Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease
Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease
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DOI：
10.1016/s0140-6736(96)90734-5
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发表时间：
1996-05-04
期刊：
影响因子：
168.9
通讯作者：
Jewell, DP
中科院分区：
文献类型：
--
作者：
Satsangi, J;Welsh, KI;Jewell, DP
背景
尽管有强有力的证据表明免疫功能失调和遗传易感性在慢性炎症性肠病（克罗恩病和溃疡性结肠炎）的发病机制中起作用，但主要组织相容性复合体基因的重要性仍不确定。我们通过非参数连锁分析（患病同胞对方法）以及关联研究策略，对人类白细胞抗原DRB1和DQB基因的作用进行了研究。还详细检查了基因型与表型之间的关系。
方法
在连锁分析中，对有两个或更多同胞患有炎症性肠病的74个家庭进行了研究。共涉及83对患病同胞：其中42对同胞均患有克罗恩病；29对均患有溃疡性结肠炎；12对中一个同胞患有克罗恩病，另一个患有溃疡性结肠炎。在关联研究中，有175例溃疡性结肠炎患者、173例克罗恩病患者和472例对照。对性别、发病年龄、疾病范围和家族史等细节进行了分析。24例溃疡性结肠炎患者和92例克罗恩病患者因难治性疾病需要手术。通过序列特异性引物聚合酶链反应进行人类白细胞抗原DRB1和DQB1基因分型。
结果
在溃疡性结肠炎中，患病同胞对之间的等位基因共享为与DRB1位点的连锁提供了证据（p = 0.017，χ² = 5.32）。在研究的29对患病同胞中，只有一对没有共享DRB1 - DQB单倍型。15对共享两个DRB - DQB单倍型。相比之下，在克罗恩病（42对同胞；p = 0.30，χ² = 0.16）或总体炎症性肠病（83对同胞，p = 0.16，χ² = 2.28）中未发现连锁。在关联研究中，罕见的DRB1*103（在患者中为8.3%，在对照中为3.2%）和DRB1*12（在患者中为8.6%，在对照中为2.1%）等位基因与溃疡性结肠炎相关（p = 0.0074，χ² = 7.22，优势比OR = 2.9 [95%置信区间1.3 - 6.4]和p = 0.0056，χ² = 12.63，OR = 4.33 [1.8 - 11.0]）。未发现与代表DR2的等位基因相关（p = 0.55，χ² = 0.34）。在克罗恩病中未发现总体关联。在溃疡性结肠炎中，女性中DRB1*0301 DQB*0201（DR3 DQ2）的频率降低（在女性中为9.8%，在对照中为26.3%，p = 0.037，χ² = 8.39，OR = 0.34 [0.15 - 0.71]），特别是在远端疾病患者中（2.3%，与对照相比p = 0.001，χ² = 11.35，OR = 0.07 [0.00 - 0.39]）。在男性和女性中，DR3 DQ2单倍型可预测广泛性溃疡性结肠炎（32.9%，在远端疾病中为10.7%，p……（此处原文似乎不完整）
Background Despite strong evidence implicating immune dysfunction and genetic predisposition in the pathogenesis of the chronic inflammatory bower diseases Crohn's disease and ulcerative colitis, the importance of the genes of the major histocompatibility complex remains uncertain, We have investigated the contribution of HLA DRB1 and DQB genes by the strategies of non-parametric linkage analysis (affected sibling pair method) as well as association study. The relation between genotype and phenotype was examined in detail.Methods For linkage analysis 74 families in whom two or more siblings had inflammatory bowel disease were studied. A total of 83 affected sibling pairs were involved: in 42 pairs both siblings had Crohn's disease; in 29 both had ulcerative colitis; in 12 one sibling had Crohn's disease, the other ulcerative colitis. for the association study there were 175 patients with ulcerative colitis, 173 with Crohn's disease, and 472 controls. Details of sex, age of onset, disease extent, and family history were analysed. 24 patients with ulcerative colitis and 92 with Crohn's disease required surgery for refractory disease, HLA DRB1 and DQB1 gene-typing was performed by polymerase chain reaction with sequence-specific primers.Findings in ulcerative colitis, the sharing of alleles among affected sibling pairs provided evidence for linkage with DRB1 locus (p=0 . 017, chi(2)=5 . 32). Of 29 affected sibling pairs studied, only one pair shared no DRB1 DQB haplotypes. 15 shared two DRB DQB haplotypes. In contrast, no linkage was noted for Crohn's disease (42 sibling pairs; p=0 . 30, chi 2=0 . 16) or for inflammatory bowel disease overall (83 sibling pairs, p=0 . 16, chi(2)=2 . 28), In the association study the rare DRB1*103 (8 . 3% vs 3 . 2% in controls) and DRB1*12 (8 . 6% vs 2 . 1% in controls) alleles were associated with ulcerative colitis (p=0 . 0074, chi(2)=7 . 22, odds ratio OR=2 . 9 [95% CI 1 . 3-6-4] and p=0 . 0056, chi(2)=12 . 63, OR=4 . 33 [1 . 8-11 . 0] respectively). No association with alleles representing DR2 (p=0 . 55, chi(2)=0 . 34) was noted, No overall association was seen in Crohn's disease, In ulcerative colitis, the frequency of DRB1*0301 DQB*0201 (DR3 DQ2) was reduced in females (9 . 8% vs 26 . 3% in controls, p=0 . 037, chi(2)=8 . 39 OR=0 . 34 (0 . 15-0 . 71]), particularly in those with distal disease (2 . 3%, p=0 . 001 vs controls, chi(2)=11 . 35, OR=0 . 07 [0 . 00-0 . 39]). In both males and females, the DR3 DQ2 haplotype was predictive of extensive ulcerative colitis (32 . 9% vs 10 . 7% in distal disease, p