Genetic determinants of complement activation in the general population.
Cell Rep
; 43(1): 113611, 2024 01 23.
Article
en En
| MEDLINE
| ID: mdl-38159276
ABSTRACT
Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement's genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways' genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Lectina de Unión a Manosa
/
Estudio de Asociación del Genoma Completo
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article