Context and objective

We examined whether a prevalent caveolin-1 gene (CAV1) variant, previously related to insulin resistance, is associated with metabolic syndrome (MetS).

Patients and methods

We included subjects genotyped for the CAV1 variant rs926198 from two cohorts: 735 Caucasians from the HyperPATH multicenter study, and 810 Hispanic participants from the HTN-IR cohort.

Results

Minor allele carriers from HyperPATH cohort (57% of subjects) had higher Framingham risk scores, higher odds of diabetes (10.7% vs 5.7%, p=0.016), insulin resistance (44.3% vs 35.1%, p=0.022), low HDL (49.3% vs 39.6%, p=0.018) and MetS (33% vs 20.5%, p<0.001) but similar BMI. Consistently, minor allele carriers exhibited higher odds of MetS, even when adjusted for confounders and relatedness (OR 2.83 (1.73-4.63), p<0.001). The association with MetS was replicated in the Hispanic cohort HTN-IR (OR 1.61, [1.06-2.44], p=0.025). Exploratory analyses suggest that MetS risk is modified by a CAV1 variant-BMI status interaction, whereby the minor allele carrier status strongly predicted MetS (OR 3.86 [2.05-7.27], p<0.001) and diabetes (OR 2.27 [1.07-4.78], p=0.03) in non-obese, but not in obese subjects. In addition, we observed a familial aggregation for MetS diagnosis in minor allele carriers.

Conclusion

The prevalent CAV1 gene variant rs926198 is associated with MetS in separate Caucasian and Hispanic cohorts. These findings appear to be driven by an interaction between the genetic marker and obesity status, suggesting that the CAV1 variant may improve risk profiling in non-obese subjects. Additional studies are needed to confirm the clinical implications of our results.

Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1(-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.