Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits
Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits
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DOI：
10.1002/art.22325
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发表时间：
2007-01-01
影响因子：
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通讯作者：
Amos, Christopher I.
中科院分区：
文献类型：
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作者：
Criswell, Lindsey A.;Chen, Wei V.;Amos, Christopher I.
Objective.通过对类风湿因子IgM（IgM-RF）和抗环瓜氨酸肽（抗CCP）自身抗体滴度的连锁分析，探讨类风湿关节炎（RA）的异质性。受试者，1,002例RA患者从491个多重家庭招募的北美RA协会，分型为379个微卫星标记。抗CCP滴度基于第二代酶联免疫吸附试验测定，IgM-RF水平通过免疫比浊法定量。我们使用Merlin统计软件包进行非参数数量性状连锁分析。对于每一个数量性状，连锁的证据，对数的优势（LOD）得分> 1.0，在9个地区被发现。对于这两个性状，连锁的最强证据是染色体6p上的标记D 6S 1629（抗CCP的LOD 14.02和RF的LOD 12.09）。另外6个LOD值大于1.0的区域在染色体1p21.1、5 q15、8p23.1、16p12.1、16q23.1和18q21.31上与2个性状重叠。在2个区域（染色体9p21.3和10q21.1）发现与抗CCP滴度连锁而不与RF滴度连锁的证据，在2个区域（染色体5p15.2和1q42.3）发现与RF滴度连锁而不与抗CCP滴度连锁的证据。几个协变量与I或两个性状显着相关，探索协变量的影响和连锁分析显示显着的影响，性别在调制连锁信号的几个染色体区域。例如，性别对染色体6p上两个数量性状的连锁结果有显著影响（抗CCP滴度P = 0.0007，RF滴度P = 0.0012），提示性别-HLA区域相互作用。RA的定量成分分析是一个很有前途的方法解剖这种复杂的疾病的遗传异质性。这些结果强调了性别或其他协变量的潜在重要性，这些协变量可能调节影响特定疾病表现风险的一些遗传效应。
Objective. To dissect the heterogeneity of rheumatoid arthritis (RA) through linkage analysis of quantitative traits, specifically, IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibody titers.Methods. Subjects, 1,002 RA patients from 491 multiplex families recruited by the North American RA Consortium, were typed for 379 microsatellite markers. Anti-CCP titers were determined based on a second-generation enzyme-linked immunosorbent assay, and IgM-RF levels were quantified by immunonephelometry. We used the Merlin statistical package to perform nonparametric quantitative trait linkage analysis.Results. For each of the quantitative traits, evidence of linkage, with logarithm of odds (LOD) scores of > 1.0, was found in 9 regions. For both traits, the strongest evidence of linkage was for marker D6S1629 on chromosome 6p (LOD 14.02 for anti-CCP and LOD 12.09 for RF). Six other regions with LOD scores of > 1.0 overlapped between the 2 traits, on chromosomes 1p21.1, 5q15, 8p23.1, 16p12.1, 16q23.1, and 18q21.31. Evidence of linkage to anti-CCP titer but not to RF titer was found in 2 regions (chromosomes 9p21.3 and 10q21.1), and evidence of linkage to RF titer but not to anti-CCP titer was found in 2 regions (chromosomes 5p15.2 and 1q42.3). Several covariates were significantly associated with I or both traits, and linkage analysis exploring the covariate effects revealed striking effects of sex in modulating linkage signals for several chromosomal regions. For example, sex had a striking impact on the linkage results for both quantitative traits on chromosome 6p (P = 0.0007 for anti-CCP titer and P = 0.0012 for RF titer), suggesting a sex-HLA region interaction.Conclusion. Analysis of quantitative components of RA is a promising approach for dissecting the genetic heterogeneity of this complex disorder. These results highlight the potential importance of sex or other covariates that may modulate some of the genetic effects that influence the risk of specific disease manifestations.