Abstract P139: Association of a Potentially Functional Wnt Pathway Mutation With Carotid Artery Wall Traits in African Ancestry Men

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Abstract

The wingless (Wnt) pathway is known to regulate many human systems, including embryonic development, bone mineralization, and cancer. There is emerging basic research evidence that the Wnt pathway is also involved in angiogenesis, atherosclerosis, and vascular damage repair. However, there have been no studies of the Wnt pathway and cardiovascular disease (CVD) in human populations. In a cohort of Afro-Caribbean men (the Tobago Health Study (THS)), we previously identified a potentially functional coding mutation (Ala64Thr) in the Frizzled-1 (FZD1) gene, which acts as a co-receptor with the low-density lipoprotein receptor protein (LRP) to initiate the Wnt signaling cascade. This mutation has a carrier frequency of ~4% in the THS and additional studies reported in the 1000 genomes project have found similar frequencies in other predominantly West African populations. In order to investigate the phenotypic consequences of this Wnt pathway mutation on subclinical CVD, we measured carotid artery wall traits using B-mode ultrasonography in 64 Ala64Thr mutation carriers and 395 controls from the THS. For this analysis, carotid artery measures of interest included carotid plaque prevalence, and common carotid mean intima-media thickness (IMT), inter-adventitial diameter (IAD), and lumen diameter (LD). We assessed differences in carotid traits by Ala64Thr status using multiple linear regression adjusting for CVD risk factors, including age, BMI, smoking, hypertension, diabetes, alcohol intake, physical activity, and sedentary behavior. Men were aged 64 years and were overweight (BMI: 27.5kg/m2), on average. Prevalence of hypertension and type 2 diabetes is high in this sample (66% and 24%, respectively). Men with Ala64Thr tended to be older and had higher prevalence of hypertension than non-carriers (P<0.05 for both). Carrying the Ala64Thr mutation was associated with significantly wider carotid diameters and, after adjustment for traditional CVD risk factors, mutation carriers had >1/3 of a SD greater LD than non-carriers (P=0.01). The effect magnitude of this mutation was similar for IAD, though not statistically significant (P=0.08). There was no significant difference in carotid IMT or plaque prevalence. While this mutation is not expected to be severely deleterious using in silico prediction software, Ala64 is highly conserved and located in a putative signaling peptide sequence. Carriers of a low frequency FZD1 coding mutation show greater remodeling of the carotid artery compared to non-carriers, suggesting that the Wnt pathway may be involved in vascular changes that occur early in the atherosclerotic disease process.

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