在5岁以下的炎症性肠道疾病中发现的新基因

研究者分析炎症性肠道疾病中的复杂遗传影响，发现了一种与5岁以下儿童的疾病相关的新基因变异。这些基因在免疫功能中起着重要作用，而这方面的知识有助于指导更精确、更个性化的治疗方法，对于非常年轻的病人。

“随着我们继续了解这类幼年发病这些基因的具体功能，我们正在设计更有效的治疗方法，”该研究的负责人朱迪思·R·凯尔森，医学博士，在费城儿童医院的儿童炎症性肠病中心儿科胃肠病学家（CHOP）。

凯尔森和他的同事在杂志上发表了他们的研究结果7月16日胃肠病学。

Inflammatory bowel disease (IBD) is a painful, chronic inflammation of the gastrointestinal tract, affecting roughly 2 million children and adults in the U。S。 IBD beginning in childhood tends to be more severe than adult-onset disease。 In fact, very early-onset IBD (VEO-IBD), diagnosed under age 5, is often more severe than IBD that starts later in childhood, and often more challenging to treat。 Kelsen specializes in caring for children with VEO-IBD。

“There has been extensive research in the genes contributing to adult-onset IBD and in children aged 10 and older,” said Kelsen, “but relatively little research has been performed in the very-early onset subtype of the disease。” Furthermore, she added, much of the previous work relied on genome-wide association studies (GWAS), which often do not find rare gene variants。 The current study used newer technology, whole exome sequencing, which has revolutionized the ability to study rare gene variants。

关于这项研究和作者的研究结果

The study team analyzed DNA from 125 children with VEO-IBD, all of them under age 4, along with DNA from 19 of their parents。 A control group of 210 subjects included 145 healthy individuals, 45 patients with pediatric IBD and 20 with adult-onset Crohn’s disease (one of the two major types of IBD)。

Because IBD is a complex disease, in which a patient’s genes may alter immune response to environmental exposure, the researchers focused on specific genes or biological pathways associated with primary immunodeficiency disorders。

The researchers found rare and novel variants in genes that regulate B-cells and T-cells — immune cells with important roles in immunodeficiency disorders。 They also discovered rare variants in the il10ra gene, a member of a key immune function pathway。 “Our findings reinforce other research that has revealed considerable overlap among genes involved in different immune-related diseases,” said Kelsen。 “This overlap is reflected in the fact that VEO-IBD may be a form of primary immunodeficiency。” She added that she expects further whole-exome studies to identify additional immune-related gene variants and pathways。

Kelsen and one of her co-authors, Kathleen E。 Sullivan, MD, PhD, chief of Immunology at CHOP, run a joint immunology/IBD clinic once a month for children with VEO-IBD。

For health providers caring for children with VEO-IBD, said Kelsen, the research underlines the importance of doing complete immunological workups for these patients, in addition to IBD evaluations。 Sometimes, she noted, a genetic workup may also be necessary。 “Evaluation and treatment guidelines are not yet standardized for children with very early-onset IBD, but we have found that this subtype of IBD is somewhat different from IBD that begins later。 As we better understand the specific components of the immune system that may be involved in this disease, clinicians will be better prepared to individualize treatment to each patient。”

Funds from the National Institutes of Health (grant K23DK100461-01A1) supported this research。 Kelsen’s and Sullivan’s co-authors at CHOP included Noor Dawany, PhD, David Piccoli, MD, Petar Mamula, MD, Robert N。 Baldassano, MD, and Marcella Devoto, PhD。

“外显子测序分析非常早期发病的炎症性肠病患者的原发性免疫缺陷揭示基因变异，”胃肠病学, published online July 17, 2015。 http://doi。org/10。1053/j。gastro。2015。07。006

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