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Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians.

Ahluwalia TS, Khullar M, Ahuja M, Kohli HS, Bhansali A, Mohan V, Venkatesan R, Rai TS, Sud K, Singal PK - PLoS ONE (2009)

Bottom Line: The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05).The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy.The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

ABSTRACT

Background: Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients.

Methodology/principal findings: Eight single nucleotide polymorphisms (SNPs) of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9) were genotyped in two independently ascertained type 2 diabetic cohorts with (DN) and without nephropathy (DM); consisting of patients from North India (n = 495) and South India (n = 188). Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR), PCR-RFLP and TaqMan allelic discrimination assays and the gene-gene interaction among genetic variants were determined by multi dimensional reduction (MDR) software. Serum high sensitive CRP (hs-CRP) levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05). The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05) and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2), DD (CCR5) and 279Gln/Gln (MMP9) conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002).

Conclusion: The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

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Related in: MedlinePlus

Gene–Gene interaction: Comparison between the number of interacting locus/loci and the odds ratio (relative risk) pertaining to each SNP combination.Testing Accuracy for different combinations: single locus, 63.7 %; two locus, 65.1%; three locus, 70.7%; four locus, 76.4%.
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pone-0005168-g006: Gene–Gene interaction: Comparison between the number of interacting locus/loci and the odds ratio (relative risk) pertaining to each SNP combination.Testing Accuracy for different combinations: single locus, 63.7 %; two locus, 65.1%; three locus, 70.7%; four locus, 76.4%.

Mentions: We analyzed the presence of epistatic interactions amongst inflammatory genes, evaluating the possible (one-to-four way) SNP combinations using the multiple dimensionality reduction approach (MDR). All the four models (one, two, three & four locus) had a prediction accuracy of >63% and showed significant interactions (p<0.05), as determined empirically by permutation testing. Four loci SNP combination of -2518AG (CCL2), II/ID (CCL2 I/D), 279Gln/Arg (MMP9), and DD (CCR5 I/D) genotypes was found to be the best model for DN risk prediction (accuracy 0.764; p = 0.0001, Figure 6). The predicted odds ratio of this model was 10.6 (95% CI: 6.6–17.0). The two loci model comprising II genotype (CCL2) and DD genotype (CCR5) and three loci combination comprising of II (CCL2 I/D), DD (CCR5 I/D), and -2518AG (CCL2) were also significantly associated with three and five folds risk of DN (p = 0.0001; p<0.02).


Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians.

Ahluwalia TS, Khullar M, Ahuja M, Kohli HS, Bhansali A, Mohan V, Venkatesan R, Rai TS, Sud K, Singal PK - PLoS ONE (2009)

Gene–Gene interaction: Comparison between the number of interacting locus/loci and the odds ratio (relative risk) pertaining to each SNP combination.Testing Accuracy for different combinations: single locus, 63.7 %; two locus, 65.1%; three locus, 70.7%; four locus, 76.4%.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663813&req=5

pone-0005168-g006: Gene–Gene interaction: Comparison between the number of interacting locus/loci and the odds ratio (relative risk) pertaining to each SNP combination.Testing Accuracy for different combinations: single locus, 63.7 %; two locus, 65.1%; three locus, 70.7%; four locus, 76.4%.
Mentions: We analyzed the presence of epistatic interactions amongst inflammatory genes, evaluating the possible (one-to-four way) SNP combinations using the multiple dimensionality reduction approach (MDR). All the four models (one, two, three & four locus) had a prediction accuracy of >63% and showed significant interactions (p<0.05), as determined empirically by permutation testing. Four loci SNP combination of -2518AG (CCL2), II/ID (CCL2 I/D), 279Gln/Arg (MMP9), and DD (CCR5 I/D) genotypes was found to be the best model for DN risk prediction (accuracy 0.764; p = 0.0001, Figure 6). The predicted odds ratio of this model was 10.6 (95% CI: 6.6–17.0). The two loci model comprising II genotype (CCL2) and DD genotype (CCR5) and three loci combination comprising of II (CCL2 I/D), DD (CCR5 I/D), and -2518AG (CCL2) were also significantly associated with three and five folds risk of DN (p = 0.0001; p<0.02).

Bottom Line: The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05).The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy.The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

ABSTRACT

Background: Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients.

Methodology/principal findings: Eight single nucleotide polymorphisms (SNPs) of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9) were genotyped in two independently ascertained type 2 diabetic cohorts with (DN) and without nephropathy (DM); consisting of patients from North India (n = 495) and South India (n = 188). Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR), PCR-RFLP and TaqMan allelic discrimination assays and the gene-gene interaction among genetic variants were determined by multi dimensional reduction (MDR) software. Serum high sensitive CRP (hs-CRP) levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05). The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05) and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2), DD (CCR5) and 279Gln/Gln (MMP9) conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002).

Conclusion: The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.

Show MeSH
Related in: MedlinePlus