Haplotype-based Analysis of Ulcerative Colitis Risk Loci Identifies Both IL2 and IL21 as Susceptibility Genes in Han Chinese
INFLAMMATORY BOWEL DISEASES
Authors: Shi, Jihua; Zhou, Lu; Zhernakova, Alexandra; Qian, Jiaming; Zhu, Feng; Sun, Gang; Zhu, Liming; Ma, Xuejun; Dijkstra, Gerard; Wijmenga, Cisca; Faber, Klaas Nico; Lu, Xinghua; Weersma, Rinse K.
Abstract
Background: The incidence of ulcerative colitis (UC) varies between Western and Eastern ethnicities. A distinct genetic background may play a role in the differences. Until now, very little was known of the UC genetics in Asian populations. Here we performed a haplotype-based analysis of six known UC susceptibility loci in Han Chinese patients. Methods: In all, 245 UC patients and 300 healthy controls of Han Chinese descent were genotyped for 27 single nucleotide polymorphisms (SNPs), which cover the major haplotypes of the chromosome regions containing IL10, IL2/IL21, MYO9B, ECM1, MST1, and IL23R in Han Chinese. Results: In contrast to the tight linkage disequilibrium (LD) block of the IL2/IL21 region in Caucasians, IL2 and IL21 reside in two independent LD blocks in Han Chinese. The IL2 SNP rs2069762 (P - 7.0 x 10(-4), odds ratio [OR] - 1.54, 95% confidence interval [CI] 1.20-1.99) and the IL21 SNP rs2055979 (P = 1.2 x 10(-4), OR = 1.50, 95% CI 1.17-1.92) were independently associated with UC. We identified one risk haplotype in IL2 and another independent risk haplotype in IL21. In addition to the IL2/IL21 locus, we observed association of the TT genotype of SNP rs1545620 in MYO9B with UC (P = 0.0169; OR = 0.29, 95% CI 0.11-0.78) and association of rs17375018 in IL23R with pancolitis in Chinese UC patients (P - 0.002; OR - 2.38, 95% CI 1.41-4.02). Conclusions: Our study confirmed the association of the IL2/IL21 region with UC in Han Chinese patients, and further implied both IL2 and IL21 as genetic risk factors for UC. Han Chinese UC patients share part of their genetic susceptibility with Caucasian patients. (Inflamm Bowel Dis 2011;17:2472-2479)
Pregnancy status alters IL-21-mediated effects on murine B lymphocytes
REPRODUCTION
Authors: Froehlich, Carolin; Ehrhardt, Jens; Krueger, Diana; Trojnarska, Dominika; Zygmunt, Marek; Muzzio, Damian Oscar
Abstract
A favorable outcome of pregnancy depends greatly on an adequate balance of immune protection and fetal tolerance at the fetomaternal interface. IL-21 is a pro-inflammatory cytokine associated with altering immune responses in autoimmune diseases. IL-21 has pleiotropic functions, including induction of Th17 T cells, inhibition of T-reg development, and modulation of antibody responses of B lymphocytes. Genetic polymorphisms of IL21 have been associated to poor pregnancy outcomes. However, the mechanism of IL-21 actions needs further evaluation. Here, we postulate that IL-21 affects splenic B cell function during pregnancy and shapes immune responses. We show that splenic B cells from CBA/J x BALB/c mice with favorable pregnancy outcome expressed lower IL21R levels than in CBA/J x DBA/2J mice, a mouse model for immune-induced bad pregnancy outcome. As a consequence, B cells from CBA/J x BALB/c mice reacted less sensitively to IL-21 than B cells from non-pregnant mice (NPM) or from CBA/J x DBA/2J mice. Also, LPS-induced apoptotic rates were altered in NPM and CBA/J x DBA/2J but not in CBA/J x BALB/c mice. This is accompanied by improved survival of B cells that produce the anti-inflammatory cytokine IL-10 upon stimulation with LPS. We also observed lower numbers of CD4(+)CXCR5(+)Bcl-6(+) follicular T-helper cells (Tfh) in normal pregnant mice, compared to non-pregnant and mice with disturbed pregnancies. Our data indicate that alterations of the Tfh/IL-21/IL-10 axis may have important influence on pregnancy outcome.