Adarichev Vyacheslav A, Nesterovitch Andrew B, Bárdos Tamás, Biesczat Darci, Chandrasekaran Raman, Vermes Csaba, Mikecz Katalin, Finnegan Alison, Glant Tibor T
Rush University at Rush-Presbyterian-St Luke's Medical Center, Chicago, Illinois 60612, USA.
Arthritis Rheum. 2003 Jun;48(6):1708-20. doi: 10.1002/art.11016.
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.
(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.
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 1 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.
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.
探讨性别对主要组织相容性复合体匹配（H-2d）的蛋白聚糖（PG）诱导性关节炎F2杂交小鼠临床和免疫特征的影响，并确定X染色体上的数量性状基因座（QTL）如何影响另一染色体上的发病QTL。
用软骨PG免疫（BALB/c×DBA/2）F2杂交小鼠，并使用200多个简单序列长度多态性标记进行全基因组连锁分析。评估主要临床特征（易感性、发病和严重程度），并在133只患关节炎和426只未患关节炎的雌性和雄性F2杂交小鼠中测量PG特异性T和B细胞反应以及促炎和抗炎细胞因子（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。将主要临床和免疫特征与遗传基因座进行连锁分析，并分析这些QTL之间的潜在连锁关系以及性别的影响。
证实了先前研究中报道的13个QTL。二元性状（对关节炎的易感性）和疾病发病具有雌性特异性，在3、7、10、11、13和X染色体上被鉴定出来。疾病严重程度的QTL大多具有雄性特异性，位于1、4、5、8、14、15和19号染色体上。此外，我们在3、4和11号染色体上鉴定出4个新的关节炎发病QTL，在14号染色体上鉴定出1个新的严重程度QTL；所有这些都显示出强烈的性别关联。X染色体上的一个基因座与10号染色体上的一个QTL相互作用，这两个基因座共同似乎控制着疾病的发病率和发病情况。大多数临床特征（QTL）与免疫特征共享共同区域，并经常显示出基因座-基因座相互作用。
众多免疫QTL与临床QTL重叠，从而提供了有关QTL功能潜在机制的信息。在X染色体上一个QTL的控制下，疾病易感性和发病与雌性有主要关联，而严重程度QTL与雄性的关联更强。
