Association of TGFbeta1, TNFalpha, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians.
BACKGROUND
Cytokines play an important role in the development of diabetic chronic renal insufficiency (CRI). Transforming growth factor beta1 (TGF beta1) induces renal hypertrophy and fibrosis, and cytokines like tumor necrosis factor-alpha (TNFalpha), chemoattractant protein-1 (MCP-1), and regulated upon activation and normal T cell expressed and secreted (RANTES) mediate macrophage infiltration into kidney. Over expression of these chemokines leads to glomerulosclerosis and interstitial fibrosis. The effect of MCP-1 and RANTES on kidney is conferred by their receptors i.e., chemokine receptor (CCR)-2 and CCR-5 respectively. We tested association of nine single nucleotide polymorphisms (SNPs) from TGFbeta1, TNFalpha, CCR2 and CCR5 genes among individuals with type-2 diabetes with and without renal insufficiency.


METHODS
Type-2 diabetes subjects with chronic renal insufficiency (serum creatinine > or = 3.0 mg/dl) constituted the cases, and matched individuals with diabetes of duration > or = 10 years and normoalbuminuria were evaluated as controls from four centres in India. Allelic and genotypic contributions of nine SNPs from TGFbeta1, TNFalpha, CCR2 and CCR5 genes to diabetic CRI were tested by computing odds ratio (OR) and 95% confidence intervals (CI). Sub-analysis of CRI cases diabetic retinopathy status as dependent variable and SNP genotypes as independent variable in a univariate logistic regression was also performed.


RESULTS
SNPs Tyr81His and Thr263Ile in TGF beta1 gene were monomorphic, and Arg25Pro in TGF beta1 gene and Delta32 polymorphism in CCR5 gene were minor variants (minor allele frequency <0.05) and therefore were not considered for case-control analysis. A significant allelic association of 59029G>A SNP of CCR5 gene has been observed and the allele 59029A seems to confer predisposition to development of diabetic CRI (OR 1.39; CI 1.04-1.84). In CRI subjects a compound group of genotypes "GA and AA" of SNP G>A -800 was found to confer predisposition for proliferative retinopathy (OR 3.03; CI 1.08-8.50, p = 0.035).


CONCLUSIONS
Of the various cytokine gene polymorphisms tested, allele 59029A of CCR5 gene is significantly associated with diabetic renal insufficiency among Asian Indians. Result obtained for 59029G>A SNP of CCR5 gene is in conformity with reports from a Japanese population but due to sub-optimal power of the sample, replication in larger sample set is warranted.
Prasad
Pushplata
P
Department of Genetics, University of Delhi South Campus, New Delhi, India. pushplata_prasad114@rediffmail.com
Tiwari
Arun K
AK
Kumar
K M Prasanna
KM
Ammini
A C
AC
Gupta
Arvind
A
Gupta
Rajeev
R
Thelma
B K
BK
D000328:Adult; D000368:Aged; D044466:Asian People; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C515334:CCR2 protein, human; D018946:Chemokine CCL5; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha