Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland.
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Genom. 2024 Sep 11;4(9):100630. doi: 10.1016/j.xgen.2024.100630. Epub 2024 Aug 13.
Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.
雷诺氏综合征是一种自主神经功能紊乱，暴露于寒冷会导致血管收缩和缺氧，特别是在四肢。我们在四个队列中进行了荟萃分析，发现了八个基因座（ADRA2A、IRX1、NOS3、ACVR2A、TMEM51、PCDH10-DT、HLA 和 RAB6C），其中 ADRA2A、ACVR2A、NOS3、TMEM51 和 IRX1 与表达数量性状基因座（eQTLs）共定位，特别是在远端动脉。CRISPR 基因编辑进一步表明 ADRA2A 和 NOS3 基因座修饰了基因表达，原位 RNAscope 阐明了 ADRA2A 在小血管中的特异性和 IRX1 在皮肤中小毛细血管周围的特异性。冷刺激下的功能收缩试验显示，ADRA2A 缺陷的平滑肌细胞收缩减少，ADRA2A 过表达的平滑肌细胞收缩增加。总的来说，我们的研究强调了全基因组关联测试与功能后续相结合作为理解复杂疾病的方法的强大功能。结果表明，ADRA2A 通过 ADRA2A 介导温度依赖性肾上腺素能信号，IRX1 影响微血管，NOS3 影响内皮信号，HLA 基因座影响免疫机制，在雷诺氏综合征中发挥作用。
