Is low-frequency distribution of TGF-beta genotype associated with increased risk for end-stage renal disease?
End-stage renal disease has been associated with an inflammatory state. TGF-beta plays a critical role in antiinflammation counteracting inflammatory cytokines, wound healing, and tissue repair. We, therefore, speculated the protective role of TGF-beta in renal inflammation rather than inducing fibrosis. Three polymorphisms of TGF-beta (713-8delC), i.e., C deletion in intron sequence 8 base prior to exon-5 by PCR-RFLP and codon-10, Leu/Pro, and codon-25, Arg/Pro by Amplification Refractory Mutation System (ARMS-PCR) techniques were genotyped in 228 end-stage renal disease (ESRD) patients and 180 controls. Linkage disequilibrium (LD) and haplotype analysis was performed by Arlequin software. Our data showed positive association between codon-10 polymorphism and ESRD risk (P < 0.001; OR 4.845, 95% CI 2.57-9.11 for Pro/Pro). However, genotype frequencies were comparable in patients and controls for 713-8delC, while in the case of codon-25, a trend of higher frequency of Pro/Pro genotype (16.2% versus 10.0%) was observed but the P-value did not reach significant (P = 0.187). Significant association of codon-10 Pro/Pro was observed in patients with glomerulonephritis (P = 0.001; OR 4.138, 95%CI 2.1-8.13). LD was found significant between codon-10 and 25 (P = 0.021). Haplotype "Pro-Pro" showed 1.8-fold higher risk for ESRD (p = 0.003; OR = 1.867, 95%CI = 1.229-2.838). A combined analysis of the effect of TGF-beta (codon-10) with C-deletion and codon-25 showed significant difference for TGF-beta(10)-TGF-beta(C-del) (P = 0.010). In conclusion, the present study suggests that low-producing genotype (Pro/Pro) of TGF-beta (codon-10) polymorphism is associated with ESRD. Haplotype analysis further suggested that "Pro-Pro" (low producer) is associated with higher risk for ESRD. Thus, high-producing genotype of TGF-beta may be beneficial and may play a potential role in the resolution of renal inflammation.
Mittal
Rama Devi
RD
Department of Urology and Renal Transplantation, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow, India. ramamittal@yahoo.com
Manchanda
Parmeet Kaur
PK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D003062:Codon / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009393:Nephritis / Q000235:genetics*; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics; D012306:Risk; D016212:Transforming Growth Factor beta / Q000235:genetics*
D003062:Codon; D016212:Transforming Growth Factor beta; D011392:Proline