The association of a single-nucleotide polymorphism in CUBN and the risk of albuminuria and cardiovascular disease

Abstract

Albuminuria is an important risk factor for cardiovascular disease (CVD). We have previously identified a missense single-nucleotide polymorphism (rs1801239) in the CUBN gene that is associated with albuminuria. Whether albuminuria is associated with CVD in the presence of the CUBN mutation is unknown. We analyzed participants from the Framingham Heart Study (n=6399, mean age 47 years, 53.4% women) who underwent genotyping of rs1801239. Cox proportional hazards models were used to test the association between microalbuminuria [UACR≥17 mg/g (men) and ≥25 mg/g (women)] and incident CVD stratified by the presence or absence of the CUBN risk allele. We tested whether the association between microalbuminuria and CVD was altered by the presence of the risk allele with interaction testing. Overall, 21.1% of participants carried the risk allele. As expected, carriers of the risk (C) allele had a higher prevalence of microalbuminuria (10.7 versus 8.9%, P=0.04). During a mean follow-up of 10.4 years, 5.6% (n=346) of participants experienced a CVD event. Microalbuminuria was associated with an increased risk of CVD [hazards ratio (HR) 1.46, 95% confidence interval (CI) 1.14-1.88]. When stratified by risk allele carrier status, the HR for CVD was 1.95 (95% CI 1.15-3.29) among those with compared to 1.33 (95% CI 1.00-1.76) among those without the risk allele. There was no interaction between microalbuminuria and rs1801239 on CVD (Pinteraction=0.49). MA is associated with CVD irrespective of the presence of the CUBN risk allele. These results challenge the concept that albuminuria in the setting of this mutation is benign.