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.     

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.     

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.     

Ethnicity-dependent association of HLA DRB1-DQA1-DQB1 alleles in Brazilian multiple sclerosis patients

OBJECTIVE: The present study focused on human leukocyte antigen (HLA) DQB1, DQA1 and DRB1 allelic variation according to ethnicity and analyzed whether susceptibility to multiple sclerosis (MS) depends on population characteristics. METHODS: Eighty-eight healthy African-Brazilians and 92 healthy white Brazilians living in Rio de Janeiro City were selected and the HLA phenotype between the two ethnic groups was compared with 44 MS patients of African descent and 40 patients of European descent. HLA class II genes were performed using polymerase chain reaction (PCR) and PCR-sequence-specific primer amplification. RESULTS: DQA1*0201-0301 alleles were associated with the white Brazilian population (P < 0.001). The DRB*1501 allele was present in White Brazilians (P=0.003), and DRB1*03-1503 in African-Brazilians. The DRB1*1501 allele confers an ethnicity-dependent MS susceptibility in White patients and the DQB1*0602 allele confers genetic susceptibility regardless of ethnicity. CONCLUSION: Heterogeneous phenotypes occur in both Brazilian ethnic groups. Taking into account that the response to immunomodulator drugs for MS treatment changes according to the DRB1*1501 allele and African-American MS patients presented poor response to the interferons, phenotype heterogeneity of HLA loci found in this study could influence therapeutic decisions in the Brazilian MS population.     

HLA class Ⅱ alleles and risk for peripheral neuropathy in type 2 diabetes patients

The potential impact of human leukocyte antigen (HLA) genotype variations on development of diabetic peripheral neuropathy (DPN) is not well determined. hTis study aimed to identify the association of HLA class II alleles with DPN in type 2 diabetes (T2D) patients. Totally 106 T2D patients, 49 with DPN and 57 without DPN, and 100 ethnic-matched healthy controls were analyzed. Both groups of the patients were matched based on sex, age, body mass index (BMI) and duration of T2D. Polyneuropathy was diagnosed using electrodiagnostic methods. HLA-DRB1 and DQB1 genotyping was performed in all subjects by the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. T2D patients with DPN showed higher frequencies of HLA-DRB1*10 and DRB1*12 alleles compared to control group (P = 0.04). HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype were associated with a decreased risk for developing DPN in T2D patients (P = 0.02 andP = 0.05 respectively). Also, patients with severe neurop-athy showed higher frequencies of DRB1*07 (P = 0.003) and DQB1*02 (P = 0.02) alleles than those with mild-to-moderate form of neuropathy. The distribution of DRB1 and DQB1 alleles and haplotypes were not statistically different between all patients and healthy controls. Our ifndings implicate a possible protective role of HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype against development of peripheral neuropathy in T2D patients. Therefore, variations in HLA genotypes might be used as genetic markers for prediction and potentially management of neuropathy in T2D patients.     

The HLA‐A*2402/Cw*0102 haplotype is associated with lamotrigine‐induced maculopapular eruption in the Korean population

The use of lamotrigine (LTG) can be limited by the occurrence of cutaneous adverse drug reactions (cADRs) that range from maculopapular eruption (MPE) to the more severe Stevens‐Johnson syndrome and toxic epidermal necrolysis. A few human leukocyte antigen (HLA)–related genetic risk factors for carbamazepine‐induced cADR have been identified. However, the HLA‐related genetic risk factors associated with LTG‐induced cADR are not yet well known. We performed HLA genotyping in 50 Korean patients with epilepsy, including 21 patients presenting LTG‐induced MPE and 29 LTG‐tolerant patients. A significant association between the HLA‐A*2402 allele and LTG‐induced MPE was identified, in comparison with the LTG‐tolerant group (odds ratio [OR] 4.09, p = 0.025) and the general Korean population (OR 3.949, p = 0.005). The frequencies of the Cw*0102 or Cw*0702 alleles were significantly higher in the LTG‐MPE group than in the Korean population, whereas the frequency of the A*3303 allele was lower. The coexistence of the A*2402 and Cw*0102 alleles was significantly associated with the LTG‐MPE group when compared to the LTG‐tolerant group (OR 7.88, p = 0.007). In addition, the Cw*0701 allele was more frequent in the LTG‐tolerant group than in the Korean population. These findings suggest the presence of HLA‐related genetic risk factors for LTG‐induced MPE in the Korean population.     

Human leucocyte antigen (HLA) class I and II typing in Belgian multiple sclerosis patients

This is one of the first studies to compare the frequencies of different human leucocyte antigen (HLA) class I and II alleles and haplotype HLA-DRB1*15-DQB1*06 in a cohort of 119 patients with multiple sclerosis (MS) and a cohort of 124 healthy controls in Belgium. An association with MS was found for the HLA-DRB1*15 (odds ratio [OR] 2.60 [95% confidence interval (CI) 1.51–4.50]) and HLA-DQB1*06 (OR 1.97 [95% CI 1.18–3.29]) alleles, and for haplotype DRB1*15-DQB1*06 (OR 2.63 [95% CI 1.52–4.56]). The HLA-B*07 allele also tended to be more frequent in MS patients (OR 1.46 [95% CI 0.80–2.65]) and more frequent among MS patients with than in those without the HLA-DRB1*15 allele (26/54 [48.1%] versus 6/65 [9.2%]; p value <0.0001). Other alleles were underrepresented in MS patients, such as the HLA-DRB1*07 (OR 0.39 [95% CI 0.21–0.73]) and HLA-A*02 (OR 0.56 [95% CI 0.34–0.94]), showing a protective role against the disease. The HLA-B*44 (OR 0.58 [95% CI 0.31–1.09]) and HLA-DRB1*04 (OR 0.75 [95% CI 0.42–1.34]) alleles tended to be less frequent in MS patients. Altogether, the significant results observed in this population are in line with those from other countries and confirm that propensity to MS can be due to a complex presence of various HLA class I and class II alleles.     

Association of HLA-DR and -DQ Genes with Familial Moyamoya Disease in Koreans

Objective

Moyamoya disease (MMD) is an uncommon cerebrovascular disorder, characterized by progressive occlusion at the terminal portion of the internal carotid artery. Incidence of the disease is high in East Asia and familial MMD accounts for about 15% of the disease. Although the pathogenesis is unknown, association of HLA class I or II alleles with MMD has been reported with conflicting results. We investigated whether there is a difference in HLA class II association between familial and non-familial forms of the disease.

Methods

A total of 70 Korean children with MMD, including 16 familial cases (10 probands), and 207 healthy controls were studied. Among familial cases, only 10 probands were used for the HLA frequency analysis. High resolution HLA-DRB1 and DQB1 genotyping was performed using polymerase chain reaction (PCR)-sequence specific oligonucleotide hybridization and PCR-single strand conformation polymorphism methods.

Results

The phenotype frequencies of HLA-DRB1^*1302 (70.0%) and DQB1^*0609 (40.0%) were significantly increased in familial MMD compared to both controls [vs. 15.5%, corrected p (p_c) = 0.008, odds ratio (OR) = 12.76; vs. 4.3%, p_c = 0.02, OR = 14.67] and non-familial MMD patients (vs. 14.8%, p_c = 0.02, OR = 13.42; vs. 1.9%, p_c = 0.02, OR = 35.33). The frequencies of DRB1 and DQB1 alleles in non-familial MMD patients were not significantly different from those in controls.

Conclusion

Our findings suggest that the genetic polymorphism of HLA class II genes or other closely linked disease relevant gene(s) could be a genetic predisposing factor for familial MMD.     

HLA class II susceptibility to multiple sclerosis among Ashkenazi and non-Ashkenazi Jews.

OBJECTIVE: To look for HLA class II alleles and haplotypes conferring susceptibility to multiple sclerosis (MS) in the Jewish population of Israel. DESIGN: Population-based cohort of clinically definite patients with MS tested prospectively over 7 years. SETTING: Referral center in a neurology clinic at a university hospital in the greater Jerusalem area in Israel. PATIENTS: A total of 162 consecutive patients with clinically definite MS from the 2 main ethnic Jewish groups in Israel: 104 Ashkenazi (80 with a relapsing remitting or secondary progressive and 24 with a primary chronic progressive course of the disease) and 58 non-Ashkenazi (36 with a relapsing remitting or secondary progressive course and 22 with a primary chronic progressive course of the disease), matched with 132 Ashkenazi and 120 non-Ashkenazi healthy controls. MAIN OUTCOME MEASURES: The relationship between the various HLA class II alleles and haplotypes and MS, as defined by the polymerase chain reaction and sequence-specific oligonucleotide probe hybridization, among the Ashkenazi and the non-Ashkenazi Jewish sections and with respect to the different clinical courses of the disease. RESULTS: The haplotype DRB1*1501, DQA1*0102, DQB1*0602 was found to be associated with MS among both Ashkenazi and non-Ashkenazi patients (P<.001 and P =.04, respectively). Among the non-Ashkenazi patients, a new association of haplotypes DRB1*1303, DQA1*05, and DQB1*030 with MS was detected (P = .03). The MS susceptibility alleles, DRB 1* 1501, DQA1*0102, and DQB1*0602 , were found in association with the Ashkenazi patients (P<.001, P=.02, and P=.01, respectively); DRB1*1501 and DRB1*1303 were more frequently observed among the non-Ashkenazi patients (P = .03, P = .04, respectively). On subdivision of the patients into clinical subgroups, associations of DRB1*0801, DQA1*0102, DQA1*0401, and DQB1*0602 with primary chronic progressive MS among the Ashkenazi patients were evident (P = .03, P = .04, P = .04 and P = .05, respectively), whereas DRB1* 1501, DRB1*03011, and DQB1*0602 were associated with relapsing remitting or secondary progressive among the non-Ashkenazi patients (P = .05, P = .05, and P = .03, respectively). CONCLUSIONS: This study, unlike previous ones, is the first to show a significant association between HLA class II alleles and MS in the Jewish population. The association with the HLA-DR2-related haplotype is similar to that among non-Jewish white patients with MS. Moreover, our data support the possibility that DRB1*1501 is the susceptibility allele responsible for the association between this haplotype and MS in the Jewish population. Our study also underscores differences in HLA profiles between Ashkenazi and non-Ashkenazi patients, and between the different clinical courses of the disease. The latter may indicate that the clinical courses of MS are influenced by the genetic background.     

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.     

DQB1*0602 allele shows a strong association with multiple sclerosis in patients in Malaga,Spain

BACKGROUND: The human leukocyte antigen (HLA) class II DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) has been associated with multiple sclerosis (MS) in all ethnic groups and very strongly in Caucasians. AIM: To investigate the possible HLA class II (DRB1, DQA1 and DQB1) associations with MS in Malaga, southern Spain. METHODS: We analysed the HLA class II sub-regions DRB1, DQA1 and DQB1 by polymerase chain reaction (PCR) and sequence-specific oligonucleotide probe hybridization (PCR/SSO) for DRB1 and DQB1 and with sequence-specific primers (PCR/SSP) for DRB1 subtypes and DQA1. Possible HLA class II associations with clinical MS characteristics were investigated in 149 subjects with and 160 without MS. RESULTS: Associations were detected between MS and the HLA class II alleles DRB1*1501 (45.6 % vs. 21.3%, p=0.001), DQA1*0102 (44% vs. 29.4%, p=0.001) and DQB1*0602 (45% vs. 20.6%, p=0.001). The DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) was associated with MS (43.6 % vs. 20%, p=0.002). DQB1*0602 was the only allele that maintained an association with MS in a logistic regression model. No HLA class II alleles or genotypes were significantly associated with any clinical characteristics of MS. CONCLUSIONS: Our results confirm the positive association of the DR2 haplotype with MS, particularly the allele DQB1*0602, in the population studied. DR4 was not associated with the disease in Malaga. HLA class II alleles or haplotypes were not associated with clinical or demographic characteristics, or clinical form or severity of MS.     

Evidence for the genetic role of human leukocyte antigens in low frequency DRB1*1501 multiple sclerosis patients in Israel

A strong association exists between multiple sclerosis (MS) and the DRB1*1501 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on chromosome 6p21 has previously been observed in DRB1*1501 positive MS families. A group of 13 Israeli multiplex MS families with a very low frequency of DRB1*1501 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB1*1501 effect of HLA on susceptibility for MS. MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRB1, DQA1 and DQB1, BAT-2, MIB and D6S248. Data analyses included: (a) an association study comparing the patient group with both healthy relative, and healthy control groups (b) a transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families, and (c) multipoint non-parametric linkage (NPL) and parametric LOD score analyses using the GENEHUNTER program. The DRB1*1303 allele was significantly more frequent among the MS patients. There was a trend towards transmission disequilibrium of DRB1*1303, but was not statistically significant. Allele sharing and LOD score analyses revealed no evidence for linkage. The high frequency of DRB1*1303 observed in our family patients provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patients. Thus, DRB1*1303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRB1*1501 patients.     

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.     

Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population

Objective

CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder.

Methods

We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G).

Results

There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive.

Conclusion

We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required.     

The association of HLA-DRB1 and HLA-DQB1 alleles with genetic susceptibility to multiple sclerosis in the Slovak population

Objective: The aim of the present study was to assess the association between HLA-DRB1 and -DQB1 allele groups with the genetic predisposition to multiple sclerosis (MS) in the Caucasian Central European Slovak population.

Methods: A total of 282 unrelated patients with sporadic MS were enrolled in this case-control study. HLA-DRB1 and HLA-DQB1 allele groups were genotyped using a polymerase chain reaction with sequence-specific primers. The DRB1 and DQB1 allele carrier frequencies, genotypes and haplotype frequencies were compared between MS cases and healthy controls.

Results: Positive association with MS was found for alleles HLA-DRB1*15 (OR = 3.64; Pcor = 6.9x10–11), DRB1*03 (after elimination of carriers of DRB1*15, OR = 2.8; Pcor = 0.0029), DQB1*06 (OR = 1.99; Pcor = 7.0x10–4), genotypes HLA-DRB1*15/*15 (OR = 7.6; Pcor = 0.001) and DQB1*06/*06 (OR = 3.81; Pcor = 4.0x10–4) and for haplotype DRB1*15-DQB1*06 (OR = 3.03; Pcor = 0.001). Carriage of alleles DRB1*07 (OR = 0.53; Pcor = 0.04), DRB1*13 (OR = 0.39; Pcor = 4.0x10–4), DQB1*03 (OR = 0.46; Pcor = 1.0x10–4), genotypes HLA-DRB1*13/*11 (OR = 0.12; Pcor = 0.004), DQB1*05/*03 (OR = 0.39; Pcor = 0.035), DQB1*03/*03 (OR = 0.38; Pcor = 0.029) and haplotypes DRB1*13-DQB1*06 (OR = 0.47; Pcor = 0.0128) and DRB1*11-DQB1*03 (OR = 0.58; Pcor = 0.0352) was found to be protective against MS development.

Discussion: This is the first study performed to analyse the association of HLA-DRB1/DQB1 with susceptibility to MS in Slovakia. The results of our study confirm that HLA class II alleles, genotypes and haplotypes are associated with MS risk.     

No association between common variations in the neuronal nicotinic acetylcholine receptor alpha2 subunit gene (CHRNA2) and bipolar I disorder

The neuronal nicotinic acetylcholine receptor alpha2 subunit gene (CHRNA2) maps to the bipolar susceptibility locus on chromosome 8p21-22. Given the biological role of the neuronal nicotinic acetylcholine receptors and the substantial comorbidity of nicotine dependence in psychiatric disorders, the CHRNA2 gene is a plausible candidate gene for bipolar disorder (BPD). We tested the hypothesis that variations in the CHRNA2 gene confer susceptibility to bipolar I disorder in a case-control association study. Genotypes of one amino acid substitution polymorphism (Ala125Thr) and five non-coding variations across the CHRNA2 gene were obtained from 345 unrelated bipolar I patients and 273 control samples. Genotypes and allele frequencies were compared between groups using chi-square contingency analysis. Linkage disequilibrium (LD) between markers was calculated, and estimated haplotype frequencies were compared between groups. We observed no statitistically significant difference in genotype and allele frequencies for all six variations between bipolar patients and controls, but we did demonstrate strong LD throughout the gene. Haplotype analysis showed that no combinations of alleles were associated with illness. Our results suggest that common variations in the CHRNA2 gene are unlikely to confer susceptibility to BPD in this sample. Further studies are required to elucidate the susceptibility locus for BPD on chromosome 8p21-22.     

HLA-DRB1 and multiple sclerosis in Argentina

Background:  The association of multiple sclerosis (MS) with HLA DR subtypes, and particularly human leukocyte antigen (HLA)-DRB1*15 has been a consistent finding across nearly all Caucasian MS populations. In South America, scarce data exist about this issue. As the complete characterization of the HLA association range around the world is important to understand the role of this locus in MS susceptibility, we analyzed the frequency of HLA-DRB1* allelic groups in an MS population in Argentina.
Methods:  HLA-DRB1 locus was genotyped using PCR and sequence-specific primer amplification in 61 MS patients born in Buenos Aires, Argentina and 1216 healthy controls. Allele frequencies were compared between groups.
Results:  The HLA-DRB1*15 allele frequency significantly differed between controls and patients (13.5% and 33.9% respectively, P  < 0.001, OR 2.51, 95% CI: 1.7–3.0). The other allele frequencies did not show significant differences between patients and controls.
Conclusions:  The present HLA class II population study is in accordance with other Caucasian MS surveys which have found that HLA-DRB1*15 allele is strongly associated with MS disease. In Argentina, this is the first study performed to analyze the association of HLA-DRB1*15 and MS susceptibility in a Caucasian population and therefore contributes with new data to the immunogenomic global MS map.     

HLA class II alleles in patients with multiple sclerosis in the Biscay province (Basque Country,Spain)

Genetic susceptibility to multiple sclerosis (MS) is associated with genes of the major histocompatibility complex, particularly with the HLA DRB1*1501-DQA1*0102-DQB1*0602 haplotype in Caucasians. To investigate the association of DRB1, DQA1 and DQB1 alleles and haplotypes with MS in Biscay, Basque Country, northern Spain, we examined 197 patients and 200 regionally matched controls. High resolution HLA class II typing was performed by polymerase chain reaction followed by sequence-specific oligonucleotide probe hybridization. Several alleles were overrepresented in MS patients compared with those of controls: DRB1*0402, DRB1*1303, DRB1*1501, DQA1*0102, DQB1*0301, and DQB1*0602. DQB1*0602 was the only potentially predisposing allele for MS that withstood Bonferroni correction and maintained the association in a logistic regression model. On the other hand, several alleles showed lower frequencies in the MS group: DRB1*0101, DQA1*0101, DQB1*0303, and DQB1*0501, but only DRB1*0101 and DQB1*0303 maintained a negative association with the disease in the regression analysis. Three haplotypes were identified as potentially predisposing for MS in our population: DRB1*1501-DQA1*0102-DQB1*0602, DRB1*0402-DQA1*0301-DQB1*0302, and HLA-DRB1*013-DQA1*05-DQB1*0301. Additionally, three haplotypes associated with a lower risk for MS were identified, exhibiting DRB1*0101-DQA1*0101-DQB1*0501 the strongest negative association with MS [12% in controls vs. 3.8% in MS, P _c = 0.00047, OR = 0.290 (95% CI = 0.160–0.528)], and suggesting, therefore, a putative protective role for this haplotype in the population under study.     

HLA typing and Parkinson's disease

Idiopathic Parkinson's disease (IPD) is a neurodegenerative disorder of unknown aetiology. Several antigens have been associated with IPD using serological methods. We systematically analysed HLA class I and II alleles in 45 German Caucasian IPD patients using sequence-specific oligonucleotides and sequence-specific primer technology. Applying Bonferroni adjusted p values, we demonstrate a statistically significant increase of the DQB1*06 allele (p = 0.002) in IPD which may indicate an association between IPD and the immune system. Alternatively, HLA alleles might be in linkage disequilibrium with genes located next to the HLA locus.     

Heterogeneous immunogenetic background in Japanese adults with myasthenia gravis

The aim of this study was to elucidate the roles of human leukocyte antigen (HLA) class II genes in disease susceptibility in Japanese adult patients with myasthenia gravis (MG). A number of studies have shown that MG is correlated with DR3 in Caucasians. In Japanese, infantile MG is associated with DR9, but the HLA class II alleles associated with adult MG remains unclear. HLA-DRB1 and DQB1 alleles were determined by genotyping in 75 Japanese adult patients with MG and in 115 race-matched healthy adults. No statistically significant difference was observed in the overall prevalences of DRB1 and DQB1 alleles between MG patients and healthy controls, even when the patients and controls were stratified on the basis of their gender. MG patients with DQB1*0604 were younger and those with DQB1*0402 were older at disease onset than those without (P=0.03 and 0.008, respectively). Concomitant autoimmune thyroid disease was associated with DRB1*0803 (P=0.0009, corrected P=0.04). In addition, anti-acetylcholine receptor antibody levels were significantly higher in patients with DQB1*0604 than in those without (P=0.045). These findings indicate that immunogenetic backgrounds in Japanese adult MG patients are heterogeneous and are apparently different from those in Caucasian patients.