The ACOT4 multi-nucleotide variant (rs35724886) was associated with a 30% lower odds of elevated blood pressure (OR 0.70; 95% CI 0.51-0.97; p=0.03) in Norfolk Island participants and a 4% lower odds (OR 0.96; p=0.00014) in UK Biobank, alongside a small increase in total cholesterol (β=0.011 mmol/L; p=0.0098) in UK Biobank.
Observational (n=201,226)
Yes
Is the ACOT4 multi-nucleotide variant associated with cardiovascular risk traits such as blood pressure and cholesterol levels?
A novel multi-nucleotide variant in the ACOT4 gene is associated with lower blood pressure but higher total cholesterol, highlighting a complex genetic regulation of cardiovascular risk factors.
Effect estimate: OR 0.70 for elevated blood pressure in Norfolk Island cohort; OR 0.96 in UK Biobank; β=0.011 mmol/L increase in total cholesterol in UK Biobank (95% CI 95% CI 0.51 to 0.97 for Norfolk Island elevated BP, 95% CI 0.95-0.98 UK Biobank elevated BP)
Absolute Event Rate: 0.7% vs 1%
p-value: p=0.03 for Norfolk Island elevated BP; 0.00014 for UK Biobank elevated BP; 0.0098 for total cholesterol in UK Biobank
Background: Cholesterol imbalances and elevated blood pressure (BP) are closely interrelated risk factors for cardiovascular disease (CVD) and are subject to genetic influences. We sought to identify novel associations between candidate genetic coding variants and CVD traits in our isolated study cohort and validate them in a general population cohort. Methods: We leveraged the population genetic features of the Norfolk Island Health Study (NIHS, n = 601), to identify candidate functional variants which were analysed for association with CVD and metabolic syndrome traits. We followed up suggestive variant-trait associations in the 2022 release of UK Biobank whole exome data (n = 200,625). Results: We identified a novel ten-base-pair in-frame missense multi-nucleotide variant (MNV), tagged by rs35724886, in the lipid metabolism gene ACOT4, which was associated with cholesterol levels and blood pressure. The MNV was associated with a lower incidence of ‘elevated BP’—systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg—(OR: 0.70; 95% CI: 0.51, 0.97; p = 0.03), and higher total cholesterol levels (β = 0.08; p = 0.04) in the NIHS. Validation in the UK Biobank revealed consistent associations between the MNV (proxied by rs35725886) and lower incidence of ‘elevated BP’ (p = 0.0001), higher total cholesterol (p = 0.01), and reduced use of medication for managing blood pressure (p = 1.8 × 10−6) and cholesterol (p = 0.002). Structural modelling and in-silico predictions suggested that the MNV introduced destabilising changes in the ACOT4 protein, likely influencing peroxisomal lipid metabolism pathways critical to CVD risk. Conclusions: This study identified a coding MNV with potential implications for understanding the genetic regulation of lipid metabolism and its impact on cardiovascular health.
Meyjes-Brown et al. (Mon,) conducted a observational in Cardiovascular risk factors including blood pressure and cholesterol (n=201,226). ACOT4 multi-nucleotide variant (MNV) tagged by rs35724886 vs. Wild-type genotype was evaluated on Association of ACOT4 MNV (rs35724886) with elevated blood pressure (defined as systolic BP ≥130 mmHg or diastolic BP ≥80 mmHg or use of blood pressure medication) and total cholesterol levels (measured in mmol/L) (OR 0.70 for elevated blood pressure in Norfolk Island cohort; OR 0.96 in UK Biobank; β=0.011 mmol/L increase in total cholesterol in UK Biobank, 95% CI 95% CI 0.51 to 0.97 for Norfolk Island elevated BP, 95% CI 0.95-0.98 UK Biobank elevated BP, p=0.03 for Norfolk Island elevated BP; 0.00014 for UK Biobank elevated BP; 0.0098 for total cholesterol in UK Biobank). The ACOT4 multi-nucleotide variant (rs35724886) was associated with a 30% lower odds of elevated blood pressure (OR 0.70; 95% CI 0.51-0.97; p=0.03) in Norfolk Island participants and a 4% lower odds (OR 0.96; p=0.00014) in UK Biobank, alongside a small increase in total cholesterol (β=0.011 mmol/L; p=0.0098) in UK Biobank.