The complement system is an important part of the innate immune response. It can be activated via three distinct pathways (classical, lectin and alternative) converging in the generation of C3 convertases and finally leading to the formation of the terminal complement complex (TCC). To maintain host defense while avoiding host damage, complement activation has to be controlled by several regulators, like factor H (FH). There are several reports on the association of complement protein deficiencies with various diseases, like FH deficiency and occurrence of chronic renal diseases or age-related macular degeneration or C7 deficiency and risk for Neisseria meningitides infections.
The aim of the present study is to identify gene polymorphisms within the human genome that are associated with elevated or decreased activation capability of the complement system via all three activation pathways. We will investigate whether carriers of risk alleles have a higher risk of infections, cardiovascular diseases and kidney diseases or whether they are subjected to a faster ageing process.
Serum samples of 5000 study participants, for whom one million single nucleotide polymorphisms (SNPs) have been genotyped, will be analyzed for complement activation. We will determine functional activity of the classical, lectin and alternative complement pathways in addition to the terminal pathway by using a commercially available assay, the WIESLAB Complement system Screen. We will select 500 samples with regard to the clinical outcome(s) and we will measure levels of several complement proteins with an in-house-ELISA.
As a first step of our analysis, we will perform genome-wide association studies (GWAS) of the three pathways on all samples. In a second step, the identified genetic variant(s) will be tested for association with individual’s information on infections, cardiovascular diseases, kidney diseases, autoimmune diseases, as well as neurological and psychiatric conditions collected in the CHRIS study (phenome-wide scan). In a third step, we will assess known polymorphisms of the respective complement proteins as well as their functional activity. Causal analysis might be investigated through Mendelian Randomization to establish causal pathways. All statistical analyses will be performed using linear mixed models to account for family structure and relatedness in general.
