Kubryn Izabela, Młynarski Wojciech, Trippenbach-Dulska Hanna, Szalecki Mieczysław, Lisowicz Lucyna, Surdej Barbara, Pilecki Olgierd, Heinrich Agnieszka, Wyka Krystyna, Perenc Małgorzata, Bodalski Jerzy
Klinika Chorób Dzieci, Instytut Pediatrii, Akademia Medyczna, ul. Sporna 36/50, 91-738 Łódź, Poland.
Med Wieku Rozwoj. 2003 Apr-Jun;7(2):157-64.
The HLA complex, located on the short arm of chromosome 6, is the strongest genetic marker for type 1 diabetes (T1DM). In previous study we demonstrated association between genes HLA-DRB1 and HLA-DQB1 and T1DM in the Polish population. There is a strong-independent association of alleles HLA-DRB10401 and DQB1302, despite population linkage disequilibrium among alleles of these genes. The aim of the current study was to verify a hypothesis that some alleles or haplotypes of HLA-DRB1, DQA1 and DQB1 genes increase the risk for familiar aggregation of T1DM. We analysed 507 patients with IDDM derived from 80 multiplex and 325 patients from simplex families. PCR and hybridisation with SSO probes performed HLA typing for DRB1, DQA1 and DQB1 alleles. Genetic analysis demonstrated strong association of allele HLA-DQB10302 with T1DM in the Polish population in families with single (DM1) and more numerous cases (DM2) cases, compared with healthy cases (n=103). The HLA-DQB1302 allele frequencies were 27.8% vs 8.7%; Pc<10(-5); OR(95%CI)=4,03(3.80-4.25) and 16.3% vs 8.7%; Pc<0.04; OR(95%CI)=2.04(1.79-2.89), respectively. The presence of allele HLA-DQB10602 has a strong protective effect from T1DM in both studied groups (1.46% vs. 13.6%; Pc<10(-5); OR(95%CI)=0.09(-0.25-0.44) and 0.98% vs. 13.6%; Pc<10(-5); OR(95%CI)=0.06(-0.46-0.58), respectively. Interestingly, HLA-DRB104 allele more often co-segregated with DM2 families as comparing the DM1 group (31.0% vs. 15.8%, respectively; Pc<10(-5)). However in both cases differences remain significant as compared to controls: Pc<10(-5), OR (95%CI)=3.52(3.33-3.70) and Pc<10(-5) OR(95%CI)=6.17(5.97-6.37), for DM1 and DM2 respectively. Subtyping of HLA-DRB104 alleles demonstrated that the strongest predisposing effect has been identified with DRB10401. Moreover, difference in frequencies of the protective allele HLA-DQB1*0301 among DM1 and DM2 group was revealed (8.8% vs. 13.7%, respectively; Pc<10(-5)) and the protective effect of this allele remained only significant in DM1 group: 8.8% vs. 19.9%; Pc<10(-5); OR(95%CI)=0.39(0.19-0.58). The results suggest that it is likely that familial aggregation of T1DM is associated with lower frequency of protective alleles of HLA-DQB1 gene.
位于6号染色体短臂上的HLA复合体是1型糖尿病（T1DM）最强的遗传标记。在先前的研究中，我们证明了波兰人群中基因HLA - DRB1和HLA - DQB1与T1DM之间的关联。尽管这些基因的等位基因之间存在群体连锁不平衡，但等位基因HLA - DRB10401和DQB1302之间存在强独立关联。本研究的目的是验证一个假设，即HLA - DRB1、DQA1和DQB1基因的某些等位基因或单倍型会增加T1DM家族聚集的风险。我们分析了来自80个多病例家庭的507例胰岛素依赖型糖尿病（IDDM）患者和来自单病例家庭的325例患者。通过PCR和与SSO探针杂交对DRB1、DQA1和DQB1等位基因进行HLA分型。遗传分析表明，与健康对照（n = 103）相比，在波兰人群中，等位基因HLA - DQB10302在单病例（DM1）和多病例（DM2）家庭的T1DM患者中均有强关联。HLA - DQB1302等位基因频率分别为27.8%和8.7%；Pc<10(-5)；OR(95%CI)=4.03(3.80 - 4.25)以及16.3%和8.7%；Pc<0.04；OR(95%CI)=2.04(1.79 - 2.89)。等位基因HLA - DQB10602的存在对两个研究组的T1DM均有很强的保护作用（分别为1.46%对13.6%；Pc<10(-5)；OR(95%CI)=0.09(-0.25 - 0.44)以及0.98%对13.6%；Pc<10(-5)；OR(95%CI)=0.06(-0.46 - 0.58)）。有趣的是，与DM1组相比，HLA - DRB104等位基因在DM2家庭中更常共分离（分别为31.0%对15.8%；Pc<10(-5)）。然而，在两种情况下，与对照组相比差异仍然显著：DM1组和DM2组的Pc<10(-5)，OR(95%CI)分别为3.52(3.33 - 3.70)和6.17(5.97 - 6.37)。HLA - DRB104等位基因的亚型分析表明，DRB10401具有最强的易患效应。此外，还揭示了DM1组和DM2组中保护性等位基因HLA - DQB1*0301频率的差异（分别为8.8%对13.7%；Pc<10(-5)），并且该等位基因的保护作用仅在DM1组中显著：8.8%对19.9%；Pc<10(-5)；OR(95%CI)=0.39(0.19 - 0.58)。结果表明，T1DM的家族聚集可能与HLA - DQB1基因保护性等位基因的低频率有关。
