BS 变异型 C4 可预防与年龄相关的脑白质微观结构完整性丧失。
The BS variant of C4 protects against age-related loss of white matter microstructural integrity.
机构信息
Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.
The Barts Heart Centre and NIHR Barts Biomedical Research Centre-Barts Health NHS Trust, The William Harvey Research Institute, Queen Mary University London, London, UK.
出版信息
Brain. 2022 Mar 29;145(1):295-304. doi: 10.1093/brain/awab261.
Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive. We performed a genome-wide association study of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity and fractional anisotropy) in up to 31 128 individuals from UK Biobank (age 45-81 years) based on a two degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP × Age effects. We identified 18 loci that were associated at genome-wide significance with either mean diffusivity (n = 16) or fractional anisotropy (n = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both mean diffusivity [best SNP: 6:28866209_TTTTG_T, beta (standard error, SE) = -0.069 (0.009); 2df P = 6.5 × 10-15] and fractional anisotropy [best SNP: rs3129787, beta (SE) = -0.056 (0.008); 2df P = 3.5 × 10-12]. Of the imputed human leukocyte antigen (HLA) alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant [for mean diffusivity: beta (SE) = -0.070 (0.010); P = 2.7 × 10-11; for fractional anisotropy: beta (SE) = -0.054 (0.011); P = 1.6 × 10-7]. After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older participants [age ≥ 65; interaction P = 0.0019 (mean diffusivity), P = 0.015 (fractional anisotropy)] and in participants without a history of smoking [interaction P = 0.00093 (mean diffusivity), P = 0.021 (fractional anisotropy)]. Taken together, our findings demonstrate a role of the complement system and of gene-environment interactions in age-related loss of white matter microstructural integrity.
年龄相关的白质微观结构完整性丧失是认知能力下降、痴呆和步态障碍的主要决定因素。然而，导致这种完整性丧失的机制和分子途径仍难以捉摸。我们对英国生物库中多达 31128 名年龄在 45-81 岁之间的个体的白质微观结构完整性进行了全基因组关联研究，该研究基于双自由度（2df）单核苷酸多态性（SNP）和 SNP×年龄效应测试对扩散 MRI 指标（平均扩散率和各向异性分数）进行量化。我们确定了 18 个与平均扩散率（n=16）或各向异性分数（n=6）呈全基因组显著相关的位点。在顶级基因座中，一个位于 6 号染色体上的区域编码人类主要组织相容性复合体（MHC）。MHC 区域的变体与平均扩散率密切相关[最佳 SNP：6:28866209_TTTTG_T，β（标准误差，SE）=-0.069（0.009）；2df P=6.5×10-15]和各向异性分数[最佳 SNP：rs3129787，β（SE）=-0.056（0.008）；2df P=3.5×10-12]。在人类 MHC 中的人类白细胞抗原（HLA）等位基因和补体成分 4（C4）结构单倍型变体中，与 C4-BS 变体的相关性最强[对于平均扩散率：β（SE）=-0.070（0.010）；P=2.7×10-11；对于各向异性分数：β（SE）=-0.054（0.011）；P=1.6×10-7]。在 C4-BS 条件下，与 HLA 等位基因没有关联仍然显著。C4-BS 的保护作用在年龄较大的参与者中更强[年龄≥65 岁；交互 P=0.0019（平均扩散率），P=0.015（各向异性分数）]，在没有吸烟史的参与者中更强[交互 P=0.00093（平均扩散率），P=0.021（各向异性分数）]。综上所述，我们的研究结果表明，补体系统和基因-环境相互作用在与年龄相关的白质微观结构完整性丧失中发挥作用。
Zotero 插件