Association of PD-1 gene polymorphisms with systemic lupus erythematosus
(Uncorrected OCR) Abstract of thesis entitled Association of PD-1 gene polymorphisms with systemic lupus erythematosus submitted by Kong Kai Pang for the Degree of Master of Philosophy at the University of Hong Kong in December 2004 Programmed death 1 (PD-1) is a negative regulator of T-cells and different lines of evidence suggest that PD-1 is a candidate gene in systemic lupus erythematosus (SLE) susceptibility. First, it maps at chromosomal region 2q37.3, which is a susceptibility locus (SLEB2) of SLE. Second, dysregulated PD-1 expression is associated with break of tolerance, through failure to induce inhibitory signal during T- and B-cells activation, which is one of the major steps in developing autoimmunity. Third, PD-1-/- mice develop lupus-like syndrome. Finally, PD-1 polymorphisms are associated with various autoimmune diseases. The aim of this study is to investigate the association of the PD-1 polymorphisms and haplotypes with systemic lupus erythematosus (SLE) in Hong Kong Chinese population. We performed a case-control association study of 3 single nucleotide polymorphisms (SNPs), PD1.1 G/A, PD1.3 G/A and PD1.5 C/T with SLE. The study included 514 SLE patients and 647 healthy controls. Association of genotypes and alleles with disease, haplotypes construction and linkage disequilibrium (LD) analysis were performed. Association between SNPs and disease phenotypes was also examined. And correlation between various SNPs and PD-1 mRNA expression was investigated. We found the AA genotype and A allele of the SNP PD1.1 were associated with a decreased risk in developing SLE (OR 0.5; P = 0.014 and OR = 0.71; P = 0.007, respectively). However, no association for SNP PD1.5 was found in SLE and SNP PD1.3 was non-polymorphic in our population. As PD1.3 is non-polymorphic in our populations, only four haplotypes were constructed from PD1.1 and PD1.5. No significant difference in haplotypes frequencies was found between SLE patients and controls. However, the frequency of A/C homozygote (i.e. having PD1.1 AA and PD1.5 CC) was reduced in patients than in controls (OR 0.69; P = 0.021). In addition, the SNP PD1.1 was associated with patients showing double positive in anti-Ro and anti-La autoantibodies (OR = 8.03; P = 0.0002). We also observed a significant difference in PD-1 mRNA expression levels among the various genotypes of PD1.1 and PD1.5. The PD1.1 AA showed the lowest expression levels when compared to PD1.1 GA (P = 0.029) and PD1.1 GG (P < 0.0001). The expression of PD1.1 GA was also lower than that of PD1.1 GG (P = 0.029). The PD1.5 CC showed the lowest expression when compared to PD1.5 CT (P = 0.03) and PD1.5 TT (P = 0.17). Moreover, the difference of PD-1 mRNA expression between A/C homozygote and non-A/C homozygote was statistically significant (P = 0.002). We concluded that PD-1 polymorphisms were associated with SLE, and the AA genotype and A allele of PD1.1 and A/C homozygote that associated with reduced PD-1 mRNA expression might be protective against SLE development in our population.
School:The University of Hong Kong
School Location:China - Hong Kong SAR
Source Type:Master's Thesis
Keywords:systemic lupus erythematosus apoptosis t cells genetic polymorphisms
Date of Publication:01/01/2005