HLA-DPB1*0501 is associated with susceptibility to anti-aquaporin-4 antibodies positive neuromyelitis optica in Southern Han Chinese
Introduction
Neuromyelitis optica (NMO) and multiple sclerosis (MS) are inflammatory demyelinating diseases of the central nervous system (CNS). Most NMO and MS cases present a unique relapsing–remitting clinical course (Wingerchuk et al., 2007). NMO was once considered to be a severe variant of MS. However, in 2004, serum anti-aquaporin-4 antibodies (AQP4-Ab, NMO-IgG) were suggested to be a reliable biomarker of NMO (Lennon et al., 2004). The cause and pathogenesis of NMO and MS are still unclear. Multiple factors, including genetic and environmental factors, may influence susceptibility to these diseases. The prevalence of MS in Asians is lower than in Western countries (Cheng et al., 2010), and lesions confined to the optic nerve and spinal cord are relatively common in Asian MS patients (Kira et al., 1999, Cheng et al., 2008, Chen et al., 2010). In Japan, there are two subtypes of MS: relapsing NMO is called as the optic-spinal form of MS (OS-MS) (Misu et al., 2008) and differs from the conventional MS (C-MS) form (Matsushita et al., 2009).
The main genetic susceptibility locus for MS is the Human Leukocyte Antigen (HLA)-DRB1 locus within the major histocompatibility complex (MHC) class II region (Etzensperger et al., 2008, Ramagopalan et al., 2008, Zuvich et al., 2009). In most Europeans, African Americans, Australians, and Japanese, DRB1*1501 has been consistently associated with susceptibility to MS (Ebers et al., 1996, Ono et al., 1998, Masterman et al., 2000), and the DRB1*1501-DQA1*0102-DQB1*0602 haplotype is particularly associated with MS in these populations (Marrosu et al., 1998, Ghabaee et al., 2009). Research in India revealed that DRB1*15 was associated with MS, not DRB1*1501 alone (Kankonkar et al., 2003). However, other studies in Asian populations reported that the frequencies of DRB1*1501 in MS patients were no different to those in controls (Kelly et al., 1995, Amirzargar et al., 1998, Karni et al., 1999), and DPB1*0501 might play an important role in the development of Chinese C-MS (Wu et al., 2009) and Japanese OS-MS (Yamasaki et al., 1999), especially in AQP4-Ab positive OS-MS (Fukazawa et al., 2006, Matsushita et al., 2009). In China, because of the small sample sizes of studies, HLA typing methodological limitations, and the absence for detecting AQP4-Ab, which HLA-DRB1 and -DPB1 alleles are associated with NMO and C-MS in Southern China remain unclear.
The aims of the present study were to investigate HLA-DRB1 and -DPB1 alleles in Southern Han Chinese NMO and C-MS cases. We sought to clarify which HLA-DRB1 and -DPB1 alleles are associated with AQP4-Ab positive NMO and C-MS.
Section snippets
Patients and controls
Thirty AQP4-Ab positive NMO patients (23 women, 7 men) were selected based on the 2006 Wingerchuk criteria (Wingerchuk, 2006), whose mean ages at onset were 28.37. Fifty-three (31 women, 22 men) C-MS patients fulfilling the 2001 McDonald criteria were enrolled and their mean ages at onset were 31.68. These patients were all enrolled from the MS database of the Third Affiliated Hospital of Sun yat-sen University between November 2007 and December 2010. Patients with only recurrent myelitis,
Statistical analyses
The Hardy–Weinberg equilibrium (HWE) was initially determined. Statistical analysis was then performed using SPSS 16.0 (SPSS Inc, Chicago, IL, USA) for Windows. Pearson chi-square test or Fisher's exact test was used to compare phenotype frequencies of each HLA-DPB1 and -DRB1 alleles between NMO, C-MS, and CTLs. The relative risk (estimated as the odds ratios, ORs) and 95% confidence intervals (95% CIs) were calculated. The P values (uncorrected P, Puncorr) were corrected by Bonferroni–Dunn's
Results
As shown in Table 1, the frequency of the DRB1*0901 allele was lower in NMO patients than in CTLs (Puncorr = 0.022, OR: 0.194, 95% CI: 0.043–0.876), and DRB1*1602 was higher in NMO patients than in C-MS (Puncorr = 0.038, OR: 3.491, 95% CI: 1.024–11.896) and CTLs (Puncorr = 0.051, OR: 2.711, 95% CI: 0.971–7.556). As shown in Table 2, the frequency of the DPB1*0501 allele was significantly higher in NMO patients than in C-MS (Puncorr = 0.018, OR: 4.629, 95% CI: 1.235–17.350) and CTLs (Puncorr = 0.001, Pcorr
Discussion
In this case-control study of HLA class II (DRB1 and DPB1) alleles distribution in Southern Han Chinese NMO and C-MS patients, we found that HLA associations with NMO and MS were different in this population.
Despite the fact that a number of genes have been identified that have an effect on the susceptibility to MS, the HLA region is generally recognized as having the strongest risk. DRB1*1501 is the main risk allele associated with Western MS populations (Ramagopalan and Ebers, 2008) and
Acknowledgments
The authors wish to thank Huada Gene (Shenzhen) for helping us on HLA-typing. This study was supported by the Sun Yat-sen University Clinical Research 5010 Program (grant number 2007027) and the Technology Project of Guangzhou City (No. 2060402).
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