HLA-DR3 antigen in the resistance to idiopathic dilated cardiomyopathy

Brazilian Journal of Medical and Biological Research (2016) 49(4): e5131, http://dx.doi.org/10.1590/1414-431X20165131 ISSN 1414-431X 1/5 HLA-DR3 antigen in the resistance to idiopathic dilated cardiomyopathy B. Jin*, B.W. Wu*, Z.C. Wen, H.M. Shi and J. Zhu Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China Abstract Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR3 antigen and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Studies were identified by searching the PUBMED and Embase database (starting from June 2015). A total of 19 case-control studies including 1378 cases and 10383 controls provided data on the association between HLA-DR3 antigen and genetic susceptibility to IDC. Overall, significantly decreased frequency of HLA-DR3 allele (OR=0.72; 95%CI=0.58–0.90; P=0.004) was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non-biopsy cases, statistically decreased risk was found for IDC in myocardial biopsy cases (OR=0.69; 95%CI=0.57–0.84; P=0.0003). In the subgroup analysis by ethnicity, borderline statistically significantly decreased risk was found among Europeans from 12 case-control studies (OR=0.76; 95%CI=0.58–1.00; P=0.05). In conclusion, our results suggest that individuals with HLA-DR3 antigen may have a protective effect against IDC. Key words: HLA-DR; Dilated cardiomyopathy; Polymorphism; Meta-analysis Introduction Idiopathic dilated cardiomyopathy (IDC) is the third most common cause of heart failure characterized by ventricular dilatation and impaired myocardial contractility (1). This multifactorial disease, although closely related to viral and immunologic mechanisms, is also influenced by the complex pattern of inheritance (2). New genetic markers for identifying high-risk populations as well as novel strategies for early detection and preventive care are urgently needed. In the past decades, a growing number of studies suggested that human leukocyte antigen (HLA)-DR was emerging as a low-penetrant risk factor in the development of IDC. However, the association between HLA-DR3 and IDC risk has been less well characterized. Therefore, this study aimed to derive a more precise estimation of this association by subgroup analysis. Material and Methods Study search strategy Case-control studies were identified from PubMed and Embase database in June 2015 using both electronic and manual search strategies. We combined search terms ‘‘HLA-DR’’, ‘‘polymorphism’’, and ‘‘dilated cardiomyopathy’’, and we restricted our search to human populations. When more than one study from the same patient population was published, only the most recent or complete study was selected for this meta-analysis. Inclusion criteria We identified eligible articles on the basis of 3 inclusion criteria: 1) case-control studies, 2) evaluation of HLADR3 antigen in IDC risk, and 3) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI). Data extraction Two reviewers (B.J. and B.W.W.) independently extracted data from all selected studies fulfilling inclusion criteria. Disagreement was resolved by discussion between the two reviewers. If these two authors could not reach a consensus, another author (Z.C.W.) was consulted to resolve the dispute and a final decision was made by voting. Data extraction included the first author’s surname, publication date, region of origin, ethnicity, myocardial biopsy, source of controls, and demographic data. Data that were not provided in tabular form or in the main text were obtained from online data appendix or from supplementary material. Correspondence: H.M. Shi: <> | J. Zhu: <> *These authors contributed equally to this study. Received September 19, 2015 | Accepted January 19, 2016 Braz J Med Biol Res | doi: 10.1590/1414-431X20165131 HLA-DR3 antigen and idiopathic dilated cardiomyopathy 2/5 Statistical analysis The Cochrane Collaboration meta-analysis methodology was used for this study. Crude ORs with 95%CIs were used to assess the strength of association between HLADR3 antigen and IDC risk. The presence of heterogeneity across trials was evaluated, and Pp0.10 was considered to be significant for statistical heterogeneity. All statistical tests were performed with RevMan version 4.2.2 available free from the Cochrane Collaboration website (http://www. cochrane.org/cochrane/hbook/htm). Results Study characteristics A total of 19 case-control studies including 1378 cases and 10383 controls met the inclusion criteria (3–21). Table 1 lists the eligible studies and their main characteristics. Of the 19 studies, sample sizes ranged from 117 to 2703. Controls were mainly healthy populations and matched for ethnicity and area. Diagnosis of IDC was primarily based on the World Health Organization (WHO) criteria by a panel of clinical cardiologists (22,23). Main results Table 2 presents the pooled ORs of this meta-analysis. Overall, significantly decreased frequency of HLA-DR3 allele (OR=0.72; 95%CI=0.58–0.90; P=0.004; Figure 1) was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non-biopsy cases, statistically decreased risk was found for IDC in myocardial biopsy cases (OR=0.69; 95%CI=0.57–0.84; P=0.0003). In the subgroup analysis by ethnicity, significantly decreased risks were found among Europeans (OR=0.76; 95%CI=0.58–1.00; P=0.05; Figure 2) and Asians (OR=0.65; 95%CI=0.46–0.92; P=0.01). Sensitivity analysis Sensitivity analysis was performed by re-running the meta-analysis removing a single study each time to reflect Table 1. Main characteristics of case-control studies included in the meta-analysis. Reference Year Region Ethnicity Sample size Myocardial Source of controls (case/ control) biopsy Agarwal et al. (3) Anderson et al. (4) 1996 1984 Oman USA Arab Caucasian 50/209 35/82 No Yes Arbustini et al. (5) 1989 Italy Italian 50/400 Yes Caforio et al. (6) 1992 Italy Caucasian 80/289 Yes Carlquist et al. (7) 1991 USA Caucasian 76/135 Yes Carlquist et al. (8) 1994 USA Caucasian 43/236 Yes Grant et al. (9) Harcombe et al. (10) Komajda et al. (11) Limas et al. (12) Liu et al. (13) Lozano et al. (14) Mahjoub et al. (15) Maharaj et al. (16) Nishi et al. (17) Osa et al. (18) Rodríguez-Pérez et al. (19) Wang et al. (20) 1994 1999 1987 1989 2006 1997 2010 1990 1995 1999 2007 England UK France USA China Canada Tunisia South Africa Japan Spain Mexico 98/857 161/2041 49/2654 102/511 136/198 32/93 76/111 57/412 78/336 50/1337 53/99 Yes Yes Yes No No Yes No No Yes Yes No 2000 China Caucasian Caucasian Caucasian Caucasian Chinese Caucasian Arab African Japanese Spanish Mexican Mestizo Chinese 68/175 No Zerbe et al. (...truncated)