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Complement C3 Associates With Incidence of Diabetes, but No Evidence of a Causal Relationship
Yan Borné1, Iram Faqir Muhammad1, Laura Lorés-Motta2
1Department of Clinical Sciences, Lund University, Sweden.
Insights
High levels of complement factor 3 (C3) in plasma are linked to an increased risk of developing diabetes. This association may be partly explained by genetic factors related to the GCKR gene.
Area of Science:
- Biochemistry
- Genetics
- Epidemiology
Background:
- The complement system plays a role in inflammation and immune responses.
- Complement factor 3 (C3) is a key component of the complement cascade.
- Understanding the relationship between C3 and metabolic diseases like diabetes is crucial.
Purpose of the Study:
- To investigate the association between plasma C3 levels and the incidence of type 2 diabetes in a population-based cohort.
- To identify genetic variants influencing C3 levels.
- To explore shared genetic determinants between C3 and diabetes.
Main Methods:
- Plasma C3 levels were measured in 4368 nondiabetic individuals from the Malmö Diet and Cancer Study.
- Diabetes incidence was tracked over a mean follow-up of 17.7 years.
- Genome-wide association studies (GWAS) identified C3-associated genetic loci, with in silico look-ups in large genetic databases.
Main Results:
- A significant association was found between higher plasma C3 levels and increased diabetes incidence (HR 1.54, P=0.005) after adjusting for risk factors.
- C3 levels were strongly associated with polymorphisms at the complement factor H locus and eight other loci.
- The glucose kinase regulatory protein (GCKR) locus showed association with both C3 levels and previously reported diabetes risk, with replication in an independent cohort.
Conclusions:
- Plasma C3 concentration serves as a significant risk marker for incident diabetes.
- The observed association between C3 and diabetes risk may be partly mediated by pleiotropic effects of the GCKR gene.
Purpose:
This study explored whether complement factor 3 (C3) in plasma is associated with incidence of diabetes in a population-based cohort. We also identified genetic variants related to C3 and explored whether C3 and diabetes share common genetic determinants.
Methods:
C3 was analyzed in plasma from 4368 nondiabetic subjects, 46 to 68 years old, from the Malmö Diet and Cancer Study. Incidence of diabetes was studied in relationship to C3 levels during 17.7± 4.4 years of follow-up. Genotypes associated with C3 were identified in a genome-wide association study. Diabetes Genetics Replication and Meta-Analysis and the European Genetic Database were used for in silico look-up.
Results:
In all, 538 (12.3%) subjects developed diabetes during 18 years of follow-up. High C3 was significantly associated with incidence of diabetes after risk factor adjustments (hazard ratio comparing 4th vs 1st quartile, 1.54 (95% confidence interval, 1.13 to 2.09; P = 0.005). C3 was associated with polymorphisms at the complement factor H locus (P < 10-8). However, no relationship with diabetes was observed for this locus. Another eight loci were associated with C3 with P < 10-5. One of them, the glucose kinase regulatory protein (GCKR) locus, has been previously associated with diabetes. The relationship between C3 levels and the GCKR locus was replicated in the European Genetic Database cohort.
Conclusions:
Plasma concentration of C3 is a risk marker for incidence of diabetes. The results suggest that this association could, in part, be explained by pleiotropic effects related to the GCKR gene.