ANALYSIS OF FAMILIES AT RISK FOR INSULIN-DEPENDENT DIABETES-MELLITUS REVEALS THAT HLA ANTIGENS INFLUENCE PROGRESSION TO CLINICAL-DISEASE
ANALYSIS OF FAMILIES AT RISK FOR INSULIN-DEPENDENT DIABETES-MELLITUS REVEALS THAT HLA ANTIGENS INFLUENCE PROGRESSION TO CLINICAL-DISEASE
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DOI：
10.1007/bf03401595
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发表时间：
1995-07-01
影响因子：
5.7
通讯作者：
TAIT, BD
中科院分区：
文献类型：
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作者：
HONEYMAN, MC;HARRISON, LC;TAIT, BD
背景：胰岛素依赖型糖尿病(IDDM)的高危个体，有受影响的一级亲属，可以通过胰岛细胞抗体(ICA)的存在来识别。ICA阳性的亲属进展到IDDM的比率各不相同，确定高危人群是可能进行预防性治疗的先决条件。与ICA阳性或ICA阴性亲属相比，IDDM患者可能表现出较少的遗传异质性。人类白细胞抗原(HL A)基因是IDDM的易感基因，但也可能影响临床前疾病的进展速度。因此，我们试图通过比较一级亲属之间的HLA抗原频率，寻找影响IDDM进展的基因。材料和方法：比较40个高加索人家族中68例IDDM、53例ICA阳性和96例ICA阴性一级亲属的HL A抗原频率。预测在270名无关的IDDM受试者中进行了测试。哈哈。进行血清学分型(HLAI和II类)和序列特异性寡核苷酸分型(第11国际)。组织相容性研讨会方案)(人类白细胞抗原II类)。ICA检测采用国际标准化的间接免疫荧光法。结果：从ICA阴性到ICA阳性到IDDM亲属，已知的易感II类HLA抗原频率总体上增加，已知的保护性II类抗原频率下降。因此，在IDDM亲属中，DR4和DQ8增加，而DR2和DQ6减少；DR3和DQ2从ICA阴性亲属增加到ICA阳性亲属，但不会进一步增加。三组高危DR3、4表型均增加，DR4、X无变化，DR3、X、DRX、X均降低。HLAI类抗原A24在ICA阳性亲属中出现频率较高，在270例非亲缘关系的IDDM患者中，DR4，4和DR3，X风险较低的II类表型与IDDM发病年龄较早相关。结论：在缺乏DR4和DQ8的情况下，HLADR3和DQ2易发生胰岛自身免疫，而不会发生临床IDDM。在ICA阳性的家系中，DR4和Dos与DR3-DQ2和其他单倍型结合时易发生临床IDDM，纯合子时则不易发生。在ICA阳性的亲属中，HLA-A24与IDDM的快速进展显著相关，并且与临床诊断的较早年龄有关。对IDDM家系的分析表明，人类白细胞抗原基因不仅易诱发胰岛自身免疫，而且影响临床疾病的进展。这一发现对确定高危亲属作为可能的预防性治疗的候选对象具有一定的意义。
Background: Individuals at risk for insulin-dependent diabetes mellitus (IDDM), with an affected first-degree relative, can be identified by the presence of islet cell antibodies (ICA). ICA-positive relatives progress at variable rates to IDDM and identification of those at highest risk is a prerequisite for possible preventative treatment. Those who develop IDDM may exhibit less genetic heterogeneity than their ICA-positive or ICA-negative relatives. Specific human leucocyte antigen (HLA) genes predispose to IDDM but could also influence the rate of progression of preclinical disease. Therefore, by comparing HLA antigen frequencies between first-degree relatives, we sought to identify HLA genes that influence progression to IDDM.Materials and Methods: HLA antigen frequencies were compared in 68 IDDM, 53 ICA-positive, and 96 ICA-negative first-degree relatives from 40 Caucasoid families. Predictions were tested in a panel of 270 unrelated IDDM subjects. HLA. typing was performed serologically (HLA class I and II) and by sequence-specific oligotyping (11th International. Histocompatibility Workshop protocol) (HLA class II). ICA tests were measured by an internationally standardized indirect immunofluorescence assay.Results: In general, known susceptibility class II HLA antigens increased in frequency and known protective class II HLA antigens deceased in frequency, from ICA-negative to ICA-positive to IDDM relatives. Thus, DR4 and DQ8 increased whereas DR2 and DQ6 decreased; DR3 and DQ2 increased from ICA-negative to ICA-positive relatives, but not further in IDDM relatives. The high-risk DR3, 4 phenotype increased across the three groups; DR4,X was unchanged, and DR3,X and DRX,X both decreased. The HLA class I antigen, A24, occurred more frequently in ICA-positive relatives who developed IDDM and, in 270 unrelated IDDM subjects, was associated with an earlier age at diagnosis of IDDM in those with the lower risk class II phenotypes DR4,4 and DR3,X.Conclusions: HLA-DR3 and DQ2 predispose to islet autoimmunity, but not development of clinical IDDM in the absence and DR4 and DQ8. DR4 and Dos predispose to the development of clinical IDDM in ICA-positive relatives, in combination with DR3-DQ2 and other haplotypes but not when homozygous. HLA-A24 is significantly associated with rapid progression to IDDM in ICA-positive relatives and with an earlier age at clinical diagnosis. Analysis of IDDM families reveals that HLA genes not only predispose to islet autoimmunity but influence progression to clinical disease. The findings have implications for identifying high-risk relatives as candidates for possible preventative therapy.