Genome-Wide Association Study of Chronic Venous Insufficiency and Lymphedema in the Million Veteran Program.

BACKGROUND

Lymphedema is a chronic condition characterized by the accumulation of fluid due to impaired lymphatic drainage, frequently occurring secondary to chronic venous insufficiency (CVI), malignancy, or obesity. Despite known environmental and clinical risk factors, the genetic contributors to lymphedema and CVI have been understudied.

METHODS

We conducted a multipopulation genome-wide association study in participants of the Million Veteran Program without cancer to identify genetic variants associated with CVI, lymphedema, and their cooccurrence. Individuals were categorized into 3 case groups: CVI only (n=34 664), lymphedema only (n=2452), and lymphedema+CVI (n=3283) and were compared with 367 684 controls.

RESULTS

We identified 11 genome-wide significant variants (P<5×10-8) in the multipopulation analysis, including 8 for CVI only, 1 for lymphedema only, and 2 for lymphedema+CVI, and 2 population-specific genetic variants. Three independent variants replicated in the UK Biobank for CVI only near CASZ1, SLC12A2, and NDP. Polygenic risk scores derived from the Million Veteran Program were associated with CVI in the UK Biobank and phenome-wide associations of CVI-associated variants revealed pleiotropic associations with cardiometabolic traits.

CONCLUSIONS

These findings enhance our understanding of the genetic architecture of lymphatic dysfunction.