Polymorphism Located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

Background: SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy. Principal Findings: EHS was significantly associated with SNP rs5770917 (Pallele = 3.6610 23; OR = 1.56; 95 % c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (Ppositivity = 9.2610 211; OR = 3.97; 95 % c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS. Conclusion: CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy

Genome-Wide Association Study Confirming Association of HLA-DP with Protection against Chronic Hepatitis B and Viral Clearance in Japanese and Korean

Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85–90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with Pmeta = 1.89×10−12 for rs3077 and Pmeta = 9.69×10−10 for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (Pmeta = 4.40×10−19 for rs3077 and Pmeta = 1.28×10−15 for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule

Common variants in P2RY11 are associated with narcolepsy.

l e t t e r s Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genomewide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10 −10 , odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The diseaseassociated allele is correlated with reduced expression of P2RY11 in CD8 + T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases

Common variants in P2RY11 are associated with narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov'tresearch support, u.s. gov't, p.h.s.2011 Jan2010 12 19importedErratum in : Nat Genet. 2011 Oct;43(10):1040

Evolutionary Analysis of Classical <em>HLA</em> Class I and II Genes Suggests That Recent Positive Selection Acted on <em>DPB1*04∶01</em> in Japanese Population

<div><p>The human leukocyte antigen (<em>HLA</em>) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical <em>HLA</em> class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific <em>HLA</em> alleles in a local population. To detect the signature of recent positive selection, we genotyped six <em>HLA</em> loci, <em>HLA-A</em>, <em>HLA-B</em>, <em>HLA-C</em>, <em>HLA-DRB1</em>, <em>HLA-DQB1</em>, and <em>HLA-DPB1</em> in 418 Japanese subjects, and then assessed the haplotype homozygosity (<em>HH</em>) of each <em>HLA</em> allele. There were 120 <em>HLA</em> alleles across the six loci. Among the 80 <em>HLA</em> alleles with frequencies of more than 1%, <em>DPB1*04∶01</em>, which had a frequency of 6.1%, showed exceptionally high <em>HH</em> (0.53). This finding raises the possibility that recent positive selection has acted on <em>DPB1*04∶01</em>. The <em>DPB1*04∶01</em> allele, which was present in the most common 6-locus <em>HLA</em> haplotype (4.4%), <em>A*33∶03-C*14∶03-B*44∶03-DRB1*13∶02-DQB1*06∶04-DPB1*04∶01</em>, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between <em>DQB1*06∶04</em> and <em>DPB1*04∶01</em> observed in Japanese cannot be explained without positive selection favoring <em>DPB1*04∶01</em>. The selection coefficient of <em>DPB1*04∶01</em> was estimated as 0.041 (95% credible interval 0.021–0.077). Our results suggest that <em>DPB1*04∶01</em> has recently undergone strong positive selection in Japanese population.</p> </div

Estimation of model parameters for positive selection acting on <i>DPB1*04∶01</i>.

<p>The recombination rate (<i>c</i>), initial haplotype frequency (<i>f</i>₁(0)), and selection coefficient (<i>s</i>), were estimated by comparing the four haplotype frequencies observed in our study population with the respective values predicted via simulation. (A) Posterior distributions of the three parameters that produced simulated data that resemble the observed data. (B) Frequency distribution of <i>s</i> accepted in simulation runs. The mean and 95% credible interval of <i>s</i> are 0.041 and 0.021−0.077.</p

Haplotype homozygosity (<i>HH</i>) × allele frequency (AF) of each <i>HLA</i> allele.

<p>The left and right panels show <i>HH</i> values of <i>HLA</i> class I alleles and <i>HLA</i> class II alleles, respectively. The class I alleles were designated as follows: <i>HLA-A</i> (red diamond), <i>HLA-C</i> (yellow square), and <i>HLA-B</i> (green triangle); the class II alleles were designated as follows: <i>HLA</i>-<i>DRB1</i> (blue diamond), <i>HLA-DQB1</i> (purple square), and <i>HLA-DPB1</i> (pink triangle). In both panels, only <i>HH</i> values of alleles with frequencies of more than 0.01 are shown.</p