Significance of genomic diversity of NOX2 complex in onset and pathogenesis of systemic lupus erythematosus

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08470
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: University of Tsukuba
• Principal Investigator: Kawasaki Aya 筑波大学, 医学医療系, 助教 (30532816)
• Co-Investigator(Kenkyū-buntansha): 河野 肇 帝京大学, 医学部, 教授 (60585074)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 全身性エリテマトーデス / 疾患感受性遺伝子 / NOX2複合体 / NCF1 / NCF2 / ロングリードシークエンス / バリアント

Outline of Final Research Achievements

Association of some missense variants in NCF1 and NCF2, components of NOX2 complex, with systemic lupus erythematosus (SLE) has been reported. However, due to the difficulties in a genomic analysis of NCF1 gene caused by the presence of pseudogenes with high homology, association analysis of the variants distributed in the entire gene has not been reported. In this study, using the long-read sequencing technology, we detected many NCF1 variants, several of which showed a tendency towards association with SLE. With respect to NCF2, the association of the missense variant previously reported in East Asian populations was confirmed in the Japanese population. These findings suggested that the effect size of NOX2 complex variants in development of SLE may be substantially larger than currently recognized.

Free Research Field

膠原病学、ゲノム医科学

Academic Significance and Societal Importance of the Research Achievements

本研究において全身性エリテマトーデス(SLE)の発症とNOX2複合体構成遺伝子の関連を見いだした。これまで特異的なシークエンシングが困難であったNCF1に、ロングリードシークエンス解析により多数のバリアントが検出され、一部はSLE感受性に関連していた。NCF1は現在でも東アジア集団ではHLA以上にSLE発症における効果量が高いことが知られているが、NCF1を含めたNOX2複合体構成遺伝子群全体のSLE発症における効果量は、現在考えられているよりさらに大きい可能性が示唆され、SLEの分子機構の解明、NOX2複合体を標的としたSLE治療薬、SLE発症予測への応用が期待される。