Ollier W E, MacGregor A
ARC Epidemiology Research Unit, University of Manchester, UK.
Br Med Bull. 1995 Apr;51(2):267-85. doi: 10.1093/oxfordjournals.bmb.a072960.
The aetiology of rheumatoid arthritis (RA) has both genetic and environmental origins. However, the relationship of these with each other and with RA disease is complicated as both genes and environment may be protective or render individuals susceptible. Diagnostic certainty and disease heterogeneity have posed serious hurdles for investigating RA. Patients with similar disease phenotypes may have different aetiologies and it may now be more appropriate to investigate genetic susceptibility with respect to disease process or characteristic immunopathology. Disease concordance studies have been a classical approach to estimating the upper threshold of the genetic contribution to RA and recent studies have approximately halved the much quoted figure of 32% reported by Lawrence for RA concordance in monozygotic twins. However, the interpretation of twin data has to be treated with caution as MZ twins can differ in terms of somatic rearrangement/mutation of immunoglobulin and T cell receptor genes, X chromosome inactivation in females, genomic imprinting and in utero immune relationship. Calculations based on heritability put the genetic component in RA much higher. HLA is an important genetic factor in RA and risk is thought to be associated with a consensus sequence of amino acids within the third hypervariable region of certain DRB1 alleles. It is now clear that HLA is not particularly associated with onset of synovitis but is more associated with progression and severity of the disease process. The HLA-DRB1*0401/0404 genotype is particularly associated with severe, erosive and seropositive RA. Clear differences in RA susceptibility exist between males and females and this may be attributed to hormonal status. Males have a higher threshold requirement for developing RA and this may explain why RA in males is more associated with HLA risk alleles. We have now reached a critical time for the investigation of RA aetio-pathology. Recent advances in molecular biology and automated microsatellite gene scanning technology are making it possible to map disease susceptibility genes over the whole genome in common disorders such as RA. This will require large numbers of well characterised multiplex affected families. It is anticipated that some of the genes identified will fit in with our current concepts of which inflammatory and immune processes are pathologically important in RA. However others may be a major surprise.
类风湿关节炎（RA）的病因既有遗传因素，也有环境因素。然而，这些因素之间以及它们与RA疾病的关系很复杂，因为基因和环境都可能具有保护作用或使个体易患该病。诊断的确定性和疾病的异质性给RA的研究带来了严重障碍。具有相似疾病表型的患者可能有不同的病因，现在根据疾病进程或特征性免疫病理学来研究遗传易感性可能更为合适。疾病一致性研究一直是估计遗传因素对RA贡献上限的经典方法，最近的研究已将劳伦斯所引用的同卵双胞胎中RA一致性高达32%的数字大致减半。然而，对双胞胎数据的解释必须谨慎，因为同卵双胞胎在免疫球蛋白和T细胞受体基因的体细胞重排/突变、女性X染色体失活、基因组印记以及子宫内免疫关系方面可能存在差异。基于遗传度的计算表明RA中的遗传成分要高得多。HLA是RA中的一个重要遗传因素，风险被认为与某些DRB1等位基因第三高变区内的氨基酸共有序列有关。现在很清楚，HLA与滑膜炎的发作并无特别关联，而是与疾病进程的进展和严重程度更相关。HLA - DRB1*0401/0404基因型与严重、侵蚀性和血清阳性RA特别相关。男性和女性在RA易感性方面存在明显差异，这可能归因于激素状态。男性患RA的阈值要求更高，这可能解释了为什么男性RA与HLA风险等位基因的关联更强。我们现在已到了研究RA病因病理学的关键时期。分子生物学和自动化微卫星基因扫描技术的最新进展使得在诸如RA等常见疾病中对全基因组的疾病易感基因进行定位成为可能。这将需要大量特征明确的多重受累家庭。预计所确定的一些基因将符合我们目前关于哪些炎症和免疫过程在RA中具有病理重要性的概念。然而，其他一些基因可能会令人大为惊讶。
