Sex effect on clinical and immunologic quantitative trait loci in a murine model of rheumatoid arthritis
Sex effect on clinical and immunologic quantitative trait loci in a murine model of rheumatoid arthritis
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DOI：
10.1002/art.11016
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发表时间：
2003-06-01
影响因子：
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通讯作者：
Glant, TT
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文献类型：
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作者：
Adarichev, VA;Nesterovitch, AB;Glant, TT
Objective.探讨性别对蛋白多糖（PG）诱导的关节炎主要组织相容性复合物（H-2d）F-2杂交小鼠临床和免疫学性状的影响，并确定X染色体上的数量性状位点（QTL）如何影响另一染色体上的起始QTL。(BALB/c × DBA/2）F-2杂交小鼠用软骨PG免疫，并使用>200个简单的序列长度多态性标记进行全基因组连锁分析。在133只关节炎和426只非关节炎雌性和雄性F-2杂交小鼠中评估主要临床特征（易感性、发作和严重程度），并测量PG特异性T和B细胞应答，以及促炎和炎性细胞因子（肿瘤坏死因子α、白细胞介素-1 [IL-1]、IL-6、干扰素-γ、IL-4、IL-10和IL-12）的产生。将主要临床和免疫学性状与遗传位点进行连锁分析，并对这些QTL之间的连锁关系和性别效应进行分析。证实了以往研究中报道的13个QTL。二元性状（关节炎易感性）和疾病发作是女性特异性的，并在染色体3，7，10，11，13和X上鉴定。病害严重度的QTL主要是雄性特异的，位于第1、4、5、8、14、15和19染色体上。此外，我们在第3、4和11号染色体上发现了4个新的关节炎发病QTL，在第14号染色体上发现了1个新的关节炎严重程度QTL;所有这些QTL都显示出很强的性别相关性。X染色体上的一个位点与10号染色体上的一个QTL相互作用，这两个位点似乎共同控制疾病的发生和发作。大多数临床性状与免疫性状具有共同的位点，且常表现为位点-位点互作。许多免疫QTL与临床QTL重叠，从而提供有关QTL功能的可能机制的信息。感病性和发病率与雌性有显著的连锁关系，受X染色体上的一个QTL控制，而感病性和发病率与雌性无显著连锁关系。严重性QTL与雄性有更强的关联。
Objective. To explore the effect of sex on clinical and immunologic traits in major histocompatibility complex-matched (H-2d) F-2 hybrid mice with proteoglycan (PG)-induced arthritis and to identify how the quantitative trait locus (QTL) on the X chromosome influences the onset QTL of another chromosome.Methods. (BALB/c X DBA/2)F-2 hybrid mice were immunized with cartilage PG, and a genome-wide linkage analysis was performed using >200 simple sequence-length polymorphic markers. The major clinical traits (susceptibility, onset, and severity) were assessed, and PG-specific T and B cell responses, and the production of proinflammatory and antiinflammatory cytokines (tumor necrosis factor alpha, interleukin-1 [IL-1], IL-6, interferon-gamma, IL-4, IL-10, and IL-12) were measured in 133 arthritic and 426 nonarthritic female and male F-2 hybrid mice. The major clinical and immunologic traits were linked to genetic loci, and potential linkages among these QTLs and the effect of sex were analyzed.Results. Thirteen QTLs reported in previous studies Were confirmed. Binary traits (susceptibility to arthritis) and disease onset were female specific and were identified on chromosomes 3, 7, 10, 11, 13, and X. QTLs for disease severity were mostly male specific and were located on chromosomes 1, 4, 5, 8, 14, 15, and 19. In addition, we identified 4 new QTLs for the onset of arthritis on chromosomes 3, 4, and 11, and I new QTL for severity on chromosome 14; all showed a strong gender association. A locus on the X chromosome interacted with a QTL on chromosome 10, and these 2 loci together seemed to control disease incidence and onset. Most of the clinical traits (QTLs) shared common regions with the immunologic traits and frequently showed a locus-locus interaction.Conclusion. Numerous immunologic QTLs overlap with clinical QTLs, thus providing information about possible mechanisms underlying QTL function. Disease susceptibility and onset showed predominant linkage with the female sex, under the control of a QTL on the X chromosome, while the. severity QTLs were more strongly linked to the male sex.