台灣僵直性脊椎炎病人第一型和第二型主要組織抗原對偶基因相關性之探討

Distinct MHC class I and class II alleles in Taiwanese patients with ankylosing spondylitis

目的：我們嘗試去探討僵直性脊椎炎（Ankylosing spondylitis, AS）病人致病基因除了HLA-B27人類白血球抗原之外，其它人類第一型和第二型主要組織抗原是否與疾病病理機轉有關。材料和方法：我們使用序列特異引子聚合酶連鎖反應的DNA序列鑑定法（PCR-SSP DNA typing）分析兩群病人的HLA class I and class II 組織抗原。第一群是130位患有僵直性脊椎炎且HLA-B27皆陽性的病人，第二群是260位HLA-B27陽性的健康人。我們使用卡方檢定法或費氏精確檢定法來分析其勝算比。結果：患有HLA-B27陽性僵直性脊椎炎這群病人其對偶基因Cw12（93.85%）、Cw7 （20.0%）、Cw8（9.23%）出現頻率明顯增加，相對的在HLA-B27陽性健康人卻是Cw3（80.0%）頻率有意義的增加。對偶基因B75（6.15%）、B60（20.0%）、B61（4.62%）在HLA-B27陽性僵直性脊椎炎病人出現較高的頻率，相對於HLA-B27陽性健康人其B13（22.31%）、B58（36.15%）卻有較高的頻率發生。這兩族群人所擁有的對偶基因差異性皆有統計學上的意義。A11/B27/Cw3（70.0%）最常出現在HLA-B27陽性健康人；相對的，A11/B27/Cw12（78.5%）是最常出現在HLA-B27陽性僵直性脊椎炎病人。A33/B58/Cw3常出現在HLA-B27陽性僵直性脊椎炎病人與HLA-B27陽性健康人，各佔20.0%和21.54%。這些關係解釋了為何對偶基因（A11/A33, B27/B58, Cw3/Cw12, DR12/DR13, DR17）在HLA-B27陽性僵直性脊椎炎病人身上有較高的頻率（15.4%），而HLA-B27陽性健康人身上其對偶基因（A11/A33, B27/B58, Cw3/Cw3, DR12/DR13, DR17）有較高的發生頻率（15.38%）。HLA-DR15以及DQ2與脊椎炎也有弱相關。 結論：A11/B27/Cw12 對偶基因跟HLA-B27陽性的僵直性脊椎炎病人有密切的關係，而A11/B27/Cw3卻是跟HLA-B27陽性的健康人有密切關係。這同時說明除了HLA-B27外，其他MHC對偶基因可能與僵直性脊椎炎的風險性有密切關係。

Objective: Our purpose was to investigate whether MHC class I and class II antigens, other than B27, were associated with Taiwanese patients with ankylosing spondylitis (AS). Methods: HLA class I and class II antigens were analyzed in B27 positive AS patients (n = 130) and B27 positive healthy controls (n = 260) using the SSP-DNA typing method. The chi-square test or Fisher's exact test was used to analyze Odds ratio. Results: Allele frequencies of Cw12 (93.85%), Cw7 (20.0%) and Cw8 (9.23%) were found to be significantly increased in AS patients as compared to B27 positive controls (OR 89.09, p<0.0001; OR 6.25, p<0.0001; OR 13.12, p<0.0001, respectively), in which Cw3 (80.0%) was significantly increased (OR 0.12, p<0.0001). Allele frequencies of B75 (6.15%), B60 (20.0%) and B61 (4.62%) were higher in patients (OR 8.46, p=0.003; OR 2.07, p=0.0128; OR 6.24, p=0.0186, respectively), so as higher frequencies of B13 (22.31%) and B58 (36.15%) in controls (OR 0.03, p<0.0001, and OR 0.44, p=0.0011). A11/B27/Cw3 was the most common alleles in controls (70.0%) (OR 0.11, p<0.0001), in contrast to A11/B27/Cw12 in AS patients (78.5%) (OR 21.28, p<0.0001). Furthermore, A33/B58/Cw3 was commonly found both in patients and controls groups (20.0% and 21.54%, respectively) (OR 0.91, p=0.83). The association explained the high allele frequencies of A11/A33, B27/B58, Cw3/Cw3, DR12/DR13, DR17 in B27(+) controls (15.38%) (p<0.0001) and A11/A33, B27/B58, Cw3/Cw12, DR12/DR13, DR17 in AS patients (15.4%) (p<0.0001). The power of association between AS and HLA-DR15 and DQ2 were found to be low, although significant (p=0.0411 and p=0.0467, respectively). Conclusions: Alleles of A11/B27/Cw12 was closely associated with HLA-B27-positive AS patients, so as A11/B27/Cw3 in B27-positive controls. Our findings are compatible with the hypothesis that alleles of MHC other than B27 may confer further risk to susceptibility of AS.