Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F, respectively, as candidate genes at a significant level of p < 5 × 10−8, while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10−6. In comparison with BBJ (180K), RARB (retinoic acid receptor-β) was detected as a candidate at a significant level of p < 5 × 10−8 in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus.
Automatic measurement becomes a preference, and indeed a necessity, when analyzing 1000 s of ECGs in the setting of either drug-inducing QT prolongation screening or genome-wide association studies of QT interval. The problem is that individual manufacturers apply different computerized algorithms to measure QT interval. We conducted a comparative study to assess the outcomes with different automated measurements of QT interval between ECG machine manufacturers and validated the related heart rate correction methods.
The aim of this study was to evaluate the factors responsible for depressed mood in rheumatoid arthritis (RA). Clinical and laboratory measures were collected from 4558 RA patients enrolled in a large clinical cohort study for RA conducted at the Institute of Rheumatology, Tokyo Women's Medical University (IORRA study). A two-question depressed screening included in the U.S. Preventive Services Task Force recommendation were utilized to identify "depressed patients." A total of 1875 (41.1%) were identified as "depressed patients" who presented with symptoms suggestive of depression. Patient's Visual Analog Scale (VAS) for general health (43.3 mm vs 24.6 mm, P < 0.0001) and pain (40.9 mm vs 23.8 mm, P < 0.0001) and the disability index scores measured by the Health Association Questionnaire (HAQ) (0.986 vs 0.574, P < 0.0001) were significantly higher in depressed patients than in nondepressed patients. The presence of three or more comorbidities (odds ratio [OR] 2.157, P < 0.0001), infection (OR 1.754, P < 0.0001), and joint surgery (OR 1.878, P < 0.0001) were significantly correlated with depressed mood in RA. The results of the Generalized Linear Model analysis showed that HAQ disability index (P < 0.0001) and patient's VAS for general health (P < 0.0001) were also strongly and significantly associated to the response variable "probability of depressed patients.' Patient appraisal of poor general health and greater disability were associated with depressed mood in RA.
Our objective was to describe outpatient medical care costs of patients with rheumatoid arthritis (RA) in the prebiologics period in Japan. The outpatient costs of 6,771 RA patients (17,666 patient years) who were enrolled in an observational cohort study at the Institute of Rheumatology, Rheumatoid Arthritis (IORRA), in Tokyo, Japan, were calculated from the billing records dated from 2000 to 2004. Associations between outpatient costs and variables such as age, RA duration, RA disease activities, and disability levels were assessed. The average outpatient cost gradually increased (+7.7% in 4 years) from 271,498 JPY per year in 2000 to 292,417 JPY per year in 2004. Medications accounted for approximately 50% of total outpatient costs, which increased 29.6% during the 4 years. The outpatient costs increased in association with aging, longer RA duration, higher Disease Activity Score of 28 Joints (DAS28), and higher Japanese version of Health Assessment Questionnaire (J-HAQ) score. Generalized linear regression analysis revealed that both DAS28 and J-HAQ scores were the most significant factors associated with outpatient costs (p < 0.001). Outpatient costs for patients with RA increased year after year over the 4-year period under observation in Japan. Medical costs were higher with increasing RA disease activity and disability levels.
To determine the most sensitive scoring method for assessment of rheumatoid arthritis (RA) disease activity using the American College of Rheumatology Core Data Set.The subjects were 4,530 patients with RA (mean age 57.9 years, mean disease duration 12.7 years) who participated in a large observational cohort study of RA patients. The 68 joints assessed were classified into 15 joint areas, and each joint variable was categorized based on the presence or absence of swelling or pain in these areas. Multiple linear regression and analysis of variance were used to evaluate the significance of effects of these 15 joint areas on variables for assessment of RA disease activity such as patient's assessment of pain on a visual analog scale (VAS), patient's and physician's global assessment of disease activity on a VAS, HAQ (Health Assessment Questionnaire), and Japanese HAQ.Although the 3 most frequently affected joints were the wrist, metacarpophalangeal joints, and proximal interphalangeal joints, the 5 joints with the largest contributions to all of the variables assessed for disease activity were the shoulder, elbow, and knee joints, followed by the wrist and ankle joints. The combination of shoulder, elbow, and knee joints accounted for approximately 70% of the contribution to all the variables, while addition of the wrist and ankle joints increased this value to approximately 90%.Scoring for assessment of RA disease activity would be more sensitive if separate joints such as the shoulder, elbow, knee, wrist, and ankle joints were weighted differently.
For prevention of joint destruction in rheumatoid arthritis, optimal management of therapy with disease-modifying antirheumatic drugs is essential. Pharmacogenomic evidence, if reliable, may be incorporated in the treatment of rheumatoid arthritis to achieve a more efficient activity control with minimized adverse events.We conducted retrospective studies to validate our previous three different results about the association between adverse events or efficacy of two different disease-modifying antirheumatic drugs and genomic variations. Association between single nucleotide polymorphisms in N-acetyltransferase 2 gene (NAT2) and adverse events by sulfasalazine and association between C677T or A1298C in 5,10-methylenetetrahydrofolate reductase gene (MTHFR) and responses to methotrexate were examined.Patients without the wild-type haplotype at NAT2 were more likely to suffer from overall adverse events [n=186, P=0.001, relative risk (RR) 3.31, 95% confidence interval (CI) 1.76-6.22] and severe adverse events (P=0.015, RR 24.6, 95% CI 2.37-254.53) by sulfasalazine. Patients with the T allele at C677T in MTHFR were more susceptible to overall adverse events (n=156, P=0.003; RR 2.4, 95% CI 1.29-4.55) while patients with the C allele at A1298C were less likely to be treated with a higher dose (>6 mg/week) of methotrexate in one year of treatment (n=159, P=0.008, RR 1.84, 95% CI 1.12-3.01). In all three association studies, the results were essentially the same as previously reported.As three studies on the associations between genomic variations and adverse events or efficacy of two different disease-modifying antirheumatic drugs were replicated, the usefulness of the tests is worth being tested in clinical practice.
The efficacy and toxicity of methotrexate (MTX) depend on individual patients with rheumatoid arthritis (RA) and are difficult to predict before treatment although MTX is the anchor drug and achieving the treatment target earlier is desirable to prevent progression of structural and functional damage. Our previous studies revealed high predictive accuracy of single nucleotide polymorphisms (SNPs) to predict the efficacy and toxicity of MTX, suggesting the influence of genetic variations in enzymes associated with MTX metabolism and folate metabolic pathway1,2. However, higher accuracy and replicability is demanded for clinical application.
Objectives
To develop combined genetic and clinical models to predict the efficacy and hepatotoxicity of MTX.
Methods
Patients with RA under the treatment of MTX according to Japanese guideline for the management of RA with MTX were enrolled. To predict the efficacy and hepatotoxicity, 1971 polymorphisms of 246 enzymes/transporters potentially relevant to pharmacokinetics and pharmacodynamics of MTX were measured by the DMET microarray (Affymetrix Inc.) and direct-sequencing method and clinical variables at baseline were collected. As for efficacy, the EULAR-CRP response criteria was chosen to classify patients with RA as responders (good response) and non-responders (moderate or no response). Hepatotoxicity was defined as either serum AST or ALT levels higher than 1.5 times the upper limit of the normal range. Among SNPs and clinical variables with significant association with outcomes using univariate analyses, stepwise model selection was conducted by Akaike information criterion in logistic regression model and receiver operating characteristic (ROC) analyses were performed. Bootstrapping (n=100,000) was used to assess the robustness of the results.
Results
A total of 166 patients with RA was included. The median age was 61.5 years with 81.3% of women. For efficacy, genetic prediction model using 7 SNPs showed area under the curve of ROC (AUC) was 0.822 with sensitivity of 74.3% and specificity of 76.8%, while combined clinical and genetic model indicated AUC was 0.844 with sensitivity of 81.5% and specificity of 76.9%. By incorporating clinical variables into the genetic model, overall category-free net reclassification improvement (NRI) was 0.700 (p<0.0001) and overall integrated discrimination improvement (IDI) was 0.089 (p=0.0005). For hepatotoxicity, genetic prediction model using 7 SNPs showed AUC was 0.783 with sensitivity of 70.0% and specificity of 80.0%, while combined clinical and genetic model indicated AUC was 0.906 with sensitivity of 85.1% and specificity of 87.8%. Overall category-free NRI was 1.122 (p<0.0001) and overall IDI was 0.279 (p<0.0001).
Conclusions
Genetic and clinical models showed higher predictive accuracy for both efficacy and hepatotoxicity of MTX. These models should be validated with a larger scale of prospective study.
References
[1] Kumagai S. Ann Rhem Dis. 2015;74(suppl2):263. [2] Kumagai S. Ann Rhem Dis. 2014;73(suppl2):119.
Background: Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease with a mean survival period estimated to be around 3 years if not treated. Although many familial cases of IPAH exhibit an autosomal dominant mode of inheritance with the majority having mutations in BMPR2, the penetrance is low with an estimated lifetime risk of 20 %. To explain the low penetrance of IPAH associated with BMPR2 mutations, it was hypothesized that other genetic loci as well as environmental factors play roles. Purpose: To identify genetic factors associated with IPAH with/ without BMPR2 mutation, we conducted a genome-wide association study (GWAS) followed by a validation study. Methods and Results: We performed GWAS in the Japanese population comprising a total of 44 individuals with IPAH and 2,993 controls. The IPAH cases were identified at three major pulmonary hypertension centers in Japan. The controls consisted of 2,002 and 991 healthy Japanese individuals, which were collected at two different times by Japan PGx Data Science Consortium (JPDSC). At first, we conducted discovery GWAS to identify SNPs related to the disease, comparing 23 cases with IPAH (first set) and 2,002 controls at 1,347,690 SNPs, and identified 8 loci each of which had more than one SNP with P values under 10-5. We then attempted to validate the associations observed in the discovery phase using 21 patients (second set) and 991 controls who were independent of the samples used in the discovery GWAS. In the validation study, we examined the associations of 9 SNPs at 8 loci, and only 2 SNPs at one locus showed significant association. And finally, we identified a novel susceptibility locus PDE1A
Food allergy is an increasingly important health problem in the world. Several genome-wide association studies (GWAS) focused on European ancestry samples have identified food allergy-specific loci in the HLA class II region. We conducted GWAS of self-reported reactivity with common foods using the data from 11011 Japanese women and identified shrimp and peach allergy-specific loci in the HLA-DR/DQ gene region tagged by rs74995702 (P = 6.30 × 10-17, OR = 1.91) and rs28359884 (P = 2.3 × 10-12, OR = 1.80), respectively. After HLA imputation using a Japanese population-specific reference, the most strongly associated haplotype was HLA-DRB1*04:05-HLA-DQB1*04:01 for shrimp allergy (P = 3.92 × 10-19, OR = 1.99) and HLA-DRB1*09:01-HLA-DQB1*03:03 for peach allergy (P = 1.15 × 10-7, OR = 1.68). Additionally, both allergies' associated variants were eQTLs for several HLA genes, with HLA-DQA2 the single eQTL gene shared between the two traits. Our study suggests that allergy to certain foods may be related to genetic differences that tag both HLA alleles having particular epitope binding specificities as well as variants modulating expression of particular HLA genes. Investigating this further could increase our understanding of food allergy aetiology and potentially lead to better therapeutic strategies for allergen immunotherapies.
