| 1. |
|
|
| 2. |
- Lindholm, Eero, et al.
(författare)
-
Association between LTA, TNF and AGER polymorphisms and late diabetic complications.
- 2008
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:6
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several candidate genes on the short arm of chromosome 6 including the HLA locus, TNF, LTA and AGER could be associated with late diabetic complications. The aim of our study was therefore to explore whether polymorphisms (TNF -308 G-->A, LTA T60N C-->A and AGER -374 T-->A) in these genes alone or together (as haplotypes) increased the risk for diabetic complications. METHODOLOGY/PRINCIPAL FINDINGS: The studied polymorphisms were genotyped in 742 type 1 and 2957 type 2 diabetic patients as well as in 206 non-diabetic control subjects. The Haploview program was used to analyze putative linkage disequilibrium between studied polymorphisms. The TNF, LTA and AGER polymorphisms were associated with the HLA-DQB1 risk genotypes. The AGER -374 A allele was more common in type 1 diabetic patients with than without diabetic nephropathy (31.2 vs. 28.4%, p = 0.007). In a logistic regression analysis, the LTA but not the AGER polymorphism was associated with diabetic nephropathy (OR 2.55[1.11-5.86], p = 0.03). The AGER -374 A allele was associated with increased risk of sight threatening retinopathy in type 2 diabetic patients (1.65[1.11-2.45], p = 0.01) and also with increased risk for macrovascular disease in type 1 diabetic patients (OR 2.05[1.19-3.54], p = 0.01), but with decreased risk for macrovascular disease in type 2 diabetic patients (OR 0.66[0.49-0.90], p = 0.009). The TNF A allele was associated with increased risk for macrovascular complications in type 2 (OR 1.53 [1.04-2.25], p = 0.03, but not in type 1 diabetic patients. CONCLUSIONS/SIGNIFICANCE: The association between diabetic complications and LTA, TNF and AGER polymorphisms is complex, with partly different alleles conferring susceptibility in type 1 and type 2 diabetic patients. We can not exclude the possibility that the genes are part of a large haplotype block that also includes HLA-DQB1 risk genotypes.
|
|
| 3. |
- Lindholm, Eero, et al.
(författare)
-
Classifying diabetes according to the new WHO clinical stages.
- 2001
-
Ingår i: European Journal of Epidemiology. - 1573-7284. ; 17:11, s. 983-989
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/Hypothesis: To test the usefulness of the new WHO criteria for clinical staging of diabetes in the characterization of 1977 diabetic patients. Methods: The following clinical stages were used: patients on diet and/or oral antidiabetic agents 2 years after diagnosis were considered as non-insulin requiring (NIR; n = 711) and patients who required insulin therapy after 1 year as insulin requiring for control (IRC; n = 543). Patients who because of deteriorating hyperglycemia within 1 year required insulin therapy were considered as insulin requiring for survival (IRS; n = 743). Results: The NIR patients had the highest age at onset (52 ± 12 years; mean ± SD), BMI (29.3 ± 5.2 kg/m2) and C-peptide concentrations (median 0.98 nmol/l; interquartile range 0.72–1.31 nmol/l) but the lowest frequency of GAD antibodies (5.5%) compared to the IRC and IRS groups. The IRC group had a high age at onset (49 ± 13 years), BMI (28.0 ± 4.8 kg/m2), frequency of GAD antibodies (16.8%), intermediate C-peptide concentrations (0.56 nmol/l, interquartile range 0.28–0.94), and the highest prevalence of nephropathy (31.5%) and neuropathy (68.1%). The IRS group had the lowest age at onset (23 ± 15 years), BMI (24.2 ± 3.4 kg/m2), C-peptide concentrations (0.05 nmol/l, interquartile range below detection limit 0.01) and highest frequency of GAD antibodies (44.5%). Retinopathy was more common in IRS than in IRC patients (62.1 vs. 43.9%; p < 0.001). Conclusions: The new WHO criteria seem to discriminate three distinct subgroups and thus provide a useful tool for clinical staging. The IRC patients seem to have a more severe disease than the IRS patients, which has not been clearly acknowledged in the etiological classification. However, because of the cross-sectional nature of these data, they need to be confirmed in a prospective study with defined cut-off limits for when insulin should be initiated.
|
|
| 4. |
|
|
| 5. |
- Lindholm, Eero, et al.
(författare)
-
Polymorphism in the MHC2TA gene is associated with features of the metabolic syndrome and cardiovascular mortality.
- 2006
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 1:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently, a -168A-->G polymorphism in the MHC class II transactivator gene (MHC2TA) was shown to be associated with increased susceptibility to myocardial infarction (MI). AIM: To confirm the association between the MHC2TA -168A-->G polymorphism and MI and to study its putative role for microalbuminuria, the metabolic syndrome (MetS) and cardiovascular mortality. MATERIALS AND METHODS: Using an allelic discrimination method we genotyped 11,064 individuals from three study populations: 1) 4,432 individuals from the Botnia type 2 diabetes (T2D) study, 2) 1,222 patients with MI and 2,345 control subjects participating in the Malmo Diet and Cancer study and comprising an MI case-control sample, and 3) 3,065 T2D patients from the Local Swedish Diabetes registry. RESULTS: No association between the -168A-->G polymorphism in MHC2TA and MI was observed. However, in the Botnia cohort the AG/GG genotypes were associated with cardiovascular mortality after MI (1.78 [1.09-2.92], p = 0.02). In addition, the AG/GG genotypes were more common in subjects with MetS (40.1% vs. 36.9%, p = 0.03) and in non-diabetic subjects with microalbuminuria (45.4% vs. 36.5%, p = 0.003) compared to control subjects. CONCLUSIONS: A polymorphism in MHC2TA was associated with cardiovascular mortality and predictors of cardiovascular mortality, microalbuminuria and MetS.
|
|
| 6. |
- Lindholm, Eero, et al.
(författare)
-
Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy.
- 2004
-
Ingår i: Journal of Diabetes and its Complications. - 1873-460X. ; 18:2, s. 103-107
-
Tidskriftsartikel (refereegranskat)abstract
- Increased production of reactive oxygen species (ROS) has been suggested as a cause of diabetic complications. Uncoupling proteins (UCPs) have been ascribed a role in reducing the formation of ROS, and genetic variation in genes encoding for UCPs could thus be putative candidate genes for diabetic nephropathy. To test this hypothesis we searched for association between the A→G (−3862) variant in UCP1, the insertion/deletion (I/D) polymorphism in exon 8 in UCP2, and the C→T (−55) polymorphism in UCP3 and diabetic nephropathy in 218 diabetic patients with normal urinary albumin excretion rate (AER), 216 with micro- or macroalbuminuria, and in 106 control subjects without a family history of diabetes. We did not find any association between the different polymorphisms and diabetic nephropathy, nor did we observe any difference in AER among carriers of different UCP1–3 genotypes. We could, however, confirm the reported association between BMI and the UCP3 −55 C→T polymorphism; patients carrying the T allele had higher BMI than patients homozygous for the C allele (26.4±4.2 vs. 25.3±4.3 kg/m2; P=.01). We conclude that studied polymorphisms in the UCP1–3 genes do not play a major role in the development of micro- or macroalbuminuria in Scandinavian diabetic patients.
|
|
| 7. |
- Lindholm, Eero, et al.
(författare)
-
The -374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients.
- 2006
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Sep 13, s. 2745-2755
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the -374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications. Methods The AGER -374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin. Results AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER -374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE -374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p < 0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sight-threatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA(1c) values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02). Conclusions/interpretation Our results show an association between the AGER -374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA(1c)-dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.
|
|
