Association of HLA class II DRB1, DPA1 and DPB1 polymorphism with genetic susceptibility to idiopathic dilated cardiomyopathy in Chinese Han nationality

Abstract

Although the aetiology of idiopathic dilated cardiomyopathy (IDC) remains unclear, many immunological abnormalities involving changes in cell-mediated and humoral immunity may be associated with cardiac impairment in IDC. Autoimmune mechanisms are likely to participate in the pathogenesis of at least a subgroup of IDC and components of the major histocompatibility complex may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class II genes, which are highly polymorphic, play an important role in the activating of immune responses and thus control the predisposition for or protection from IDC. This study explores the possible contribution of HLA-DRB and DP polymorphisms to IDC susceptibility. DNA genotyping for HLA-DRB1, DPA1 and DPB1 was performed using polymerase chain reaction-sequencing based typing (PCR-SBT) method in 198 IDC patients and 136 random selected healthy Han ethnic individuals living in Northern China. IDC patients were, sub-grouped into asymptomatics (subgroup A), with arrhythmia (subgroup B) and with overt congestive heart failure (subgroup C) according to the clinical manifestations and electrocardiogram or echocardiographic characteristics. ADP/ATP autoantibody was detected in IDC group by immunoblot analysis. The results revealed that HLA-DR15, -DPB*0601 frequencies were significantly elevated in IDC group compared with normal control. The DPB1*0601 allele in homozygous form or in combination with allele DPB1*2301 or *3901, was found present more often in IDC patients. The predominance of HLA-DR4 allele was observed in subgroup B after stratification. However, the frequency of DPB1*0101 allele increased in the control than in the IDC group. The frequency of HLA-DPB1*0601 allele was significantly higher in IDC patients with positive autoantibody against ADP/ATP carrier of myocardial mitochondria in contrast to those with negative autoantibody. We conclude that HLA-DR4, -DR15, -DPB1*0601 alleles confers susceptibility to, while DPB1*0101 allele confers protection from IDC among individuals of northern Chinese Han nationality. The glutamate at position 69 in the second exon of DPB1*0601, as a key residue for special conformation of HLA-DP, may confer predisposition to IDC. HLA-DR and -DP alleles polymorphisms may serve as genetic markers for IDC and be involved in the regulation of the immune specific response to auto or exterior anti-myocardium antibodies.

Cardiac Autoimmunity: Myocarditis

“…Specifically, HLA-DR4 is statistically associated with DCM based on retrospective studies [90–92]. Other DCM-HLA-positive associations had been reported, mainly HLA-DR12, DR15, and DRB*0601, as well as negative associations (HLA-DR11, DQB1*0301) [93–95]. …”

14 bp deletion polymorphism in the HLA‐G gene is a risk factor for idiopathic dilated cardiomyopathy in a Chinese Han population

“…Previous evidence suggested that genetic susceptibility to IDC is linked to HLA class II alleles, particularly the HLA-DR4 seems to be associated with a high risk (23). However, results remain inconsistent and discrepant among different studied populations, such as HLA-DQA1*0501, HLA-DQB1*0303, and HLA-DPB1*0601 had been observed as a susceptible factor for the IDC in northern China (5,8), while in Mexican, HLA-DQB1*0301 and HLA-DQB1*0302 was found to be positively related to the IDC (7).…”

“…A large number of genetic studies have been carried out and addressed that various candidate genes such as alleles of HLA-DP, HLA-DQ, and HLA-DR in HLA class II gene may predispose to the pathogenesis of IDC. These studies indicated that abnormal expression of the HLA class II on cardiac endothelium was one of important autoimmune features in IDC, especially HLA-DR4 antigen seems to be associated with a high risk (5)(6)(7)(8)(9).…”

Susceptible and protective associations ofHLA DRB1*/DQB1* alleles and haplotypes with ischaemic stroke

“…Previous studies have demonstrated that genes linked to HLA‐DR molecules may contribute to the aetiological process of cardiac and cerebral damage (Zou et al ., ; Liu et al ., ; Zhang et al ., ). A review on immunogenetic susceptibility of atherosclerotic stroke reported the occurrence of microbial interactions with MHC antigens, TcR, cytokines and a number of systemic markers in the formation of atherosclerotic plaque in brain leading to stroke (DeGraba, ).…”