Honeyman M C, Harrison L C, Drummond B, Colman P G, Tait B D
Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Mol Med. 1995 Jul;1(5):576-82.
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.
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.
In general, known susceptibility class II HLA antigens increased in frequency and known protective class II HLA antigens decreased 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.
HLA-DR3 and DQ2 predispose to islet autoimmunity, but not development of clinical IDDM in the absence and DR4 and DQ8. DR4 and DQ8 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.
有胰岛素依赖型糖尿病（IDDM）风险且有一位患病一级亲属的个体，可通过胰岛细胞抗体（ICA）的存在来识别。ICA阳性的亲属患IDDM的进展速度各不相同，识别出风险最高的个体是进行可能的预防性治疗的前提。那些患IDDM的个体可能比其ICA阳性或ICA阴性的亲属表现出更少的遗传异质性。特定的人类白细胞抗原（HLA）基因易导致IDDM，但也可能影响临床前期疾病的进展速度。因此，通过比较一级亲属之间的HLA抗原频率，我们试图识别出影响向IDDM进展的HLA基因。
比较了来自40个白种人家庭的68名IDDM患者、53名ICA阳性和96名ICA阴性一级亲属的HLA抗原频率。在一组270名无关的IDDM受试者中对预测结果进行了测试。HLA分型采用血清学方法（HLA I类和II类）以及序列特异性寡核苷酸分型法（第11届国际组织相容性研讨会方案）（HLA II类）。ICA检测通过国际标准化的间接免疫荧光测定法进行。
总体而言，已知的易感性II类HLA抗原频率从ICA阴性亲属到ICA阳性亲属再到IDDM亲属逐渐增加，而已知的保护性II类HLA抗原频率逐渐降低。因此，DR4和DQ8增加，而DR2和DQ6降低；DR3和DQ2从ICA阴性亲属到ICA阳性亲属增加，但在IDDM亲属中没有进一步增加。高危DR3,4表型在三组中均增加；DR4,X不变，DR3,X和DRX,X均降低。HLA I类抗原A24在发展为IDDM的ICA阳性亲属中更常见，并且在270名无关的IDDM受试者中，与具有较低风险II类表型DR4,4和DR3,X的个体中IDDM的较早诊断年龄相关。
HLA - DR3和DQ2易导致胰岛自身免疫，但在没有DR4和DQ8的情况下不会发展为临床IDDM。DR4和DQ8与ICA阳性亲属中临床IDDM的发展相关，与DR3 - DQ2和其他单倍型组合时相关，但纯合时不相关。HLA - A24与ICA阳性亲属中快速进展为IDDM以及临床诊断时的较早年龄显著相关。对IDDM家庭的分析表明，HLA基因不仅易导致胰岛自身免疫，还影响向临床疾病的进展。这些发现对于识别高危亲属作为可能的预防性治疗候选者具有重要意义。
