Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population

原発性胆汁性胆管炎の新たな遺伝要因を同定 --ヒト全ゲノム領域へのRHM法による世界初の成果--. 京都大学プレスリリース. 2021-04-09.While the advent of GWAS more than a decade ago has ushered in remarkable advances in our understanding of complex traits, the limitations of single-SNP analysis have also led to the development of several other approaches. Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (STAT4, ULK4, and KCNH5) at the genome-wide significance level, two of which (ULK4 and KCNH5) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases. These findings thereby provide strong empirical evidence that RHM is an effective and practical complementary approach to GWAS in this context. Also, liver tissue mRNA microarray analysis revealed higher gene expression levels in ULK4 in PBC patients (P < 0.01). Lastly, we estimated the common SNP heritability of PBC in the Japanese population (0.210 ± 0.026)

Trans-ethnic study confirmed independent associations of HLA-A*02:06 and HLA-B*44:03 with cold medicine-related Stevens-Johnson syndrome with severe ocular surface complications

Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes. Cold medicines including non-steroidal anti-inflammatory drugs and multi-ingredient cold medications are reported to be important inciting drugs. Recently, we reported that cold medicine related SJS/TEN (CM-SJS/TEN) with severe mucosal involvement including severe ocular surface complications (SOC) is associated with HLA-A*02:06 and HLA-B*44:03 in the Japanese. in this study, to determine whether HLA-B*44:03 is a common risk factor for CM-SJS/TEN with SOC in different ethnic groups we used samples from Indian, Brazilian, and Korean patients with CM-SJS/TEN with SOC, and investigated the association between CM-SJS/TEN with SOC and HLA-B*44:03 and/or HLA-A*02:06. We found that HLA-B*44:03 was significantly associated with CM-SJS/TEN with SOC in the Indian and Brazilian but not the Korean population, and that HLA-A*02:06 might be weakly associated in the Korean-but not the Indian and Brazilian population.Ministry of Education, Culture, Sports, Science and Technology of the Japanese governmentJapanese Ministry of Health, Labour and WelfareKyoto Foundation for the Promotion of Medical ScienceIntramural Research Fund of Kyoto Prefectural University of MedicinePromotion Project of Knowledge-Based Industrial Clustering of Okinawa PrefectureKyoto Prefectural Univ Med, Dept Ophthalmol, Kyoto, JapanDoshisha Univ, Fac Life & Med Sci, Res Ctr Inflammat & Regenerat, Kyoto 602, JapanLV Prasad Eye Inst, Prof Brien Holden Eye Res Ctr, Hyderabad, Andhra Pradesh, IndiaUniversidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilSeoul Natl Univ, Coll Med, Dept Ophthalmol, Seoul, South KoreaChonnam Natl Univ, Dept Ophthalmol, Kwangju, South KoreaYonsei Univ, Coll Med, Severance Hosp, Inst Vis Res,Dept Ophthalmol, Seoul, South KoreaCatholic Univ Korea, Seoul St Marys Hosp, Coll Med, Dept Ophthalmol & Visual Sci, Seoul, South KoreaLV Prasad Eye Inst, Cornea & Anterior Segment Serv, Hyderabad, Andhra Pradesh, IndiaUniv Tokyo, Grad Sch Med, Dept Human Genet, Tokyo, JapanUniversidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilWeb of Scienc

Updates in SJS/TEN: collaboration, innovation, and community

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15–20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1–5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28–29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper

Japan: Diagnosis and Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis With Severe Ocular Complications

In 2005, the 'Japanese Research Committee on Severe Cutaneous Adverse Reaction' (J-SCAR) presented the official 'Diagnostic Criteria' for SJS/TEN, and the specific ocular findings are included in these very important criteria. In SJS/TEN cases involving ocular disorder, conjunctivitis often occurs prior to the onset of the high fever. In a Japanese survey, ocular involvement was observed in 77% of the cases, and the incidence of ocular sequelae increased depending on the score of the acute ocular severity findings. Pseudo-membrane formation and epithelial defects are considered to be high-risk signs of ocular sequelae. At the chronic stage, limbal stem cell deficiency, visual disturbance, and severe dryness of the ocular surface are the primary disease characteristics. In 2002, we started performing Cultivated Oral Mucosal Epithelial Transplantation (COMET) for the treatment of severe ocular disorders, including SJS/TEN. As an additional treatment method, we developed a new type of rigid contact lens (CL) that is 13 to 14.0-mm in diameter, known as the 'Limbal Rigid Contact Lens (Limbal CL).' Our Limbal Rigid CL greatly enhances the postoperative outcome of COMET. The detection rate of ocular surface bacteria is high in SJS/TEN cases. Thus, appropriate use of topical antibiotics reduces the risk of ocular surface inflammation. Moreover, rebamipide is an ophthalmic solution for dry eye that was developed in Japan, and it also has the effect of suppressing ocular surface inflammation. From disease onset until the chronic stage, the control of inflammation and stem cell loss is key to successfully treating eyes afflicted with SJS/TEN