Interaction of loci within the HLA region influences multiple sclerosis course in the Sardinian population

We examined the influence of alleles at the HLA loci, previously found to be associated with multiple sclerosis (MS) in Sardinia, on the clinical course of the disease in 835 relapsing (R) and 100 primary progressive (PP) patients. Multivariate analysis was carried out on predisposing 0301 or non–associated DPB1 alleles, susceptible or non–associated DRB1–DQB1 haplotypes, both predisposing and non–predisposing, and negatively and non–negatively associated D6S1683 alleles, taking interaction between them into account. Intra–patient analysis showed that the presence of the susceptible or protective D6S1683 allele interacting with predisposing DP 0301 modulated risk of PP disease. These findings suggest that a locus telomeric to HLA class I exerts an effect on alleles at the DPB1 locus in modulating disease course.     

Genomic HLA profiles of MS in Hokkaido, Japan: important role of DPB1*0501 allele

The polymorphism of the HLA class II genes was investigated in 97 patients with multiple sclerosis (MS) in Hokkaido, the northernmost main island of Japan. Of these, 80 patients were classified as having conventional MS and 17 as having opticospinal MS (OS-MS). Our findings confirmed a previous report that the DPB 1*0501 allele is positively associated with OS-MS (P = 0.0043). The frequency of DPB 1*0501 was also found to be higher in conventional MS patients than in controls (79% vs. 58%, P = 0.0084), although the differences were not statistically significant. Our results indicate that OS-MS is a DPB 1*0501-associated subgroup of MS, and that DPB1*0501 is also correlated with risk of conventional MS in Japanese.     

HLA-dPB1*0501 is not uniquely associated with opticospinal multiple sclerosis in Japanese patients. Important role of DPB1*0301

Apart from its unique lesion distribution pattern, the opticospinal form of multiple sclerosis (OSMS) is distinct among Japanese patients who satisfy the diagnostic criteria of MS. OSMS has been suggested to be strongly associated with HLA-DPB1*0501 in Japanese. However, association of DPB1*0301 with non-OSMS and lack of DPB1*0301 in OSMS were also reported. To verify the role of DPB1*0501 and DPB1*0301 in Japanese MS patients we determined the frequencies of these alleles in 26 patients with OSMS, 167 with non-OSMS and 156 normal subjects, who were all residents of Hokkaido, the northernmost island of Japan. All (100%) OSMS were negative for DPB1*0301 while 32 (19%) of the non-OSMS were positive for the allele. In DPB1*0301-negatives, the frequencies of DPB1*0501 in OSMS (85%) and non-OSMS (82%) were similar, but both were higher than in the controls (66%). In DPB1*0301-positives, the frequency of DPB1*0501 was low but similar in non-OSMS (12/32; 38%) and controls (6/14; 43%). Periventricular white matter lesions (PVL) were noted in 31 of 32 (97%) DPB1*0301-positive non-OSMS patients but in only 22 out of 135 (16%) DPB1*0301-negative non-OSMS patients and two out of 26 (8%) OSMS patients. Our findings indicate that DPB1*0501 plays an important role in the development of MS in general, but not in OSMS. The strong association of DPB1*0501 with OSMS may be due to the over-representation of the DPB1*0301 allele among individuals in the non-OSMS group. In addition, DPB1*0301 might be relevant to the development of periventricular lesions in Japanese patients with MS.     

A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients

The association of multiple sclerosis with alleles/haplotypes from the HLA region on chromosome 6p21 is well established although the remainder of the genome remains relatively unexplored. We have completed a genome-wide screen for linkage disequilibrium in a cohort of Australian multiple sclerosis patients positive for HLA-DRB1*1501. A total of 4346 microsatellite markers provided through the "Genetic Analysis of Multiple sclerosis in EuropeanS" (GAMES) collaborative were analysed in DNA separately pooled from cases (n=217) and controls (n=187). Associations were found in four genomic regions (12q15, 16p13, 18p11 and 19q13) previously identified in linkage genome screens. Three additional regions of novel association were also identified (11q12, 11q23 and 14q21). Further analysis of these regions is required to establish whether the associations observed are due to epistatic interaction with the HLA locus.     

Association of HLA and T-cell receptor gene polymorphisms with Semple rabies vaccine-induced autoimmune encephalomyelitis.

Semple rabies vaccine is derived from brain tissue infected with rabies virus that is subsequently inactivated with phenol. Semple rabies vaccine-induced autoimmune encephalomyelitis (SAE) occurs in 1 in 220 immunized individuals. The immune response to myelin basic protein and pathological changes of demyelination in SAE suggest that this disease is the human homologue of experimental autoimmune encephalomyelitis (EAE). SAE and EAE are frequently studied as models for the human demyelinating disease multiple sclerosis. Major histocompatibility complex (MHC) class II and T-cell receptor (TCR) gene polymorphisms play important roles in rodent susceptibility to EAE and were analyzed to determine if the same was true in humans with SAE. HLA-DRB1, HLA-DQB1, and TCRBV gene polymorphisms were studied in Thai individuals with SAE (n = 18), with vaccination without neurological complications (n = 43), and without vaccination (n = 140). The allele frequencies of HLA-DR9 (DRB1*0901) and HLA-DR17 (DRB1*0301) were increased in SAE patients (DR9 = 22%, DR17 = 14%) compared with vaccinated controls (DR9 = 13%, DR17 = 6%) and with unvaccinated controls (DR9 = 9%, DR17 = 4%). The allele frequency of HLA-DQ7 (DQB1*0301) was decreased in SAE patients (8%) compared with vaccinated controls (15%) and with unvaccinated controls (25%). These susceptibilities are distinct from those associated with multiple sclerosis. The frequencies of TCRBV alleles and haplotypes were similar in SAE patients and vaccinated controls. These data suggest that genetic susceptibility associated with MHC class II alleles may have a role in the pathogenesis of SAE and its mechanism may be different from those involved in multiple sclerosis.     

94例缺血性脑卒中患者HLA基因表达分析

目的 探讨人类白细胞抗原(HLA)基因遗传与缺血性脑卒中发病的关联.方法 采用聚合酶链反应-直接测序分型技术(PCR-SBT)对广东医学院附属南山医院2008年收治的94例缺血性脑卒中患者和同期122例正常对照者进行HLA-A、B、DRB1位点的等位基因分型.结果 缺血性脑卒中患者表达HLA-A位点16个等位基因,HLA-B位点32个等位基因,HLA-DRB1位点25个等位基因.患者组HLA-A*1102基因频率较对照组明显降低,HLA-A*1102与缺血性脑卒中呈负相关(RR=0.06,P=0.019).结论 JLA-A*1102与缺血性脑卒中呈易感负相关,提示HLA等位基因与缺血性脑卒中的发生存在遗传免疫关联,对该病具有临床预测意义.

Abstract：

Objective To discuss the relationship between human leukocyte antigen (HLA) gene heredity and morbidity of cerebral infarction by a random survey on the allele expression of HLA-A, B and DRB1 seats of patients with cerebral infarction. Methods The genotypes of HLA-A, B and DRB1 alleles in 94 patients with cerebral infarction and 122 healthy blood donors were detected by polymerase chain reaction-sequencing based typing (PCR-SBT) method. Results Sixteen alleles in HLA -A locus,32 alleles in HLA -B locus and 25 alleles in HLA -DRB1 locus expressed themselves in these patients with cerebral infarction. The gene frequency of HLA -A*1102 in patients was lower than that in healthy controls, and negative association was found between HLA -A* 1102 allele and cerebral infarction (RR=0.06,P=0.019). Conclusion The research reveals susceptibility association of HLA -A*1102 with patients having cerebral infarction, displaying close genetic immunity correlation between HLA alleles and pathogenesis of cerebral infarction. So, the research in this paper is useful in the clinical prediction of this disease.     

Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles

We have previously reported that the association between Bsm I polymorphism, one of the vitamin D receptor genes (VDRG) polymorphism, and multiple sclerosis (MS). In this report, we investigated the further possible role or relevance of VDRG in the pathogenesis of MS. Apa I polymorphism was detected by PCR-RFLP from the DNA of 77 conventional MS patients and 95 healthy controls. The study of the Bsm I and Apa I haplotypes was carried out by employing previously reported Bsm I data. The AA genotype and the [A] allele in the profiles were significantly more prevalent in MS patients than in controls (P=0.0070 and P=0.0321, respectively). In the [A] allele-positive MS patients, the positive rate of DPB1*0501 in HLA was significantly higher than that of the [A] allele-positive controls and that of the [A] allele-negative MS patients even when the corrected P value (P(corr)) was applied (P(corr)=0.0220 and P(corr)=0.0077, respectively). The frequency of DRB1*1501 was higher in the [A] allele-positive patients than in the [A] allele-positive controls and the [A] allele-negative patients (P(uncorr)=0.0431 and P(uncorr)=0.0089, respectively), but the P values did not reach statistical significance after P corrections. The rate of Bsm I and Apa I haplotypes was much higher in bA/bA-positive MS patients than in the controls (P=0.0003), and in the bA positive MS patients, the positive rate of DPB1*0501 was higher than that of the bA-positive controls and that of the bA-negative MS patients (P(corr)=0.0308 and P(corr)=0.0033, respectively). These results indicate that VDRG polymorphism may be associated with susceptibility to MS, and HLA alleles may correlate with risk for MS together with VDRG.     

HLA‐DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population

Background and objective: The association of HLA‐DRB1*15 with susceptibility to multiple sclerosis (MS) has been consistently reported although its effect on the clinical phenotype is still controversial. The objectives of this study are to investigate the influence of the HLA‐DRB1 alleles on the genetic susceptibility to MS and to study their impact on disability progression in a Spanish population. Methods: HLA‐DRB1 typing was performed by PCR‐SSP in 380 patients with sporadic MS and 1088 unrelated healthy controls. Allelic frequencies were compared between groups. We studied the correlation between the different alleles and the progression of MS. Results: The HLA‐DRB1*15 allele in patients with MS had a statistically significant higher frequency when compared with controls (18.9% in patients vs. 10.1% in controls, Odds ratio (OR) = 2.07, 95% CI = 1.64–2.60, P < 0.001). In the univariate analysis, the DRB1*01 and DRB1*04 alleles were associated with a worse prognosis when considering the time to reach an EDSS of 6, whereas the DRB1*03 was correlated with a better outcome. In the multivariate analysis, the alleles*01 and *04 were demonstrated to be independent factors to have a worse prognosis. Conclusions: HLA‐DRB1*15 is associated with MS when comparing patients with unrelated healthy controls in a Spanish population. The HLA‐DRB1*01 and HLA‐DRB1*04 alleles are related to a worse prognosis when considering the time taken to reach severe disability.     

人类白细胞抗原-DQB1等位基因多态性与我国南方汉族人群多发性硬化的相关性研究

目的探讨人类白细胞抗原(HLA)-DQB1基因多态性与我国南方汉族人群多发性硬化(MS)的相关性。方法采用基因测序的方法(SBT)对42例南方汉族MS患者及48名健康对照者进行HLA-DQB1等位基因的检测,并比较MS组与健康对照组之间等位基因型频率的差异。结果共检测到15种HLA-DQB1等位基因片段,其中DQB1*0502等位基因频率MS组(35.7%)显著高于健康对照组(8.9%)(P=0.0018,Pc=0.027,OR=4.29);DQB1*0303等位基因频率MS组(19.0%)低于健康对照组(39.6%)(P=0.04,OR=0.48),但差异经校正后无统计学意义。HLA-DQB1*0601和DQB1*0602等位基因频率在MS组患者与健康对照组之间差异无统计学意义。结论我国南方汉族人群MS与HLA-DQB1*0502等位基因有关,而与HLA-DQB1*0601和DQB1*0602等位基因无关。     

CSF and serum ganglioside antibody patterns in MS

The authors determined CSF and serum IgG and IgM antibodies to seven gangliosides in 48 patients with multiple sclerosis. Differing ganglioside antibody patterns in CSF but not serum allowed to reclassify 93% of MS patients correctly when compared to patients with Guillain-Barré syndrome or neuroborreliosis. This suggest that the antibody patterns are neither random nor alike in inflammatory diseases of the nervous system. CSF ganglioside antibody titres were found to be different for patients with relapsing remitting (RRMS; n = 35) and chronic progressive (CPMS; n = 13) multiple sclerosis. Our study reveals characteristic ganglioside antibody patterns in MS and confirms previous evidence of disturbed immunoregulation in MS.     

Association of HLA‐DRB1*15 allele and CSF oligoclonal bands in a Spanish multiple sclerosis cohort

Background and objective: The HLA‐DRB1*15 allele is consistently associated with multiple sclerosis (MS) susceptibility in most studied populations. This study investigated the association between HLA‐DRB1 alleles and the presence of oligoclonal immunoglobulin G bands (OCB) in the cerebrospinal fluid (CSF) in a Spanish population with MS. Methods: The HLA‐DRB1 typing was performed in 268 patients with sporadic MS and the detection of OCB in CSF. HLA‐DRB1 allelic frequencies were compared between OCB‐positive and OCB‐negative patients, and both groups were also compared with 1088 unrelated healthy controls. Moreover, we correlated the various HLA‐DRB1 genotypes, considering all the combinations of both parental alleles found with the presence or absence of OCB. Results: We found 206 OCB‐positive and 62 OCB‐negative patients. The HLA‐DRB1*15 allele in OCB‐positive patients had a higher frequency when compared with OCB‐negative patients (39.3% in OCB‐positive vs. 16.1% in OCB‐negative, OR = 1.38 95% CI = 1.18–1.61, P < 0.001). The other alleles did not show differences. When we compared with controls, the HLA‐DRB1*15 allele was associated with the disease only in the OCB‐positive patients group. None of the 55 genotypes found showed any association with the presence or absence of OCB. Conclusions: HLA‐DRB1*15 allele is associated with OCB‐positive patients with MS when studying a Spanish MS population.     

CD226 Gly307Ser association with neuromyelitis optica in Southern Han Chinese

Background: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are autoimmune diseases of the central nervous system with complex pathogeneses. NMO was once considered to be a severe variant of MS. There has been more evidence that a non-synonymous exchange (rs763361/Gly307Ser) in the gene for CD226 is linked to several autoimmune diseases including multiple sclerosis (MS). However, no studies have investigated the role of rs763361 in the pathogenesis of NMO. Objectives: The goal of our study is to evaluate the role of CD226 Gly307Ser in neuromyelitis optica (NMO) in Southern Han Chinese. Methods: Eight-nine NMO patients, 93 relapsing-remitting multiple sclerosis (RRMS) patients, and 122 controls (CTLs) were enrolled. The rs763361 alleles of the subjects were determined by sequencing-based typing. Results: The results strongly support that the TT genotypes are associated with NMO but are not significantly correlated with susceptibility for MS. Conclusions: CD226 Gly307Ser may correlate with risk of NMO in Southern Han Chinese.     

A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up.

One hundred and one of 146 patients presenting with isolated idiopathic optic neuritis, previously reviewed in 1978, were reassessed clinically, and retyped for HLA antigens and Factor B alleles, after a mean follow-up of 11.6 years. Fifty eight patients (57%) had developed multiple sclerosis at the time of reassessment in the present study, of whom 51 (88%) had clinically definite disease. This compared with 40% of the original group, in 1978, of whom 62% then had clinically definite multiple sclerosis. When the life-table method of analysis was used, the probability of developing multiple sclerosis was 75%, 15 years after the initial episode of optic neuritis. The frequencies of HLA-DR2 and the recently defined D-region antigen, DQw1, were significantly increased in patients with isolated optic neuritis and those who subsequently developed multiple sclerosis compared with normal controls, but neither allele appears to influence progression from optic neuritis to multiple sclerosis. Patients with optic neuritis who were HLA-DR3 positive had an increased risk for the development of multiple sclerosis (RR = 2.8) and this risk was further enhanced when DR3 occurred in combination with DR2 (RR = 6.7). The overall increased risk of developing multiple sclerosis for patients with this combination was 26 times that for the normal population. When the patients' original tissue-typing was considered BT 101 no longer influenced conversion of optic neuritis to multiple sclerosis. This may partly be explained by improved methods of tissue-typing, since not all BT 101 patients were subsequently found to be positive for HLA-DR2 or HLA-DQw1 and vice versa and by extended follow-up as multiple sclerosis conversion in HLA-DR2 negative individuals increased with time. All 101 patients were typed for Factor B alleles. No significant differences in frequencies were found between individuals with isolated optic neuritis or those who progressed to multiple sclerosis compared with the control population. Recurrent episodes of optic neuritis were associated with an increased risk for the development of multiple sclerosis in this study.     

The presence of glutamic acid at positions 71 or 74 in pocket 4 of the HLA-DRbeta1 chain is associated with the clinical course of multiple sclerosis

BACKGROUND: Primary progressive multiple sclerosis (PP-MS) differs from relapsing-remitting or secondary progressive MS (RR/SP-MS) in ways suggesting differences in the pathogenic pathways. Susceptibility to both PP-MS and RR/SP-MS is linked to carriage of the HLA molecule DRB1*1501. Several serologically defined HLA-DR groups (DR1, DR4, DR6, and DR9) occur less often in RR/SP-MS than in controls. Some or all of the HLA-DR molecules encoded by alleles in these serologically defined groups have a negatively charged glutamic acid at residue 71 or 74 of the beta1 chain (beta1(71)/beta1(74)). Residues at these positions are important in the formation of pocket 4 in the antigen binding site of the HLA-DR molecule. OBJECTIVES: To investigate whether the presence of alleles encoding HLA-DR molecules containing glutamic acid at beta1(71)/beta1(74) correlates with the course of MS. METHODS: HLA-DR and HLA-DQ alleles and genotypes were analysed in 121 MS patients (50 with PP-MS) and 109 controls by molecular typing. RESULTS: Alleles encoding HLA-DR molecules containing a glutamic acid at beta1(71)/beta1(74) occurred less often in patients with RR/SP-MS than in those with PP-MS or controls. In subjects not carrying the DRB1*1501 allele, a much higher proportion of PP-MS patients carried alleles encoding HLA-DR molecules containing a glutamic acid at beta1(71)/beta1(74) than did RR/SP-MS patients or controls. CONCLUSIONS: The amino acid residues involved in determining the shape and charge of pocket 4 of the HLA-DR beta1 chain could influence the clinical course of MS by determining protection against RR/SP-MS or susceptibility to the development of PP-MS.     

Infrequent detection of human herpesvirus 6 DNA in peripheral blood mononuclear cells from multiple sclerosis patients

Several studies have suggested an association between human herpesvirus 6 (HHV-6) infection and multiple sclerosis. As HHV-6 is predominantly a T-cell tropic virus, we examined the frequency of detection of HHV-6 genome in peripheral blood mononuclear cells from relapsing–remitting (n = 32) and chronic progressive (n = 14) patients and from healthy (n = 17) and neurological (n = 7) controls. Two sensitive polymerase chain reaction assays were used to target different regions within the HHV-6 genome. Depending on the polymerase chain reaction assay used, the detection of HHV-6 genome ranged from 11.7 to 23.5% (controls), 3.1 to 23.0% (relapsing–remitting), and 14.2 to 28.5% (chronic progressive). Although these observations do not exclude a pathogenic role for HHV-6 in multiple sclerosis, they indicate a lack of correlation between HHV-6 infection of peripheral blood mononuclear cells and the development of multiple sclerosis.     

HLA typing in the United Kingdom multiple sclerosis genome screen

The United Kingdom multiple sclerosis genome screen demonstrated a peak maximum lod score of 2.8 in the HLA region, together with statistically significant excess transmission of the 121-base pair (bp) allele of the tumour necrosis factor-a marker. In order to determine whether this association is independent of the established HLA association, or simply a consequence of the 121-bp allele being part of the same haplotype, we HLA-DR and -DQ typed the 227 sibling-pair families used in the original screen. The expected associations of multiple sclerosis with the DR15 (p=8.7E-18), DQ6 (p=2.0E-09) and DR51 (p=2.8E-16) phenotypes were confirmed, and excess transmission of the DRB1*1501 and DQB1*0602 alleles was demonstrated. Combining HLA typing with the original microsatellite data demonstrated extensive linkage disequilibrium between the 121-bp allele and the 1501-0602 haplotype. Outside this extended haplotype (121-1501-0602), none of the alleles demonstrated significant transmission distortion. Having established the importance of this extended haplotype, we reanalysed the entire genome screen data after excluding those sibling pairs sharing the extended haplotype (n=27). Conditioning the full genome screen data on the basis of identity by state sharing showed that some potential linkage regions identified in the original screen clustered in families, in which the extended haplotype was shared (1p, 2p and 17q), whereas others grouped with those in which it was not (5cen, 7p and Xq). This suggests complexity in the genetics of multiple sclerosis. Received: May 22, 1998 / Accepted: July 1, 1998 / Published online: December 9, 1998     

HLA-DRB1基因型与北方汉族多发性硬化易感性的研究

目的 探讨人类白细胞抗原(HLA)-DRB1基因型与中国北方汉族多发性硬化(MS)的关联.方法 应用序列特异性引物-聚合酶链反应(PCR-SSP)技术检测58例中国北方汉族MS患者及63名健康对照者的HLA-DRB1基因型分布;同时将MS患者分为西方型MS和视神经脊髓炎(NMO)两亚组,对其DR4和DR15基因频率进行比较.结果 与对照组比较,MS患者DR15和DR4等位基因频率显著升高(分别为P=0.025,P=0.003);此外,NMO亚组DR4频率显著高于西方型MS(P=0.013).结论 我国北方汉族人MS与HLA-DRB1等位基因的关联与西方人群有所不同,DR15可能是MS的易感基因,而DR4则可能为我国汉族人NMO的易感基因.关联基因的差异可能是导致东西方MS病变部位不同的原因.     

Analysis of HLA class I and II alleles in sporadic inclusion-body myositis

Abstract. Sporadic inclusion body myositis (s-IBM) is characterised by progressive weakness of proximal and distal limb muscles. Most patients are aged over 50 years at disease onset. Muscle biopsy reveals an inflammatory myopathy and cytoplasmic amyloid deposits. The mononuclear infiltrate is dominated by CD8+ T-cells. Several investigators have described associations between s-IBM and certain HLA antigens and alleles. However, to date neither HLA class I nor II alleles have been analysed in a large series of patients. We typed various HLA class I and II alleles in 47 patients suffering from s-IBM using sequence specific-primer pairs (SSPPCR). The results were compared with published German controls. Additional Bonferroni adjustment was performed over all allele groups corresponding to serologically defined antigens within one HLA class I or II locus. After Bonferroni adjustment, we found a significant increase in frequency of the following HLA alleles for s-IBM patients when compared with normal controls: A*03 (p = 0.0002), B*08 (p = 0.002), DRB1*03 (p = 0.0000002), and DQB1*05 (p = 0.02). HLA typing may be helpful to distinguish between subgroups of s-IBM patients. Moreover, HLA analysis may aid in identifying patients who might profit from future therapeutic strategies.     

The myelin basic protein gene in multiple sclerosis: identification of discrete alleles of a 1.3 kb tetranucleotide repeat sequence

Myelin basic protein (MBP) is a potential autoantigen in multiple sclerosis (MS) and its gene therefore is an attractive candidate to confer genetic susceptibility to this disease. Linkage and association with certain alleles of a 1.2 kb tetranucleotide repeat region 5'to the MBP gene with MS have been reported in Finnish patients, and an association has been reported from Denmark. However, these findings have not been confirmed in subsequent analyses in other populations. A limitation of previous studies has been the low resolution of the typing procedure. We have investigated the same polymorphism in thirty-four Swedish nuclear families with 2 or 3 MS patients, and in 149 unrelated Swedish MS patients and 95 healthy controls using a fluorescence-based semi-automated technique which allowed the identification of discrete tetrarepeat numbers. Neither parametric two-point linkage analysis nor a nonparametric affected pedigree members analysis showed any sign of linkage. In addition, the distribution of alleles was similar in patients and controls. We conclude that the MBP gene does not influence susceptibility to MS in Swedish patients.     

Human leukocyte antigen alleles in patients with bipolar disorder in the Korean population

We performed an association study between human leukocyte antigen (HLA) alleles and bipolar disorder to evaluate the potentiality of HLA as a genetic marker in bipolar disorder. HLA class I and class II allele frequencies were assessed in 87 bipolar patients and were compared with those of 206 normal controls in the Korean population. HLA class I typing was performed using the microlymphocytotoxicity method, whereas class II (DRB1 and DQB1) genotyping was performed with polymerase chain reaction-sequence specific oligonucleotide probes. When the allele frequency of HLA in bipolar patients was compared with that in normal controls, there were some significant differences. Bipolar patients showed statistically significant increased allele frequencies of HLA-A29 and B54. Allele frequencies of HLA-B51 and DRB1*02 were significantly higher in normal controls. However, these results were no longer significant after correcting for the number of alleles. The results of the present study suggest that HLA alleles may not confer susceptibility to bipolar disorder in the Korean population. To clarify the genetic influence of HLA on bipolar disorder, we should conduct a consecutive study with a larger cohort of subjects.