Cystatin C and Risk of Diabetes and the Metabolic Syndrome – Biomarker and Genotype Association Analyses

BACKGROUND We recently reported a relationship between plasma levels of cystatin C and incidence of the metabolic syndrome (MetS) among the first 2,369 subjects who participated in the re-examination study of the population-based Malmö and Diet Cancer Cardiovascular cohort (MDC-CC-re-exam). In this study we aimed to replicate these results and also investigate if cystatin C was causally associated with MetS and diabetes. METHODS We estimated the effect size of the strongest GWAS derived cystatin C SNP (major allele of rs13038305) on plasma cystatin C in the now completed MDC-CC-re-exam (n = 3,734) and thereafter examined the association between plasma cystatin C (403 cases of diabetes and 2665 controls) as well as rs13038305 (235 cases and 2425 controls) with incident diabetes. The association of rs13038305 and incident MetS (511 cases of MetS and 1980 controls) was similarly investigated in the whole MDC-CC-re-exam. We also attempted to replicate our previously shown association of cystatin C with incident MetS in subjects from the MDC-CC-re-exam (147 cases and 711 controls) that were not included in our previous report. RESULTS In the entire MDC-CC-re-exam, each copy of the major allele of rs13038305 was associated with approximately 0.30 standard deviation (SD) higher plasma concentration of cystatin C (β = 0.33, p = 4.2E-28) in age and sex adjusted analysis. Cystatin C in plasma was not associated with incident diabetes after adjustment for known diabetes risk factors (OR per 1 SD increment 0.99 (0.86-1.13), p = 0.842). In the replication cohort of MDC-CC-re-exam, the OR (95% CI) for incident MetS in subjects belonging to quartiles 1, 2, 3 and 4 of plasma cystatin C levels was 1.00 (reference), 1.21 (0.70-2.07), 1.62 (0.95-2.78) and 1.72 (1.01-2.93) (ptrend = 0.026) in age and sex adjusted analysis. In the entire MDC-CC-re-exam the odds ratio for incident MetS and diabetes per copy of the major rs13038305 allele was 1.13, (0.95-1.34), p = 0.160 and 1.07, 95% CI 0.89-1.30, p = 0.478, respectively. CONCLUSION We were able to replicate our previously shown association between high levels of cystatin C and increased risk of future development of MetS. However, a causal involvement of cystatin C in the etiology of MetS or diabetes seems unlikely since genetic elevation of plasma cystatin C was not significantly related to incidence of these diseases.