Medical Records-Based Genetic Studies of the Complement System.
J Am Soc Nephrol
; 32(8): 2031-2047, 2021 08.
Article
in En
| MEDLINE
| ID: mdl-33941608
ABSTRACT
BACKGROUND:
Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts.METHODS:
We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network.RESULTS:
In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci chr.1q31.3 (CFH locus; rs3753396-A; ß=0.20; 95% CI, 0.14 to 0.25; P=1.52x10-11) and chr.19p13.3 (C3 locus; rs11569470-G; ß=0.19; 95% CI, 0.13 to 0.24; P=1.29x10-8). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; ß=0.40; 95% CI, 0.34 to 0.45; P=4.58x10-35). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels C4-BS (ß=-0.36; 95% CI, -0.42 to -0.30; P=2.98x10-22) and C4-AL-BS (ß=0.25; 95% CI, 0.21 to 0.29; P=8.11x10-23). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation.CONCLUSIONS:
We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Variation
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Complement C3
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Complement C4
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Medical Records
Type of study:
Observational_studies
Limits:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
J Am Soc Nephrol
Journal subject:
NEFROLOGIA
Year:
2021
Type:
Article