Influence Of Polymorphism In Tumor Necrosis Factor α Gene And Parental Age At Delivery,Birth Order On Ankylosing Spondylitis

Background: Ankylosing spondylitis(AS)is a chronic,systemic inflammatory disorder of theaxial skeleton,affecting sacroiliac joints and the spine. The presence of sacroiliitis isits hallmark. Hip and shoulder joints,and less commonly,peripheral joints orextra-articular structures may also be involved. The etiology of AS is as yet not fullyunderstood,but there is a strong genetic predisposition associated with thehistocompatibility antigen,especially HLA-B27.However,some studies support thepresence of non-B27 genetic-susceptibility factors in AS and point to their likelylocations.Despite all these associations,data has emerged to indicate that the sharedepitope is not the entire story and that the susceptibility and severity of AS could begoverned by multiple genes.Studies in transgenic mice have demonstrated that therisk of ankylosing enthesopathy in offspring was related to birth order and maternalage at the time of birth.It has been shown in humans that parental age at delivery,birth order have a significant influence on AS. The first aim of our study is to assesswhether birth order and maternal age are risk factors for AS in humans. The genesfor TNFα lie within the class III region of the MHC. The TNF genes encode closelyrelated cytokines which play an important role in the regulation of the immuneresponse. Recent studies find that anti-TNF therapy is effective in patients with AS.These observations raise the possibility that AS is related to the genetic propensity ofindividuals to produce TNF-α. Several studies have shown that individualdifferences in TNF-α production can be linked to HLA type,suggesting that TNFresponsitiveness is controlled by variable genetic elements within the MHC. Apossible explanation for differential TNF-α production could be the involvement of a - 7 -第二军医大学 硕士学位论文polymorphism within the regulatory regions for TNF-α gene,especially at position-308 and -238 in the promoter region of the gene. Our objective is to investigate theinfluence of polymorphisms in the promoter region of the TNF-α gene onsusceptibility and phenotype of AS through DNA direct sequencing.Part 1:Influence of parental age at delivery and birth order on ankylosing spondylitisObjective: To study the influence of maternal age at delivery and birth order on AS.Methods: AS patients were recruited from Changhai hospital.Definite AS was definedaccording to the modified New York criteria.The 215 patients were asked tocomplete a questionnaire.This included questions concerning information ofsiblings,e.g.,birth order,age,HLA-B27 typing and history of AS.Haldane and Smithmethods were applied in 215 patients with definite AS and comparison was donebetween HLA-B27 negative and positive groups, formula X=|∑6A-∑?X6A|/(∑V6A)1/2;Baudoin's method was applied in first and last born siblings.Results: Haldane and Smith methods exhibited X=4.02>2 in 215 patients, X=3.54>2in B27 positive groups and X=1.58<2 in B27 negative groups.The number offirst-born children with AS was significantly lower than would be expected(37versus 52.6 for all families [P<0.01]);The number of last-born children with ASwas significantly higher than would be expected(81 versus 52.6 for all families [P<0.05]).Conclusion: Parental age at delivery and birth order have some influence on AS .The oldermaternal age at delivery or later birth order makes patients more liable to thedisease.There are no effects of parental age at delivery and birth order in negativegroup, which were found in positive group. The results indicated genetic - 8 -第二军医大学 硕士学位论文heterogeneity in HLA-B27 negative and positive AS. Lower risk to AS of first-bornchildren compared to non-first-born c...