Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.
Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class I/genetics , Polymorphism, Single Nucleotide/genetics , Alleles , Asian People/genetics , Case-Control Studies , Gene Frequency/genetics , Genome-Wide Association Study/methods , Genotype , Humans , Linkage Disequilibrium/genetics , White People/genetics
Renal hypouricemia is an inherited disorder characterized by impaired tubular uric acid transport. Impairment of the function of URAT1, the main transporter for the reabsorption of uric acid at the apical membrane of the renal tubules, causes renal hypouricemia. The G774A mutation in the SLC22A12 gene encoding URAT1 predominates in Japanese renal hypouricemia. From data on linkage disequilibrium between the G774 locus and the 13 markers flanking it (12 single nucleotide polymorphisms and 1 dinucleotide insertion/deletion locus), we here estimate the age of this mutation at approximately 6820 years [95% confidence interval (CI) 1860-11,760 years; median = 2460 years]. This indicates that the origin of the G774A mutation dates back from between the time when the Jomon people predominated in Japan and the time when the Yayoi people started to migrate to Japan from the Korean peninsula. These data are consistent with a recent finding that this G774A mutation was also predominant in Koreans with hypouricemia and indicate that the mutation originated on the Asian continent. Thus, this mutation found in Japanese patients was originally brought by immigrant(s) from the continent and thereafter expanded in the Japanese population either by founder effects or by genetic drift (or both).
Kidney Diseases/genetics , Organic Anion Transporters/genetics , Organic Cation Transport Proteins/genetics , Point Mutation , Uric Acid/metabolism , Age Factors , Asian People/genetics , Female , Haplotypes , Homozygote , Humans , Japan , Kidney Diseases/ethnology , Kidney Diseases/metabolism , Linkage Disequilibrium , Male , Polymorphism, Single Nucleotide
Arthritis, Rheumatoid/complications , Cryptomeria/adverse effects , Rhinitis, Allergic, Seasonal/etiology , Adult , Aged , Arthritis, Rheumatoid/genetics , Cohort Studies , Female , Genetic Predisposition to Disease , Humans , Japan , Linear Models , Male , Middle Aged , Rhinitis, Allergic, Seasonal/genetics , Severity of Illness Index
BACKGROUND: An imbalance in cytokine homoeostasis is thought to have a key role in the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), and recently, a role for chemokines has been noted. OBJECTIVE: To compare concentrations of monocyte chemotactic protein-1 (MCP-1)/CCL2 in cerebral spinal fluid (CSF) of patients with SLE, and with and without neuropsychiatric symptoms. METHODS: CSF was obtained from 185 patients with SLE: 96 with NPSLE and 89 patients with SLE without neuropsychiatric symptoms (non-NPSLE patients). MCP-1/CCL2 concentrations were measured with an ELISA. RESULTS: The average concentration of CSF MCP-1/CCL2 in patients with NPSLE was 1959 pg/ml, and in non-NPSLE patients 712 pg/ml. The average MCP-1/CCL2 concentration was significantly higher in the NPSLE group than in the non-NPSLE group (p<0.001). In one representative patient with NPSLE, MCP-1/CCL2 levels in the CSF decreased in parallel with a decline in neuropsychiatric symptoms. CONCLUSIONS: CSF MCP-1/CCL2 levels are higher in patients with NPSLE than in non-NPSLE patients. MCP-1/CCL2 may have an important role in the expression of NPSLE. These results indicate that CSF MCP-1/CCL2 reflects an inflammatory activity in the brain, suggesting that it might be used as a diagnostic tool and a monitor for therapeutic responses in patients with NPSLE.
Chemokine CCL2/cerebrospinal fluid , Lupus Erythematosus, Systemic/cerebrospinal fluid , Mental Disorders/cerebrospinal fluid , Adolescent , Adult , Biomarkers/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/psychology , Male , Mental Disorders/complications , Middle Aged , Statistics, Nonparametric
