Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11

Hitman, G. A.; Tarn, A. C.; Winter, R M; Drummond, V.; Williams, Larry G.; Jowett, N. I.; Bottazzo, G. F.; Galton, D. J.

doi:10.1007/bf00282236

Cited by 84 publications

(47 citation statements)

References 20 publications

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“…A consistent finding in both American and European Caucasoid subjects has been an association of the Class 1 allele of the insulin gene and Type 1 diabetes; the meaning of this association is unclear [17,47]. This association is not seen in this study or Japanese or American black subjects with Type I diabetes [32,33,48].…”

Section: Discussionsupporting

confidence: 55%

The genetic predisposition to fibrocalculous pancreatic diabetes

et al. 1989

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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.

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Section: Discussionsupporting

confidence: 55%

The genetic predisposition to fibrocalculous pancreatic diabetes

et al. 1989

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“…Young GADA-positive patients had younger age at onset (25 vs 28 years; p<0.0001), lower median BMI (22 vs 29 kg/m 2 ; p<0.0001), were less likely to have a family history of diabetes (23% vs 43%; p=2.8×10 −12 ), were more frequently treated with insulin (93% vs 59%; p= 1.1×10 −57 ) and had lower median fasting plasma C-peptide concentrations (0.23 vs 0.70 nmol/l; p<0.0001) than their GADA-negative counterparts (Table 1). HLA-DQB1, PTPN22 and INS VNTR As expected, young GADA-positive diabetic patients had higher frequency of risk HLA-DQB1 (60% vs 25%; p=9.4×10 −34 ), PTPN22 CT/TT (34% vs 26%; p=0.0023), INS VNTR (class I/I) AA (69% vs 53%; p=1.3×10 −8 ) and INS VNTR (class IIIA/IIIA) CC (75% vs 63%; p=4.3×10 −6 ) genotypes than young GADA-negative patients [36][37][38][39] ( Table 2). TCF7L2 The frequency of type 2 diabetes risk genotypes CT/TT of TCF7L2 (rs7903146) was significantly increased in young GADA-negative (53% vs 43%; p=0.0004) compared with GADA-positive diabetic patients.…”

Section: Resultsmentioning

confidence: 98%

Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15–34 years) but not in middle-aged (40–59 years) diabetic patients

et al. 2008

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Aims/hypothesis Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients.Methods In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide. Results Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p=9.4×10 −34 ; 45% vs 18%, p=1.4×10 −16 ), PTPN22 CT/TT (34% vs 26%, p=0.0023; 31% vs 23%, p=0.034), INS VNTR class I/I (69% vs 53%, p=1.3×10 −8 ; 69% vs 51%, p=8.5×10 −5 ) and INS VNTR class IIIA/IIIA (75% vs 63%, p= 4.3×10 −6 ; 73% vs 60%, p=0.008) was increased in young and middle-aged GAD antibodies (GADA)-Diabetologia

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“…This does not exclude VDR gene involvement in IDDM as true linkage is easily missed in complex diseases, and for particular candidate loci association-based approaches such as TDT may be more powerful than linkage. Hence both the insulin gene and CTLA4 gene have been implicated in IDDM primarily by association studies, despite weak evidence in favour of linkage to these genes [4,5,7]. Because linkage disequilibrium only occurs over very short genetic distances in out-bred populations, association studies are not suitable for studying random markers in a genome scan but are the method of choice for candidate gene study.…”

Section: Discussionmentioning

confidence: 99%