The genetic predisposition to fibrocalculous pancreatic diabetes

Abstract

Summary. Fibrocalculous pancreatic diabetes (previously known as tropical pancreatic diabetes) is a rare cause of diabetes confined to countries within the tropical belt. The aetiology of fibrocalculous pancreatic diabetes is thought to be environmental although the agent(s) is unknown. We have investigated a possible genetic basis of this disease by looking for restriction fragment length polymorphisms of genes implicated in the aetiology of diabetes rnellitus. Seventy-six Dravidian patients with fibrocalculous pancreatic diabetes were studied, and the restriction fragment length polymorphisms obtained compared to racially matched control subjects (n=94), patients with Type2 (non-insulin-dependent) diabetes (n=87) and Type 1 (insulin-dependent) diabetes (n = 58). No association of fibrocalculous pancreatic diabetes was found with restriction fragment length polymorphisms of the insulin receptor gene. Although no association of fibrocalculous pancreatic diabetes was found with polymorphism of the HLA DRc~/DQc~/DXct genes, an association was found with the Taq 1 restriction fragment length polymorphisms of the DQ[~ gene (DQ[~ T2/T6 present in 39% of patients with fibrocalculous pancreatic diabetes compared to 19% in control subjects; p = 0.01 ; corrected p value = 0.04) which is similar to that found in Type 1 but not Type 2 diabetes. An association of fibrocalculous pancreatic diabetes was also found with the hypervariable region in the 5-prime flanking region of the insulin gene; 40% of patients possessed the class 3 allele compared to 9.5% of control subjects p = 0.0001 ; corrected p value = 0.0008). In Type 2 diabetes, similar results were obtained with 33% subjects possessing the class 3 allele (t7 value compared to control subjects = 0.0005; corrected p value = 0.004). This study suggests that fibrocalculous pancreatic diabetes has a genetic component in its aetiology. Furthermore, its origin might be related to an individual with part of the genetic predisposition to diabetes (Type 1 or Type 2) who additionally has evidence of chronic calcific pancreatitis.

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

“…We were unable to support our previous observation in south Indians of an association between FCPD and the insulin gene locus. 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.…”

“…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.…”

“…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.…”

“…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 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.…”

The EIF2AK3 gene region and type I diabetes in subjects from South India

“…2 Furthermore, whereas an association between the insulin gene hypervariable region and T1DM has been found in most ethnic groups, this has not been found in South Indian subjects. 1,3 It is therefore conceivable that individuals with T1DM in South India might have input from a greater range of different susceptibility loci compared to other ethnic groups.…”