HLA‐DQA1, ‐DQB1 Polymorphism and Genetic Susceptibility to Idiopathic Dilated Cardiomyopathy in Hans of Northern China

Abstract

SummaryAutoimmune mechanisms are likely to participate in the pathogenesis of at least a subgroup of idiopathic dilated cardiomyopathy (IDC), and components of the major histocompatibility complex (MHC) may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class II genes, especially HLA-DQ genes, which are highly polymorphic, play an important role in the activation of immune responses and thus control the predisposition to, or protection from, IDC. This study was conducted to investigate the association of HLA-DQA1, -DQB1 allele polymorphisms with an autoantibody against the myocardial mitochondria ADP/ATP carrier, and to explore susceptibility to idiopathic dilated cardiomyopathy (IDC) among the Han ethnic group in northern China and the immunological mechanisms and hereditary susceptibility to IDC. Polymerase chain reaction sequence-specific primer (PCR-SSP) techniques were used to analyze polymorphisms of the second exon of HLA-DQA1 and -DQB1 alleles among 68 unrelated IDC patients, 4 probands of IDC pedigrees, and 100 healthy controls, all of Han nationality and having lived in northern China for a long time. Following echocardiography examination the IDC subjects were stratified according to ejection fraction (EF) values. Those with EF values higher than 50% were placed in subgroup 1, subgroup 2 included the patients with an EF value of 15-35%, and subgroup 3 consisted of those whose EF values were less than 15%. An autoantibody against the myocardial mitochondria ADP/ATP carrier was examined using immunoblot analysis. The frequencies of HLA-DQA1 * 0501 and HLA-DQB1 * 0303 were 0.3889 and 0.1806 in the IDC group, significantly higher than those of the healthy controls (0.0900 and 0.0364 respectively, both P < 0.05). The OR was 5.20 (95% CI: 3.60-8.50) and 4.85 (95% CI: 2.56-9.39) respectively. Further analysis of the three subgroups showed a higher frequency of HLA-DQA1 * 0501 among patients whose EF was less than 15% than those whose EF values were ≥ 15%. Conversely, the frequencies of HLA-DQA1 * 0201 and -DQB1 * 0502, * 0504 were significantly lower in the IDC group (0.0139, 0.0139 and 0.0417 respectively) than in the control group (0.2000, 0.0727 and 0.1091 respectively) (P < 0.05). The frequency of the HLA-DQA1 * 0501 allele was significantly higher in IDC patients whose autoantibody is positive in contrast with those whose autoantibody is negative (18.57% vs. 5.86%, P < 0.05); the relative risk (RR) was 4.32. The other frequencies of HLA-DQA1 and -DQB1 alleles showed no significant difference in the antibody positive and negative groups of IDC patients.

Human leukocyte antigen-DQ beta 1 chain (DQB1) gene polymorphisms are associated with dilated cardiomyopathy: A systematic review and meta-analysis

“…[12][13][14][15][16][17][18][19][20][21][22][23][24] Of these, 1 study was performed for cases of familial dilated cardiomyopathy (FDC), 16 and the data could not be extracted from another study. 24 In addition, 1 study 17 was awaiting classification because we could not confirm whether the patients in that study were included in another similar study performed by the same first author.…”

“…18 The control individuals in these 2 studies were the same. In total, 10 case-control studies were therefore included in the meta-analysis, [12][13][14][15][18][19][20][21][22][23] and the included studies that examined the HLA-DQB1 *0201, *0504, *0301, *0302, and *0602 alleles comprised 8, 3, 9, 8, and 7, respectively. Table 1 lists the identified studies and their primary characteristics.…”

“…11,13 In recent years, the relationship between polymorphisms in the HLA-DQA1 and HLA-DQB1 genes and DCM has received much attention. [12][13][14][15][16][17][18][19][20][21][22][23][24] The present meta-analysis indicates that the frequencies of the HLA-DQB1 *0201 and *0504 alleles are greater in normal control subjects than in patients with DCM, suggesting that these 2 genes may confer h e a r t & l u n g 4 1 ( 2 0 1 2 ) 3 6 0 e3 6 7 protection against DCM. This result is consistent with a previous meta-analysis reporting that the HLA class II (DR and DQ) antigen was associated with DCM.…”

“…[8][9][10][11][12][13] The HLA class II genes, especially the HLA-DQ alleles (including HLA-DQ beta 1 chain [DQB1]), are highly polymorphic and may play an important role in the activation of immune responses, thereby potentially affecting an individual's predisposition to DCM. [12][13][14][15][16][17][18][19][20][21][22][23][24] However, the results of these studies have been inconsistent. In addition, because of the small number of samples in most of the relevant case-control studies, the statistical power of these previous results has been limited.…”

Contribution of Acquired Factors to the Pathogenesis of Dilated Cardiomyopathy - The Cause of Dilated Cardiomyopathy: Genetic or Acquired? (Acquired-Side) -

“…Interestingly, the presence of the polymorphism was associated with the presence of autoantibody directed against mitochondrial ADP/ATP carrier. 46 These types of polymorphisms have been reported in patients with myocarditis. 47 From these findings, it is hypothesized that polymorphisms of MHC class II genes may play a pivotal role in susceptibility to myocarditis and subsequent development of DCM by mechanisms of prolonged antigen presentation and persistent immune activation.…”