DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans

The association of narcolepsy with HLA-DQB1*0602 is established in Japanese, African-Americans, European, and North American Caucasians. We examined DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 in 163 patients with centrally mediated daytime sleepiness (100 with narcolepsy) and 211 Korean controls. In this population, the DQB1*0602 association was always evident in the context of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. The DQB1*0602 association was highest in cases with hypocretin deficiency (100% vs 13% in controls), most of which had narcolepsy-cataplexy (81%). A weaker DQB1*0602 (45%) association was present in cases without cataplexy. No human leukocyte antigen (HLA) association was present in idiopathic hypersomnia or in cases with normal cerebrospinal fluid (CSF) hypocretin-1. As in other populations, DQB1*0602 homozygosity increased risk in cases with cataplexy and/or hypocretin deficiency (odds ratio = 2.0 vs heterozygotes). Non-DQB1*0602 allelic effects were also observed but could not be interpreted in the context of DQB1*0602 overabundance and linkage disequilibrium. We therefore next analyzed compound heterozygote effects in 77 subjects with either hypocretin deficiency or cataplexy and one copy of DRB1*1501-DQA1*0102-DQB1*0602, a sample constructed to maximize etiologic homogeneity. In this analysis, we found additional predisposing effects of DQB1*0301 and protective effects for DQA1*0103-DQB1*0601. Unexpectedly, the predisposing effects of DQB1*0301 were present in the context of various DQA1-bearing haplotypes. A predisposing effect of DQA1*0303 was also suggested. These results indicate a remarkable consistency in the complex HLA association present in narcolepsy across multiple ethnic groups.     

Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status

STUDY OBJECTIVES: Hypocretin (orexin) deficiency (< 40 pg/ml) is highly associated with narcolepsy with cataplexy (89.5%) and more specifically with patients with cataplexy who are HLA DQB1*0602 positive (95.7%). The relationship between hypocretin-1 levels and narcolepsy without cataplexy or the DQB1*0602 allele is less clear. METHODS/DESIGN: This study compared cerebrospinal (CSF) hypocretin-1 in 13 patients with HLA DQB1*0602 allele and cataplexy to 4 HLA negative patients with cataplexy, 3 HLA positive patients without cataplexy, and 6 HLA negative patients without cataplexy, plus 15 neurologic controls. SETTING: Data were collected at a sleep disorders center. PATIENTS/PARTICIPANTS: Twenty-six patients with narcolepsy, with and without HLA DQB1*0602 and with and without cataplexy, as well as 15 neurologic controls. INTERVENTIONS: N/A. MEASUREMENT & RESULTS: Using analysis of variance techniques, statistically significant differences were found between the CSF hypocretin-1 levels in HLA positive patients and all other groups (P < 0.01). Although the sample size was small, subjects with the DQB1*0602 allele without cataplexy had lower hypocretin-1 levels than did other groups (other than the HLA and cataplexy positive group). Hypocretin-1 levels were not associated with age at diagnosis, age at lumbar puncture, body mass index at time of diagnosis, or body mass index at time of lumbar puncture. CONCLUSION: This data confirms the previous finding that undetectable hypocretin-1 levels are highly specific for HLA positive narcolepsy with cataplexy. The data suggests that the pathophysiology and, by extension, etiology of this disorder are distinctly different from the other conditions studied. The relationship of the DQB1*0602 allele and reduced hypocretin-1 levels needs further study.     

Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy

Narcolepsy is a sleep disorder that has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58 non-DR15 patients with narco-lepsy-cataplexy were typed at the HLA DRB1, DQA1 and DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from multiplex families. Additional markers studied in the class II region were the promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII) located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus. Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0T02 and DQBI*0602, a DQ1 Subtype normally associated with DRB1*15 in DR2-positive narcoleptic subjects. Additional microsatellite and DQA1 promoter diversity was found in some of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602 subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes for narcolepsy in the HLA class II region.     

HLA-DQB1 allele and hypocretin in Korean narcoleptics with cataplexy

Cataplexy is one of the most pathognomonic symptoms in narcolepsy. This study was designed to investigate the frequency of the HLA-DQB1 allele and cerebrospinal fluid (CSF) hypocretin levels in Korean narcoleptics with cataplexy as compared with those who do not have cataplexy. Seventy-two narcoleptics were selected based on polysomnography and multiple sleep latency test as well as their history and clinical symptoms at Sleep Disorders Clinic. The patients were divided into a narcolepsy with cataplexy group (n=56) and a narcolepsy without cataplexy group (n=16). All patients were subjected to HLA typing to determine the frequency of DQB1 allele and to spinal tapping to measure the level of CSF hypocretin. In cataplexy-positive patients, as compared with cataplexy-negative patients, the frequency of HLA-DQB1*0602 was found to be significantly high (89.3% vs. 50.0%) (p=0.003). On the other hand, the frequency of HLA-DQB1*0601 was found to be significantly low (0% vs. 43.8%) (p<0.001). In 48 of 56 cataplexy-positive patients (85.7 %), hypocretin levels were decreased (相似文献   

Search for neuron-specific and nonneuron-specific antibodies in narcoleptic patients with and without HLA DQB1*0602

STUDY OBJECTIVES: Narcolepsy is strongly associated with the presence of HLA DQB1*0602. This and other evidence suggests that human narcolepsy is an autoimmune disease. This is in distinction to that found in canine models where hypocretin receptor 2 mutations are etiologic. We decided to test for the presence of several neuron-specific and organ-specific autoantibodies to see if they were present in HLA DQB1*0602-associated or cataplexy-associated narcolepsy or could serve as a serologic marker of the illness. DESIGN: We tested for N-type and P/Q-type voltage-gated calcium-channel antibodies, neuronal nicotinic acetylcholine receptor alpha3 subunit, acetylcholine receptor-binding antibodies, striated muscle antibodies, Type 1 Purkinje cell cytoplasmic antibodies, types 1 and 2 antineuronal nuclear antibodies and amphiphysin antibodies, GAD-65 antibody, and thyroid microsomal and thyroglobulin antibodies in the serum of 43 patients with or without cataplexy, 41 with known HLA status. SETTING: Narcoleptic subjects were recruited from the Mayo Sleep Disorders Center. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: No antibody test yielded significantly positive results for the group as a whole or for subgroups of patients with cataplexy or positive HLA DQB1*0602 status. CONCLUSIONS: These results do not support the hypothesis that narcolepsy is an autoimmune disease. However, it is possible that the autoimmune attack is very selective and does not involve the epitopes measured in this study. Recent findings that the hypocretin neurotransmission system is involved in animal models of narcolepsy should lead to research to look for antibodies directed against components of the hypocretin neurotransmission system in narcolepsy.     

CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in Norway

OBJECTIVE: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. METHOD: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. RESULTS: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. CONCLUSION: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings.     

HLA-DQ association and allele competition in Chinese narcolepsy

In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQβ*06:02 narcolepsy heterodimer to reduce susceptibility.     

Segregation of HLA genes in multicase narcolepsy families

In the past 15 years, 411 sporadic narcolepsy patients have been diagnosed in the Hephata Klinik, Schwalmstadt, Germany. They were explored for presence or absence of excessive daytime sleepiness and narcolepsy in their relatives. A subset of 39 patients were explored for presence or absence of parasomnias. Six patients had more than one relative affected by narcolepsy-cataplexy. Forty-seven family members were investigated with the Stanford Center for Narcolepsy Sleep Inventory and a standardized parasomnia questionnaire. Twenty-four relatives had nocturnal polysomnographies and Multiple Sleep Latency Tests. HLA class I typing was performed in all sporadic and familial cases, class II and microsatellite typing was performed in all members of multicase families. Based on the Finnish prevalence study by Hublin et al., 1994, the relative risk for first degree relatives to develop narcolepsy-cataplexy was in our sample 16.5, 34.2 for excessive daytime sleepiness and 426.9 for parasomnias. Cataplexy, excessive daytime sleepiness and single narcoleptic symptoms in the multicase families segregate with the DRB1*1501, CARII:200, CARI:103, DQB1*0602 haplotype. In two families, members with narcolepsy and isolated symptoms have inherited the DRB1*1501/DQB1*0602 haplotype from the non-affected parent. The observed segregations in these two families may support the view that narcoleptic symptoms are expressed by DRB1*1501/DQB1*0602 carriers, independent of haplotype origin. Parasomnias do not segregate with a specific haplotype. The frequency of parasomnias in narcolepsy is much higher than in the general population. The empirical risk for first degree family members of narcolepsy patients to develop cataplexy seems to be low, whereas it is higher for EDS and highest for parasomnias.     

Association of HLA-DR and -DQ genes with narcolepsy in Koreans: comparison with two control groups, randomly selected subjects and DRB1*1501-DQB1*0602--positive subjects

The purpose of this study was to investigate the association of human leukocyte antigen (HLA) class II alleles with narcolepsy-cataplexy susceptibility in Koreans. The distribution of HLA-DRB1 and -DQB1 alleles and presence or absence of DRB3/4/5 alleles were examined in 60 narcoleptic patients with clear-cut cataplexy, and the results were compared with two groups of healthy controls: 200 randomly selected controls and 144 DRB1*1501-DQB1*0602 positive controls. All of the narcoleptic patients were DRB1*1501 and DQB1*0602 positive, and their frequencies were significantly higher in patients than in random controls (100% vs 17.0%, p(c) = 2.3 x 10(-30), OR = 583.96; 100% vs 16.5%, p(c) = 3.9 x 10(-31), OR = 605.00). The HLA association in Koreans was as tight as that reported in Japanese. Several DRB1 (*0101, *0405, *0901) and DQB1 alleles (*0303, *0401, *0501, *0601, *0604) were found to have weak protective effects against narcolepsy. DRB4 showed strong protective effect, and this was also significant when compared with DRB1*1501-DQB1*0602 positive controls (18.3% vs 44.4%, p(c) = 0.001, OR = 0.28). DRB3 (OR = 1.86) and DQB1*0301 (OR = 2.45) were found to have weak predisposing effect, when compared with DRB1*1501-DQB1*0602 positive controls. The protective effect of DRB4 has to be further studied in other populations.     

Voxel-based morphometry in hypocretin-deficient narcolepsy

STUDY OBJECTIVES: Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy. DESIGN: We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes. SETTING: Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London. PARTICIPANTS: Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects. MEASUREMENTS AND RESULTS: We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls. CONCLUSIONS: VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.     

HLA-DQA, -DQB AND -DRB ALLELE CONTRIBUTION TO NARCOLEPSY SUSCEPTIBILITY

The association of narcolepsy with HLA class I antigens and HLA class II alleles was studied in a series of Spanish narcoleptic patients. The haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 was found to be significantly associated with the disease, while the haplotype DRB1*0701-DRB4*01-DQA1*0201-DQB1*02 might confer a slight protective effect against narcolepsy. Gene dose–effect was not seen in any of the involved alleles, and linkage disequilibrium between the positively associated alleles was found to be stronger in patients than in controls. Statistical analysis applied to identify the HLA allele truly responsible for the association did not clearly discriminate between the contribution of DRB1*1501 and that of DQB1*0602, but it proved that the association with DQA1*0102 is secondary to that with DRB1*1501/DQB1*0602. Analysis of the diagnostic value of typing for the narcolepsy-associated alleles demonstrated a very high negative predictive value and revealed that this test can be convenient for exclusion of narcolepsy in cases when the diagnosis is not evident after clinical evaluation and the marker haplotype is absent. Finally, a family study indicated that narcolepsy is a multifactorial disorder that involves HLA genes under an incomplete penetrance model, with possible influences from environmental factors or other genes different to HLA genes.     

Validation of the ICSD-2 Criteria for CSF Hypocretin-1 Measurements in the Diagnosis of Narcolepsy in the Danish Population

Study Objectives:

The International Classification of Sleep Disorders (ICSD-2) criteria for low CSF hypocretin-1 levels (CSF hcrt-1) still need validation as a diagnostic tool for narcolepsy in different populations because inter-assay variability and different definitions of hypocretin deficiency complicate direct comparisons of study results.

Design and Participants:

Interviews, polysomnography, multiple sleep latency test, HLA-typing, and CSF hcrt-1 measurements in Danish patients with narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwC), CSF hcrt-1 measurements in other hypersomnias, neurological and normal controls. Comparisons of hypocretin deficiency and frequency of HLA-DQB1*0602-positivity in the Danish and eligible NC and NwC populations (included via MEDLINE search), by (re)calculation of studyusing the ICSD-2 criterion for low CSF hcrt-1 (<30% of normal mean).

Measurements and Results:

In Danes, low CSF hcrt-1 was present in 40/46 NC, 3/14 NwC and 0/106 controls (P < 0.0001). Thirty-nine of 41 NC and 4/13 NwC patients were HLA-DQB1*0602-positive (P < 0.01). Hypocretin-deficient NC patients had higher frequency of cataplexy, shorter mean sleep latency, more sleep onset REM periods (P < 0.05) and more awakenings (NS) than did NC patients with normal CSF hcrt-1. Across populations, low CSF hcrt-1 and HLA-DQB1*0602-positivity characterized the majority of NC (80% to 100%, P = 0.53; 80% to 100%, P = 0.11) but a minority of NwC patients (11% to 29%, P = 0.75; 29% to 89%, P = 0.043).

Conclusion:

The study provides evidence that hypocretin deficiency causes a more severe NC phenotype. The ICSD-2 criterion for low CSF hcrt-1 (<30% of normal mean) is valid for diagnosing NC, but not NwC. HLA-typing should precede CSF hcrt-1 measurements because hypocretin deficiency is rare in HLA-DQB1*0602-negative patients.

Citation:

Knudsen S; Jennum PJ; Alving J; Sheikh SP; Gammeltoft S. Validation of the ICSD-2 criteria for CSF hypocretin-1 measurements in the diagnosis of narcolepsy in the Danish population. SLEEP 2010;33(2):169-176.     

Molecular, serological and population studies on a novel HLA-B allele — HLA-B*5002

Abstract: A novel HLA-B allele (B*5002), detected as a discrepancy between serological and PCR-SSP HLA-A and B phenotyping of bone marrow panel donors, was identified by nucleotide sequencing of exons 2 and 3. Titration studies on 39 HLA-B12/B21 cross-reactive antisera showed that the serological specificity of HLA-B*5002 was HLA-B45. PCR-SSP testing of 287 serologically defined HLA-B45-positive subjects from a panel of 12,411 donors, together with HLA-B*45 and B*5002 frequency data on 4,342 PCR-SSP typed subjects, indicated that 4.53% of serologically defined HLA-B45-positive subjects possess HLA-B*5002 and not HLA-B*4501. The pheno-type frequency of HLA-B*5002 was 0.08954%; gene frequency was 0.00045 ( n =16,753). In 73.3% of instances B*5002 appeared to be present on a haplotype with DRBl*0406 and DQB1*0402, 54.6% of which possessed A*2301. The B*5002, DRBl*0406, DQB1*0402 haplotype represents 52.4% of all haplotypes with DRB1*04 and DQB1*04 and 78.6% of haplotypes possessing DRBl*0406 and DQBl*0402.     

Heterogeneity of HLA-DR2 haplotypes in Caucasoid Americans,African Americans,Chinese Americans,Native Americans and Xiamen Chinese

HLA-DR, -DQ specificities were determined by PCR amplification with SSOP in 4560 individuals: Caucasoid Americans (CA), African Americans (AA), Chinese Americans (ChA), Native Americans (NA) and Xiamen Chinese (XC). DR2 subtypes were compared amongst the five ethnic populations. The DRB1*1501-DRB5*0101 haplotype was found to be the most frequent in all populations except African Americans, in which DRB1*1503-DRB5*0101 was the predominant haplotype, accounting for 65% of DR2 subtypes. In contrast to Caucasoid Americans, the DRB1*1602 is strongly associated with the DRB5*0101 allele in Chinese populations. The presence of DRB5*0203 and DRB1*1602-DRB5*0101 haplotypes in Chinese populations, especially in Xiamen Chinese, suggests that various DR2 haplotypes may be generated via multiple gene conversion events together with point mutations and reciprocal recombination. The strong DR and DQ associations are found in DRB1*1501/DQB1*0602 (66.22%) for CA, DRB1*1503/DQB1*0602 (56.58%) for AA, DRB1*1501/DQB1*0602 (30.20%) and DRB1*1602/ DQB1*0502 (15.76%) for ChA, DRB1* 1501/ DQB1*0602 (41.55%) and DRB1*1602/ DQB1*0301 (40.25%) for NA, and DRB1*1501/ DQB1*0602 (30.26%) and DRB1*1602/DQB1*0502 (25.81%) for XC.     

HLA-encoded susceptibility to insulin-dependent diabetes mellitus is determined by DR and DQ genes as well as their linkage disequilibria in a Chinese population

HLA-DRB1 and -DQB1 genes were analyzed in 98 Chinese IDDM patients and 205 control subjects from Taiwan. The DRB1^*0301-DQB1^*0201 haplotype conferred strong susceptibility (RR = 7.7, p_c < 10−5). DRB1^*0405 also conferred susceptibility (RR = 3.1, p_c < 0.0005) whereas DRB1^*0403 (RR = 0.7) and DRB1^*0406 (RR = 0.2) conferred protection. Indeed, the relative risk for the DRB1^*0405-DQB1^*0302 haplotype (RR = 33.7, p_c < 0.002) was 48 and 168 times higher than those conferred by the DRB1^*0403-DQB1^*0302 and DRB1^*0406-DQB1^*0302 haplotypes, respectively, suggesting that the protection conferred by DRB1^*0403 and 0406 is dominant over DQB1^*0302. The strong linkage disequilibrium observed between DQB1^*0302 and DRB1^*0403(0406) can thus explain the surprising finding that the frequency of DQB1^*0302 was not significantly increased in the Chinese IDDM patients (RR = 0.9). Because the DRB1^*0405-DQB1^*0302 haplotype (RR = 33.7) conferred higher susceptibility than the DRB1^*0405-DQB1^*0401 (RR = 2.5) or DRB1^*0405-DQB1^*0301 (RR = 2.1) haplotypes, DQB 1^*0302 is indeed a susceptibility factor, while both DQB1^*0301 and DQB1^*0401 may confer protection against IDDM. The increased frequency of the protective DQB1^*0401 allele in patients compared to controls is due to linkage disequilibrium between DRB1^*0405 and DQB1^*0401. Interestingly, the previously demonstrated protective effect of DQB1^*0602 was not very strong in the Chinese (RR = 0.4). Our results suggested that HLA-encoded susceptibility to IDDM is determined by the combined effects of all DR and DQ molecules present in an individual. Therefore, the genotypic combinations of DR and DQ genes as well as their linkage disequilibria can influence IDDM susceptibility. At least four DR and DQ molecules conferring high susceptibility (DRB1^*0301, DRB1^*0405, and DQ/β0301/0201 and 0301/0302) occur at high frequency in the Chinese population. However, linkage disequilibria between highly susceptible DR and protective DQ or vice versa (e.g., DRB1^*0405-DQB1^*0301(0401] and DRB1^*0403[0406]-DQB1^*0302) are probably responsible for the lower incidence of IDDM in the Chinese.     

Heterogeneity of HLA-DR2 haplotypes in Caucasoid Americans, African Americans, Chinese Americans, Native Americans and Xiamen Chinese.

HLA-DR, -DQ specificities were determined by PCR amplification with SSOP in 4560 individuals: Caucasoid Americans (CA), African Americans (AA), Chinese Americans (ChA), Native Americans (NA) and Xiamen Chinese (XC). DR2 subtypes were compared amongst the five ethnic populations. The DRB1*1501-DRB5*0101 haplotype was found to be the most frequent in all populations except African Americans, in which DRB1*1503-DRB5*0101 was the predominant haplotype, accounting for 65% of DR2 subtypes. In contrast to Caucasoid Americans, the DRB1*1602 is strongly associated with the DRB5*0101 allele in Chinese populations. The presence of DRB5*0203 and DRB1*1602-DRB5*0101 haplotypes in Chinese populations, especially in Xiamen Chinese, suggests that various DR2 haplotypes may be generated via multiple gene conversion events together with point mutations and reciprocal recombination. The strong DR and DQ associations are found in DRB1*1501/DQB1*0602 (66.22%) for CA, DRB1*1503/DQB1*0602 (56.58%) for AA, DRB1*1501/DQB1*0602 (30.20%) and DRB1*1602/DQB1*0502 (15.76%) for ChA, DRB1* 1501/DQB1*0602 (41.55%) and DRB1*1602/DQB1*0301 (40.25%) for NA, and DRB1*1501/DQB1*0602 (30.26%) and DRB1*1602/DQB1*0502 (25.81%) for XC.     

CSF versus serum leptin in narcolepsy: is there an effect of hypocretin deficiency?

STUDY OBJECTIVE: To determine if hypocretin deficiency is associated with abnormally low serum leptin levels, a putative cause of increased body mass index in narcoleptics. DESIGN: Cross-sectional controlled study. PARTICIPANTS: Three hundred seventy subjects, including 111 healthy controls, 93 narcoleptic subjects with hypocretin deficiency (cerebrospinal fluid [CSF] hypocretin-1 levels < 110 pg/mL), 72 narcoleptic subjects with normal hypocretin levels, and 89 subjects with other sleep disorders INTERVENTION: After completing the Stanford Sleepiness Inventory, participants underwent spinal taps and blood sampling for measurement of CSF leptin and hypocretin-1 levels, HLA DQB1*0602 phenotyping, and serum leptin and C-reactive protein levels. RESULTS: Serum leptin levels were similar in narcoleptic subjects, whether hypocretin-deficient (13.2 +/- 1.7 ng/mL, mean +/- SEM) or not (13.0 +/- 1.8 ng/mL), controls (10.1 +/- 1.1 ng/mL) and subjects with other sleep disorders (11.5 +/- 1.6 ng/mL). Similarly, the CSF leptin levels and the CSF: serum leptin ratios (an indicator of brain leptin uptake) were not different between groups. Serum and CSF leptin levels were higher in women and in subjects with higher body mass indexes. Leptin brain uptake decreased in women, in the aged, and in more-obese subjects. In contrast with a presumed inhibitory effect of leptin on hypocretin-containing cells, CSF leptin levels tended to correlate positively with CSF hypocretin-1 levels. C-reactive protein was higher (4.2 +/- 0.9 mg/L) in narcoleptic subjects with hypocretin deficiency than in controls (1.4 +/- 0.3 mg/L, p = .0055), a difference still significant after adjustment on confounding factors. DISCUSSION: Our data do not support a role for leptin in mediating increased body mass index in narcolepsy. A moderate but selective increase in C-reactive protein in hypocretin-1 deficient subjects should prompt research on inflammation in narcolepsy.     

The familial risk and HLA susceptibility among narcolepsy patients in Hong Kong Chinese

STUDY OBJECTIVES: To explore the familial aggregation and HLA susceptibility of narcolepsy in Hong Kong Chinese by objective sleep measurements and HLA typing. DESIGN: Case control design PARTICIPANTS: Twelve narcoleptic probands, 34 first-degree relatives, and 30 healthy controls. INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: Each subject underwent a standardized nocturnal polysomnogram (PSG), followed by a daytime multiple sleep latency test (MSLT). HLA typing was performed for all subjects. One relative (2.9%) was diagnosed as suffering from narcolepsy with cataplexy. Nearly 30% of the relatives fulfilled the criteria of narcolepsy spectrum disorder (shortened mean sleep latency [MSL] and/or the presence of sleep onset REM periods [SOREMPs]). When using the population data for comparison, the relative risk of narcolepsy in first-degree relatives was 85.3. The odds ratio of narcolepsy spectrum disorder in first-degree relatives was 5.8 (95% CI: 1.2 - 29.3) when compared to healthy controls. There existed 6 multiplex families, in which all 10 relatives with narcolepsy spectrum disorders, including all 3 relatives with multiple SOREMPs, were positive for HLA DQB1*0602. CONCLUSIONS: Our study demonstrated a definitive familial aggregation of narcolepsy, narcolepsy spectrum disorders, and possibly cataplexy in Hong Kong Chinese. This familial aggregation supported an inherited basis for narcolepsy spectrum. The tight co-segregation of HLA DQB1*0602 and narcolepsy spectrum disorders might suggest that HLA typing, especially DQB1*0602, at least partly confer the familial risk of narcolepsy. In addition, our study suggested that the subjective questionnaire measurements including Ullanlinna Narcolepsy Scale and Epworth Sleepiness Scale were unable to detect the presence of narcolepsy spectrum disorders among the relatives. A stringent objective measurement-based design for family studies is suggested for future study. Further studies are indicated for the determination of the mode and molecular level of narcolepsy transmission.     

Case-control study with narcoleptic patients and healthy controls who, like the patients, possess both HLA-DRB1*1501 and -DQB1*0602

In previous studies, we suggested that the tumor necrosis factor (TNF-alpha and its receptor 2 (TNFR2) genes could be associated with the susceptibility to human narcolepsy, and that haplotype carrying DRB1*1502 had a negative association with the disorder. To further evaluate these associations, we herein compared narcoleptic patients with healthy individuals who, like the patients, possessed both DRB1*1501 and DQB1*0602. Results agreed with the negative association of DRB1*1502 and positive association of the TNF-alpha(-857T) and TNFR2-196R combination with the disorder. In addition, a significant association of the TNF-alpha(-857T) homozygote with the disorder and an increase in a rare haplotype carrying DRB1*1501 and TNF-alpha(-857T) in the patients were also observed in the present study.