Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, GA.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA.
Inflamm Bowel Dis. 2018 Mar 19;24(4):829-838. doi: 10.1093/ibd/izx084.
The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59).
To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC.
HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB10103 (odds ratio [OR] = 6.941, p = 1.9210-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB11301 (OR = 2.25, p = 7.9210-9) and another SNP rs17188113 (OR = 0.48, p = 7.5610-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB10103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13).
In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.
儿科发病溃疡性结肠炎（UC）的遗传贡献尚不清楚，其特征为疾病严重且结肠广泛受累。在成人发病 UC 中，全基因组关联研究（GWAS）已确定了许多位点，其中大多数具有适度的易感性风险（OR 0.84-1.14），除了染色体 6 上的人类白细胞抗原（HLA）区域（OR 3.59）。
为了研究儿科发病 UC 的遗传贡献，我们对 466 例儿科发病 UC 患者和 2099 名健康对照者进行了基于英国生物银行阵列的 GWAS。SNP2HLA 用于推断经典 HLA 等位基因及其相应的氨基酸，其结果与成人发病 UC 进行了比较。
HLA 解释了几乎所有的关联信号，主要由 191 个单核苷酸多态性（SNP）（p=5x10-8 至 5x10-10）组成。尽管作用很小，但成人发病 UC 位点中已确定的 SNP 在儿科发病 UC 中具有相似的方向和幅度。SNP2HLA 推断出 HLA-DRB10103（比值比[OR]6.941，p=1.92x10-13）与成人发病 UC（OR=3.59）相比，与儿科 UC 最显著相关。进一步的条件分析显示 HLA-DRB11301（OR=2.25，p=7.92x10-9）和另一个 SNP rs17188113（OR=0.48，p=7.56x10-9）具有独立作用。两个 HLA-DRB1 致病等位基因与成人发病 UC 共享，而至少有 2 个信号是儿科 UC 特有的。随后的分层分析表明，HLA-DRB1*0103 与广泛疾病（E4：OR=8.28，p=4.66x10-10）和女性（OR=8.85，p=4.82x10-13）的关联更强。
在儿科发病 UC 中，HLA 几乎解释了所有的遗传关联。此外，由于新的和共享的效应的结合，HLA 与儿科 UC 的关联比成人发病 UC 强约两倍。我们推测抗原刺激（无论是感染性的还是非感染性的刺激）作为儿科 UC 发病的因果事件具有至关重要的意义。
