Noble J A, Valdes A M, Cook M, Klitz W, Thomson G, Erlich H A
Department of Human Genetics, Roche Molecular Systems, Alameda, USA.
Am J Hum Genet. 1996 Nov;59(5):1134-48.
We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB10302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB10302 and DQB10301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB11501-DQB10602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB11601-DQB10502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB10301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB10101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB10301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.
我们在此报告了对180个白种人核心家庭的HLA - II类等位基因的分析，这些家庭中至少有两个患有胰岛素依赖型糖尿病（IDDM）的孩子。采用聚合酶链反应/序列特异性寡核苷酸探针分型方法确定了DRB1、DQA1、DQB1和DPB1基因型。除三个家庭外，这些数据能够明确确定所有家庭的四位点单倍型。与其他研究一致，我们的数据表明，与对照组相比，患者中DR3/DR4、DR3/DR3和DR4/DR4基因型有所增加。此外，我们还发现DR1/DR4、DR1/DR3和DR4/DR8基因型有所增加。虽然在DR3/DR4患者中，DR4单倍型上DQB10302的频率显著增加，但DR1/DR4患者中DR4单倍型的DQB10302和DQB10301频率与对照人群更为相似。DR2的保护作用在该数据集中很明显，且仅限于常见的DRB11501 - DQB10602单倍型。大多数DR2 +患者携带较不常见的DR2单倍型DRB11601 - DQB10502，相对于对照组，患者中该单倍型并未减少。DPB1似乎也在疾病易感性中起作用。患者中DPB10301增加（P <.001），可能会增加多种不同DR - DQ单倍型的疾病风险。DPB10101在患者中几乎仅见于DR3单倍型，略有增加，且DRB10301 - DPB1*0101单倍型从母亲向受影响孩子的传递频率是从父亲传递频率的两倍。携带其他DPB1等位基因的DR3单倍型的传递在母亲和父亲中的频率大致相等。从这些数据中可以明显看出HLA - II类相关的IDDM易感性具有复杂的多基因性质。
