLA-DQ9 (A* 0201-B*0303); this was different to that found in T1DM and protein deficiency diabetes mellitus. 8 Despite these reported HLA associations there is little evidence to support FCPD being an autoimmune disease. For example, there is no increase in antibodies to islet cells or glutamic acid decarboxylase compared to a control population, 10 and the clinical picture is very different from T1DM.…”

“…2,4,5 The aetiology of FCPD is likely to be multifactorial, involving both environmental and genetic factors . 2,[6][7][8] Our previous work in south Indians with FCPD, using case-control studies, reported an HLA-DQB1 restriction fragment length polymorphisms (RFLP) association with FCPD pain, 6 similar to that found in type 1 diabetes (T1DM). That study also found an association with the hypervariable region in the 5Ј flanking region of the insulin gene (INS), with 40% of FCPD patients possessing the class 3 allele compared with 9.5% of control subjects; similar to that found in type 2 diabetes (T2DM) in the same ethnic group.…”

“…6 The HLA-DQB1 association found in this study is different to that found in eastern and south Indian populations. 6,8,9 The most marked difference is the non-transmission of HLA-DQ2, indicating that this allele protects from FCPD, in contrast to T1DM in which it is positively associated in many ethnic groups, including subjects from the Indian sub-continent. 8,11 Furthermore three FCPD patients in this study were positive for the HLA-DQB1*0602 allele; this underlines the difference between genetic susceptibility to FCPD and T1DM, as the HLA-DQB1*0602 allele is extremely rare in cases of T1DM.…”

“…6,8,9 The most marked difference is the non-transmission of HLA-DQ2, indicating that this allele protects from FCPD, in contrast to T1DM in which it is positively associated in many ethnic groups, including subjects from the Indian sub-continent. 8,11 Furthermore three FCPD patients in this study were positive for the HLA-DQB1*0602 allele; this underlines the difference between genetic susceptibility to FCPD and T1DM, as the HLA-DQB1*0602 allele is extremely rare in cases of T1DM. A combination of HLA-DQB1 and TNF microsatellite typing also revealed that the A1, B8, DR3, DQB1*0201 extended haplotype (TNFa2, c1, d1), which is commonly associated with T1DM susceptibility in Caucasians 12 was rare in this population, and indeed was not seen in this collection of Bangladeshi FCPD families.…”