Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.
Hum Immunol. 2020 Feb-Mar;81(2-3):59-64. doi: 10.1016/j.humimm.2020.01.006. Epub 2020 Jan 28.
Patients with celiac disease (CeD) carry the major histocompatibility complex class II, HLA-DQ2 or DQ8 haplotype; the absence of these haplotypes excludes a diagnosis of CeD. While the most common and highest risk HLA haplotypes in CeD have been established, the risk profiles of the less common and equivocal HLA haplotypes need further refinement. The aim of this study was to use a large national patient cohort to further stratify the risk gradient of HLA-DQ haplotypes.
The study cohort included 24,339 adult patients with suspected CeD and immunoglobulin (Ig)A sufficiency (total IgA ≥ 70 mg/dL) whose samples were assessed at Mayo Clinic Laboratories for HLA-DQ genotyping, total IgA, and tissue transglutaminase (tTG)-IgA. Data from a subset of the patients who had duodenal biopsies were analyzed to determine the risk gradient of CeD. Logistic regression models were used to evaluate the risk gradient and to calculate odds ratios (ORs) for being positive to CeD serology according to different HLA-DQ2 and DQ8 heterodimers.
Of the 24,339 patients, 55% (n = 13,456) expressed HLA-DQ2 or DQ8 heterodimers. Compared with patients who had non-permissive HLA-DQ heterodimers, patients who had HLA-DQ2 homozygosity (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, or HLA-DQ2.2/DQ2.2) showed increased odds for tTG-IgA positivity (OR = 96.9; 95% CI, 58.3-147.9). Interestingly, the odds for patients who were compound heterozygous for HLA-DQ2.5 and HLA-DQ8 were similar to those for HLA-DQ2.5 heterozygotes. However, a single HLA-DQ2.2 haplotype (without HLA-DQ8, DQ2.2 heterozygous) was not associated with tTG-IgA positivity. These findings were confirmed in a subset of patients (n = 738) who had duodenal biopsies performed in addition to CeD serologic testing.
This large national reference laboratory cohort study demonstrated that HLA-DQ2.2 heterozygous is not associated with positive tTG-IgA serology, suggesting the reclassification of this haplotype as non-permissive for CeD.
乳糜泻（CeD）患者携带主要组织相容性复合体 II 类、HLA-DQ2 或 DQ8 单倍型；缺乏这些单倍型可排除 CeD 的诊断。虽然 CeD 中最常见和最高风险的 HLA 单倍型已经确定，但较少见和不确定的 HLA 单倍型的风险特征需要进一步细化。本研究的目的是使用大型全国性患者队列进一步分层 HLA-DQ 单倍型的风险梯度。
研究队列包括 24339 名疑似 CeD 且免疫球蛋白（IgA）充足（总 IgA≥70mg/dL）的成年患者，其样本在 Mayo 诊所实验室进行 HLA-DQ 基因分型、总 IgA 和组织转谷氨酰胺酶（tTG）-IgA 检测。对部分进行十二指肠活检的患者进行数据分析，以确定 CeD 的风险梯度。使用逻辑回归模型评估风险梯度，并根据不同的 HLA-DQ2 和 DQ8 异二聚体计算 CeD 血清学阳性的比值比（OR）。
在 24339 名患者中，55%（n=13456）表达 HLA-DQ2 或 DQ8 异二聚体。与非许可性 HLA-DQ 异二聚体患者相比，HLA-DQ2 纯合子（HLA-DQ2.5/DQ2.5、HLA-DQ2.5/DQ2.2 或 HLA-DQ2.2/DQ2.2）患者的 tTG-IgA 阳性率升高（OR=96.9；95%CI，58.3-147.9）。有趣的是，HLA-DQ2.5 和 HLA-DQ8 复合杂合子患者的 OR 与 HLA-DQ2.5 杂合子患者相似。然而，单一 HLA-DQ2.2 单倍型（无 HLA-DQ8、DQ2.2 杂合子）与 tTG-IgA 阳性无关。在另外进行了 CeD 血清学检测的亚组患者（n=738）中证实了这些发现。
本项大型全国参考实验室队列研究表明，HLA-DQ2.2 杂合子与 tTG-IgA 血清学阳性无关，提示该单倍型重新分类为 CeD 非许可性。
