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Association between a restriction fragment length polymorphism at the islet/liver (Glut2) glucose transporter and familial type 2 (non-insulin-dependent) diabetes mellitus
No full textPatients with Type 2 (non-insulin-dependent) diabetes mellitus and a strong family history of the disease may represent a sub-group where genetic factors play a preeminent role in transmission of the disease. A defect in the liver/islet cell glucose transporter (GluT 2) could explain many of the pathophysiological features of the disease. In order to test the hypothesis that genetic variation at the GluT 2 locus contributes genetic susceptibility to Type 2 diabetes, 60 unrelated Caucasian diabetic patients with at least one affected sibling were genotyped for a Taq 1 restriction fragment length polymorphism marker. Hybridisation with a cDNA GluT 2 probe identified two alleles of sizes 13 kilobase (T1) and 19 kilobase (T2). The allele frequencies in the diabetic group with a family history were significantly different from those in a racially-matched control population of 122 subjects with no personal or family history of the disease (diabetic patients T1 = 0.96, T2 = 0.04, control subjects T1 = 0.89, T2 = 0.11, p less than 0.03). However, when the study was repeated with 54 diabetic patients with indeterminate family history, statistical significance was not reached although the allele frequencies showed a similar trend. The findings of this study support the hypothesis that a genetic variant of the liver/islet cell glucose transporter may contribute to familial susceptibility in Type 2 diabetes
Association between a restriction fragment length polymorphism at the islet/liver (Glut2) glucose transporter and familial type 2 (non-insulin-dependent) diabetes mellitus
No full textPatients with Type 2 (non-insulin-dependent) diabetes mellitus and a strong family history of the disease may represent a sub-group where genetic factors play a preeminent role in transmission of the disease. A defect in the liver/islet cell glucose transporter (GluT 2) could explain many of the pathophysiological features of the disease. In order to test the hypothesis that genetic variation at the GluT 2 locus contributes genetic susceptibility to Type 2 diabetes, 60 unrelated Caucasian diabetic patients with at least one affected sibling were genotyped for a Taq 1 restriction fragment length polymorphism marker. Hybridisation with a cDNA GluT 2 probe identified two alleles of sizes 13 kilobase (T1) and 19 kilobase (T2). The allele frequencies in the diabetic group with a family history were significantly different from those in a racially-matched control population of 122 subjects with no personal or family history of the disease (diabetic patients T1 = 0.96, T2 = 0.04, control subjects T1 = 0.89, T2 = 0.11, p less than 0.03). However, when the study was repeated with 54 diabetic patients with indeterminate family history, statistical significance was not reached although the allele frequencies showed a similar trend. The findings of this study support the hypothesis that a genetic variant of the liver/islet cell glucose transporter may contribute to familial susceptibility in Type 2 diabetes
Genetic variation around the collagen IV gene locus and proliferative retinopathy in type 2 diabetes mellitus
No full textThe development of proliferative retinopathy in type 2 diabetes mellitus may be under genetic control. A well-documented pathological change in the fundal capillaries of patients with diabetic retinopathy is basement membrane thickening, with an increased amount of collagen IV protein. Variation at the collagen 1a IV gene therefore may explain familial susceptibility to this complication. It has been previously reported that genetic variation at the collagen 1a locus, as shown by allelic association with a HindIII restriction site, predisposes to diabetic nephropathy where basement membrane thickening is also prevalent. In order to test the hypothesis that the collagen 1a IV gene locus is important in the development of diabetic retinopathy, a population association study was performed comparing allele frequencies of the HindIII RFLP in diabetic patients with retinopathy and controls. No statistically significant differences were found between allele frequencies or genotypes in the two groups. The future use of similar studies in diabetic retinopathy is discussed
Genetic variation around the collagen IV gene locus and proliferative retinopathy in type 2 diabetes mellitus
No full textThe development of proliferative retinopathy in type 2 diabetes mellitus may be under genetic control. A well-documented pathological change in the fundal capillaries of patients with diabetic retinopathy is basement membrane thickening, with an increased amount of collagen IV protein. Variation at the collagen 1a IV gene therefore may explain familial susceptibility to this complication. It has been previously reported that genetic variation at the collagen 1a locus, as shown by allelic association with a HindIII restriction site, predisposes to diabetic nephropathy where basement membrane thickening is also prevalent. In order to test the hypothesis that the collagen 1a IV gene locus is important in the development of diabetic retinopathy, a population association study was performed comparing allele frequencies of the HindIII RFLP in diabetic patients with retinopathy and controls. No statistically significant differences were found between allele frequencies or genotypes in the two groups. The future use of similar studies in diabetic retinopathy is discussed
Sib-pair analysis of the adenosine deaminase (ADA) locus in non-insulin-dependent diabetes mellitus (NIDDM)
No full textRecently, linkage between the ADA gene locus and MODY, a subtype of NIDDM, has been reported. The possibility that the region of chromosome 20q containing the ADA locus also may play a role in susceptibility to NIDDM needs to be investigated. Therefore, we examined the linkage between the ADA locus and NIDDM in affected siblings of 50 European white diabetic pedigrees--21 Italian and 29 British. Departure from independent segregation of the disease and an Alu VpA polymorphism within the 5' flanking region of the ADA locus was tested in the affected sib-pairs with the APM statistical method. After DNA amplification by the PCR and PAGE, five alleles were identified in the ALU VpA tract at the ADA locus in the two populations. Allele frequencies did not differ significantly between the two populations (chi 2 = 2.426, P > 0.05 [NS]). Analysis of the 50 diabetic sib sets, and independently of the Italian and British groups of affected sib pairs, revealed no segregation distortion between the marker locus and NIDDM. We conclude that mutations within or around the ADA locus are unlikely to play a major role in the etiology of NIDDM
Sib-pair analysis of the adenosine deaminase (ADA) locus in non-insulin-dependent diabetes mellitus (NIDDM)
No full textRecently, linkage between the ADA gene locus and MODY, a subtype of NIDDM, has been reported. The possibility that the region of chromosome 20q containing the ADA locus also may play a role in susceptibility to NIDDM needs to be investigated. Therefore, we examined the linkage between the ADA locus and NIDDM in affected siblings of 50 European white diabetic pedigrees--21 Italian and 29 British. Departure from independent segregation of the disease and an Alu VpA polymorphism within the 5' flanking region of the ADA locus was tested in the affected sib-pairs with the APM statistical method. After DNA amplification by the PCR and PAGE, five alleles were identified in the ALU VpA tract at the ADA locus in the two populations. Allele frequencies did not differ significantly between the two populations (chi 2 = 2.426, P > 0.05 [NS]). Analysis of the 50 diabetic sib sets, and independently of the Italian and British groups of affected sib pairs, revealed no segregation distortion between the marker locus and NIDDM. We conclude that mutations within or around the ADA locus are unlikely to play a major role in the etiology of NIDDM
Analysis of the GLUT1 (glucose transporter) gene locus in sib-pairs affected by non-insulin-dependent diabetes mellitus
No full textDespite the strong evidence for a major role played by genetic factors in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), the genes involved are still unknown. Association studies of candidate genes for the inheritance of NIDDM have so far yielded inconclusive results. Some evidence exists for an association between NIDDM and the glucose transporter gene GLUT1, involved in basal glucose transport, although this has not been confirmed. In the present study we have tested the hypothesis of linkage between NIDDM and the GLUT1 gene, using affected sib-pairs. With this method the concordance observed for a given gene marker is compared with that expected under the assumption of no linkage between that marker and the disease. Fifty-four pedigrees (22 Italians and 32 British), for a total of 82 sib-pairs were studied by the affected sib-pair method proposed by Weeks and Lange, using two restriction frag ment length polymorphisms (RFLPs) at the GLUT1 locus, the MspI RFLP, at an estimated 0.171 recombination frequency from the GLUT1 gene, and the XbaI RFLP, located within the GLUT1 gene and previously shown to be associated with the disease. Results showed that the MspI marker and NIDDM segregate independently; for the XbaI RFLP, linkage could be shown only if the results were weighted by the allele frequency [f(p) = 1/p], and only in the Italian and the combined (Italian and British) sib-pair groups. Multilocus analysis with both markers was also negative. We conclude that the GLUT1 gene is very unlikely to play a major role in the aetiology of NIDDM, although an accessory role cannot be excluded, and studies of the gene sequence should help to clarify this question
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