Role of the Functional Toll-Like Receptor-9 Promoter Polymorphism (-1237T/C) in Increased Risk of End-Stage Renal Disease:A Case-Control Study

Inflammation induced by infectious and noninfectious triggers in the kidney may lead to end stage renal disease (ESRD). Toll-like receptor 9 (TLR-9) a receptor for CpG DNA is involved in activation of immune cells in renal disease and may contribute to chronic inflammatory disease progression through an interleukin-6 (IL-6) dependent pathway. Previous studies indicate that -1237T/C confers regulatory effects on TLR-9 transcription. To date the effect of TLR-9 polymorphisms on ESRD remains unknown. We performed a case-control study and genotyped 630 ESRD patients and 415 controls for -1237T/C, -1486T/C and 1635G/A by real-time PCR assays and assessed plasma concentration of IL-6 by ELISA. Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -1237T/C promoter polymorphism. A significant association between -1237T/C in TLR-9 and ESRD was identified. The TCA, TTA and CCA haplotype of TLR-9 were associated with ESRD. ESRD patients carrying -1237TC had a higher mean plasma IL-6 level when compared with -1237TT. The TLR-9 transcriptional activity of the variant -1237CC allele is higher than the -1237TT allele. The results indicate that in a Han Chinese population the presence of the C allele of -1237T/C in the TLR-9 gene increases susceptibility towards development of ESRD. In vitro studies demonstrate that -1237T/C may be involved in the development of ESRD through transcriptional modulation of TLR-9

Structure of cyclo(-L-leucyl-L-tyrosyl-) monohydrate, C15H20N2O3.H2OC_{15}H_{20}N_2O_3.H_2O

$M_r = 294.3$, monoclinic, $P2_1$, a = 8.883 (5), b = 6. 105 (3), c = 14.582 (5) \AA, \beta= 99.53 (4)°, U= 779.9 ${\AA}^3$, Z = 2, $D_m = 1.25$, $D_x = 1.25 Mg m^{-3}$, \lambda(Cu Ka) = 1.5418 \AA, $\mu = 0.666 mm^{-1}$, F(000) = 316, room temperature, R =0.075 for 1147 significant reflections. One of the cis peptide units shows significant non-planarity with \omega =-11.7 (10)°, the other is planar with \omega =-2.8 (10)°. The diketopiperazine ring takes a boat form. The leucyl side chain is in an extended conformation $[X^2= 173.7 (7)°]$; the tyrosyl residue shows a folded geometry $[X^1 = 59.5 (7)°]$. $X^2$ of the tyrosyl side chain is 98.4 (8)°