| Background:Single nucleotide polymorphism (SNP) is a DNA sequence variation occurring in a single nucleotide, which including transitions, transversions, insertions and deletions. The frequency of occurrence of this variation is more than1%in the crowd. It is an abundant form of DNA variation throughout the genomes, accounting for90%of the genetic polymorphism in the human genome. The detection technologies of SNP have been widely used in the study of human diseases, especially in genetic susceptibility of mufti-gene complex diseases, such as cancer, rheumatism.KIF21B, which locates on chromosome1q32, encodes proteins belonging to kinesin superfamily. KIF21B contains3characteristic kinesin domains:an N-terminal head motor domain, a coiled-coil stalk region, and a C-terminal tail. The protein is responsible for intracellular trafficking of vesicles and organelles along microtubules and for the formation of cytoskeleton. Recently, it has been detected that KIF21B is associated with autoimmune diseases, such as multiple sclerosis (MS), Crohn’s disease (CD) and ulcerative colitis (UC).ERAP1locates on chromosome5q15and is mainly expressed in the endoplasmic reticulumis. The main function of ERAP1is the N-terminal proteolysis of peptides, which are formed during the proteasome-dependent degradation of cellular proteins. The formed peptides are then exposed on the cell’s surface by MHC-I molecules. Also ERAP1might be involved in the formation of the soluble form of the type I tumor necrosis factor receptor (TNFR-1), along with the soluble forms of interleukin1and6(IL) receptors. ERAP1thus plays an important role in the pathogenesis of autoimmune diseases.Objective:1. To investigate the association between the polymorphism of KIF21B gene and ankylosing spondylitis (AS).2. To explore the association of the polymorphism of ERAP1gene and AS. Methods:1.904Chinese patients with AS and898controls of the same ethnic origin and matched for age and sex were included in the study. The KIF21B polymorphism was genotyped using SNaPshot.2. The articles about the association of the polymorphism of ERAP1gene and AS were searched and the Meta analysis was performed.Results:1. The distribution of genotypes of all the11SNPs in AS patients and healthy controls were in agreement with genomic balance (P>0.05) using Hardy-Weinberg equilibrium (HWE) detection.2. For rs756254, the T allele was significantly associated with an increased risk of AS (P=0.022, OR=1.41,95%CI1.14-1.74). The homozygous TT genotype and heterozygous AT significantly increased the risk of AS (P=0.033, OR=3.52,95%CI1.41-8.83and P=0.033, OR=1.28,95%CI1.01-1.62, respectively, Table3). And for rs296560, the homozygous AA genotype significantly increased the risk of AS (P=0.044, OR=2.24,95%CI1.37-3.65), but there were no significant differences in the allele frequencies between cases and controls. The rest of the SNPs, rs10920091, rs3738255, rs3198583, rs957957, rs7536000, rs12087649, rs56368827, rs12568529and rs296565were not statistically associated with AS.3. Analyses were done to reveal the relationship between the T allele of rs756254and the clinical or laboratory index of AS patients. However, we found no association between the T allele of rs756254and gender, age, disease duration, BASDAI, BASFI, BASMI or MASES of AS patients.4. To better understand the relationship between the SNPs in KIF21B gene, the linkage analysis and the haplotype structure were analyzed. The KIF21B gene region contains two haplotype blocks of eight and two SNPs respectively. The haplotype GCGGTAAA in block1appeared to reduce the risk of AS (P=0.005, OR=0.71,95%CI0.58-0.87), while the haplotype AA in block2was significantly associated with an increased risk of AS (P=0.039, OR=1.22,95%CI1.04-1.43).5. Seventeen studies were enrolled in the Meta analysis with11411AS patients and16511controls in total. The analysis showed that the frequencies of alleles and genotypes of rs27044, rs30187, rs10050860, rs2287987, rs17482078, rs27434and rs27037of ERAPl gene were associated with AS.Conclusion:1. The AA genotype of KIF21B rs296560, the T allele, TT and AT genotype of KIF21B rs756254were associated with susceptibility to AS. Haplotype analysis shows that the haplotype GCGGTAAA in block1had a protective role in AS, while the haplotype AA in block2appeared to increase the risk of AS. It implies that KIF21B plays an important role in the pathogenesis of AS.2. ERAP1gene polymorphisms are related to the genetic susceptibility to AS. |
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