Related Experiment Video
Updated: Feb 13, 2026
Fundus Photography as a Convenient Tool to Study Microvascular Responses to Cardiovascular Disease Risk Factors in Epidemiological Studies
Published on: October 22, 2014
Complement C3 and Risk of Diabetic Microvascular Disease: A Cohort Study of 95202 Individuals from the General
Katrine Laura Rasmussen1, Børge Grønne Nordestgaard1, Sune Fallgaard Nielsen2
1Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark.
Insights
High complement C3 levels significantly increase the risk of diabetic microvascular complications, including retinopathy, nephropathy, and neuropathy. This association suggests a potential causal link between complement C3 and the development of these diabetic conditions.
Area of Science:
- Immunology
- Endocrinology
- Genetics
Background:
- The role of the complement system in diabetic microvascular complications remains unclear.
- This study investigates the association between complement C3 concentrations and the risk of diabetic retinopathy, nephropathy, and neuropathy.
Purpose of the Study:
- To test the hypothesis that elevated complement C3 levels are linked to an increased risk of diabetic microvascular complications.
- To explore the potential causal relationship using a Mendelian randomization approach.
Main Methods:
- Analysis of 95,202 individuals from the Copenhagen General Population Study with baseline complement C3 measurements.
- Genotyping for complement C3-determining SNPs (rs1065489, rs429608, rs448260) identified through genome-wide association scans.
- Longitudinal follow-up to assess the incidence of diabetic retinopathy, nephropathy, and neuropathy.
Main Results:
- A significant trend of increased cumulative incidence for diabetic retinopathy, nephropathy, and neuropathy with rising tertiles of complement C3.
- Hazard ratios indicated a 1.87-fold increased risk for retinopathy, 1.90-fold for nephropathy, and 1.56-fold for neuropathy per 1 SD increase in complement C3.
- Individuals in the highest tertile of complement C3 showed a 3.29-fold increased risk for retinopathy, 2.71-fold for nephropathy, and 2.40-fold for neuropathy compared to the lowest tertile.
Conclusions:
- High baseline complement C3 concentrations are significantly associated with an increased risk of diabetic retinopathy, nephropathy, and neuropathy in the general population.
- Epidemiological findings supported by Mendelian randomization suggest a potential causal role for complement C3 in these diabetic complications.
Background:
Whether the complement system is involved in the development of diabetic microvascular disease is unknown. We tested the hypothesis that high concentrations of complement C3 are associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population.
Methods:
We studied 95202 individuals from the general population with baseline measurements of complement C3, genotyped for rs1065489, rs429608, and rs448260 determining concentrations of complement C3, and enrolled in the Copenhagen General Population Study from 2003 through 2013, following them until April 10, 2013. Rs1065489, rs429608, and rs448260 were identified with genome-wide association scans in 3752 individuals from the Copenhagen City Heart Study.
Results:
The cumulative incidence was increased from the lowest tertile to the highest tertile of complement C3 for diabetic retinopathy (log-rank trend, P = 1 × 10-20), nephropathy (P = 7 × 10-15), and neuropathy (P = 5 × 10-10). Multifactorially adjusted hazard ratios for a 1 SD higher concentration of complement C3 were 1.87 (95% CI, 1.61-2.18) for diabetic retinopathy, 1.90 (1.62-2.23) for diabetic nephropathy, and 1.56 (1.29-1.89) for diabetic neuropathy. The multifactorially adjusted hazard ratio for individuals with the highest vs lowest tertile of complement C3 was 3.29 (1.78-6.07) for retinopathy, 2.71 (1.42-5.16) for nephropathy, and 2.40 (1.26-4.54) for neuropathy.
Conclusions:
High baseline concentrations of complement C3 were associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. These epidemiological findings were substantiated by a Mendelian randomization approach, potentially indicating causality.
Related Concept Videos
02:04Conservation of Small Populations
01:23Mechanistic Models: Compartment Models in Individual and Population Analysis
01:25What is Population Genetics?
01:27Complement System
00:57Population Growth
00:30What are Populations and Communities?