Association between LTA, TNF and AGER Polymorphisms and Late Diabetic Complications

• Published in: PloS one Vol. 3; no. 6; p. e2546
• Main Authors: Lindholm, Eero, Bakhtadze, Ekaterina, Cilio, Corrado, Agardh, Elisabet, Groop, Leif, Agardh, Carl-David
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.06.2008; Public Library of Science (PLoS)
• Subjects: Aged; Alleles; Analysis; Atherosclerosis; Bioinformatics; Cardiac and Cardiovascular Systems; Cardiology and Cardiovascular Disease; Cardiovascular disease; Cardiovascular Disorders; Chromosome 6; Chromosomes, Human, Pair 6; Clinical Medicine; Complications; Complications and side effects; Cytokines; Diabetes; Diabetes and Endocrinology/Type 1 Diabetes; Diabetes and Endocrinology/Type 2 Diabetes; Diabetes Complications - genetics; Diabetes mellitus; Diabetic nephropathies; Diabetic nephropathy; Diabetic retinopathy; Diabetics; Female; Gene polymorphism; Genes; Genetic aspects; Genetics and Genomics/Genetics of Disease; Genomes; Genotype; Genotypes; Haplotypes; Health risks; Heart attacks; Histocompatibility antigen HLA; HLA antigens; Humans; Inflammation; Kardiologi; Kardiologi och kardiovaskulära sjukdomar; Kinases; Klinisk medicin; Linkage disequilibrium; Lymphotoxin-alpha - genetics; Male; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Middle Aged; Nephrology/Chronic Kidney Disease; Nephropathy; Ophthalmology/Diabetic Retinopathy; Patients; Polymorphism; Polymorphism, Genetic; Receptor for Advanced Glycation End Products; Receptors, Immunologic - genetics; Regression analysis; Retinopathy; Risk; Studies; TNF inhibitors; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0002546

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. 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. 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.