HLA-DRB1基因多态性与克山病及其核心家系的关系研究

目的探讨HLA-DRB1基因多态性在我国北方克山病地区的分布特征及其与克山病核心家系的关联和连锁。方法采用聚合酶链反应-序列特异性寡核苷酸探针(polymerase chain reaction-sequence specific oligonucleotide probing,PCR-SSOP)技术,对118例克山病(Keshan disease,KD)患者HLA-DRB1基因进行分型,其中潜在型KD63例,慢型KD55例,65名正常人为对照;采用单倍型相对风险(haplotype based haplotype relative risk,HHRR)和传递不平衡检验(transmission disequilibrium test,TDT)方法对该基因在18个KD核心家系中的分布进行关联和连锁分析。结果(1)在KD患者和对照人群中,HLA-DRB1位点共检出13种等位基因;(2)DR7等位基因在KD组中的分布频率显著低于对照组(P<0.01,OR=0.1695);(3)DR7等位基因在慢型KD中的分布频率显著低于对照组(P<0.01,OR=0.091),而在潜在型KD中的分布频率与对照组比较差异无统计学意义;(4)DR15等位基因与KD显著关联(χ2=9.32,P<0.01),并与KD易感位点连锁(χ2=7.40,P<0.01)。结论KD可能存在遗传易感性,HLA-DRB1的DR7等位基因可能是KD保护性基因,携带DR7等位基因的KD患者可能不易发展为慢型KD,DR15等位基因可能与KD易感基因连锁。

The study on relation of HLA-DRB1 gene polymorphism to Keshan disease and its association and linkage in the core families

OBJECTIVE: To investigate HLA-DRB1 gene polymorphism in patients with Keshan disease (KD) in the north of China, and its relation to KD in the core families. METHODS: Polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method was used to determine HLA-DRB1 genotypes in 118 KD patients, including 63 with latent KD and 55 with chronic KD. Sixty-five normal from the same area were selected as controls. The haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) methods were used to analyze the genetic association and linkage of HLA-DRB1 with KD in 18 KD core families. RESULTS: (1) Thirteen kinds of alleles of HLA-DRB1 gene were found in all patients and the controls. (2) The distributive frequency of DR7 allele was significantly lower in chronic KD patients than that in controls (P< 0.01, OR is 0.1695). (3) The distributive frequency of DR7 allele was statistically lower in chronic KD (P< 0.01, OR is 0.091) and showed no differences in latent KD patients as compared with the controls. (4) DR15 allele of HLA-DRB1 gene showed significant association (chi square is 9.32, P< 0.01) and linkage (chi square is 7.40, P< 0.01) with KD patients in the core families. CONCLUSION: The results show that there might be the genetic susceptibility in the pathogenesis of KD. DR7 allele of HLA-DRB1 gene might be the protective gene of KD. Patients with DR7 allele might be more difficult to become to chronic KD. DR15 allele of HLA-DRB1 gene might be linked to the susceptive site of KD.