HLA CLASS-II (DR AND DQ) ANTIGEN ASSOCIATIONS IN IDIOPATHIC DILATED CARDIOMYOPATHY - VALIDATION-STUDY AND METAANALYSIS OF PUBLISHED HLA ASSOCIATION STUDIES

We previously reported antigen frequency differences for HLA-DR4 and HLA-DRw6 between idiopathic dilated cardiomyopathy (IDC) patients and healthy controls in a pilot study. To confirm these findings, we undertook an independent study with a prospective hypothesis regarding the frequencies of DR4 and DRw6; typing for a second family of class II antigens (HLA-DQ) was included because of the proximity of the DQ loci to the DR loci and the strong linkage disequilibrium between some of the DR and DQ alleles. Comparing a new consecutive series of IDC patients (n = 41) and healthy blood bank controls (n = 53), we confirmed an increase of DR4 antigen frequency in patients (49% versus 21%, p < 0.005). A trend toward decreased expression of DRw6 among patients was also noted (10% of patients versus 23% of controls). HLA-DQw4 was significantly elevated in patients compared with controls (27% versus 6%, p < 0.005; relative risk, 6.1; etiologic fraction, 0.22). We identified the combined DR4-DQw4 haplotype in five of 41 Caucasian IDC patients (12%) and none of 53 controls (p < 0.007). A comparison of specific antigen frequencies between the preliminary and validation studies did not reveal significant differences; therefore, the data from the two studies were examined in combination. For the combined studies, DR4 was elevated (51% versus 27% in controls, p < 0.001), and DRw6 was decreased (9% versus 24% in controls, p < 0.01). The relative risk for DR4 was 2.8, and the etiologic fraction was 0.33. In this study, the DR4-DQw4 haplotype bears an indeterminately high risk for disease; the presence of DR4, DQw4, or both antigens was found in 26 of 41 ID C cases (63%) compared with 14 of 53 controls (26%) (p < 0.001). Meta-analysis of the exploratory and validation studies in combination with all reported studies comparing the frequency of HLA-DR antigens in IDC patients and controls was performed. This overview indicated that for all five studies, there is a significant increase in the frequency of HLA-DR4 in cases of IDC (overall odds ratio, 2.06; 98% confidence interval, 1.61-2.65; p < 0.0001). In conclusion, we have verified HLA-DR4 involvement in IDC and suggested an additional association with DQw4. The meta-analysis of reported studies confirms that the DR4 association can be replicated in several different patient populations. Thus, in a portion of IDC cases, predisposing genetic factors linked to immunoregulatory loci appear to be present.