Abstract
BackgroundSeveral 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 FindingsThe 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/SignificanceThe 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.
Highlights
The etiology of diabetic complications is complex, and inflammation may play a role [1]
The TNF/LTA locus is in linkage disequilibrium with HLADQB1 [21] and we have previously shown that the AGER 374TRA polymorphism is associated with the HLA-DQB1 risk genotypes [13]
No difference in allele frequencies of the TNF polymorphism was seen between patients with or without HLA-DQB1 risk genotypes, the minor allele (A) of the AGER polymorphism was more common in patients with than without HLA-DQB1 risk alleles (34.5 vs. 22.9%), p,0.000001)
Summary
The etiology of diabetic complications is complex, and inflammation may play a role [1]. The mRNA expression for pro-inflammatory cytokines such as IL-1 and Tumor Necrosis Factor Alpha (TNF-a) is increased in the retina and animal studies suggest that inhibition of TNF-a has beneficial effects in prevention of diabetic retinopathy [2,3]. Inflammatory markers are elevated in diabetic nephropathy [5] and inflammation is associated with development of macrovascular complications such as myocardial infarction [6]. 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 to explore whether polymorphisms (TNF 308 GRA, LTA T60N CRA and AGER -374 TRA) in these genes alone or together (as haplotypes) increased the risk for diabetic complications
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