Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

No abstract

Abstract. Chronic allograft nephropathy (CAN) is due to both immunologic and non-immunologic factors and results in the development of nonspecific pathologic features that may even be present in long-term well-functioning renal allografts. To investigate the natural history of CAN and potential risk factors associated with progression of these histologic lesions, this study evaluated the of histologic alterations of 124 sequential protocol biopsies performed at 2, 3, and 5 yr after transplantation in 46 patients who exhibited histologic evidence of CAN in the 1-yr biopsy.

Narcolepsy with cataplexy is likely caused by a loss of the orexin-producing neurons. In addition, loss of dynorphin and neuronal activity-regulated pentraxin may contribute to the symptoms of narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. Using genome-wide association (GWA) in narcolepsy patients versus controls, with replication and fine mapping across three ethnic groups (3406 individuals of European ancestry, 2414 Asians, and 302 African Americans), we found a novel association between SNP rs2305795 in the 3′UTR of the purinergic receptor subtype 2Y11 (P2RY11) gene and narcolepsy (p(Mantel Haenszel)=6.1×10-10; odds ratio 1.28; n=5689). The disease-associated allele is correlated with a 3-fold lower expression of P2RY11 in CD8+ T lymphocytes (p=0.003) and natural killer (NK) cells (p=0.031) but not in other peripheral blood mononuclear cell (PBMC) types. The low expression variant is also associated with decreased P2RY11 mediated resistance to adenosine triphosphate (ATP) induced cell death in T lymphocytes (p=0.0007) and NK 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.

The new polynomial eGFR formula showing the relationship with body length and serum Cr level may be applicable for clinical screening of renal function in Japanese children and adolescents aged between 2 and 18 years.

Background The Committee for the Standardization of Renal Pathological Diagnosis and the Working Group for Renal Biopsy Database of the Japanese Society of Nephrology started the first nationwide, web-based, and prospective registry system, the Japan Renal Biopsy Registry (J-RBR), to record the pathological, clinical, and laboratory data of renal biopsies in 2007. Methods The patient data including age, gender, laboratory data, and clinical and pathological diagnoses were recorded on the web page of the J-RBR, which utilizes the system of the

Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB1*1501 (M17378) and HLA-DQB1*0602 (M20432). Susceptibility genes other than those in the HLA region are also likely involved. We conducted a genome-wide association study using 500K SNP microarrays in 222 Japanese individuals with narcolepsy and 389 Japanese controls, with replication of top hits in 159 Japanese individuals with narcolepsy and 190 Japanese controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. rs5770917, a SNP located between CPT1B and CHKB, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 x 10(-7)) and other ancestry groups (OR = 1.40, P = 0.02). Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates beta-oxidation, a pathway involved in regulating theta frequency during REM sleep, and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.