Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis

Abstract

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland's population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.

Fig. 1. GWAS results for coronary atherosclerosis in FinnGen.

Total number of independent genome-wide significant associations (GWS; p < 5 × 10^-8) is 38, the lead variant in each marked with diamonds. Four previously unreported associations for CVD-related phenotypes are highlighted with ±750 Mb around the lead variant in the region as red and the lead variant marked with red diamond.

Fig. 2. Results for rs534125149 against coronary heart disease and myocardial infarction across cohorts where available and meta-analysis results.

Logistic regression has been applied, adjusted for age and sex. Meta-analysis was performed using inverse-variance weighted fixed-effects meta-analysis method. Black dots represents odds ratios, and lines 95% confidence interval from the the single cohorts and red diamonds represent the results from meta-analysis ends of the diamonds representing the ends of the 95% confidence interval. Source data for the figure is in Supplementary Data 1.

Fig. 3. Results for rs118042209 in TMEM200A and rs5974585 in FHL1 against coronary heart disease and myocardial infarction across different cohorts across cohorts where available.

Logistic regression has been applied, adjusted for age and sex. Meta-analysis was performed using inverse-variance weighted fixed-effects meta-analysis method. Black dots represent odds ratios, and lines 95% confidence interval from the single cohorts and red diamonds represent the results from meta-analysis ends of the diamonds representing the ends of the 95% confidence interval. Source data for the figure is in Supplementary Data 1.

Fig. 4. Phenome-wide association study (PheWAS) results for rs534125149.

Total number of tested endpoints is 2861 (A complete list of endpoints analyzed and their definitions is available at https://www.finngen.fi/en/researchers/clinical-endpoints). The dashed line represents the phenome-wide significance threshold, multiple testing corrected by the number of endpoints = 0.05/2861 = 1.75 × 10⁻⁵. All endpoints reaching that threshold are labeled in the figure.

Fig. 5. Effect size comparison.

Comparison of the effects (OR) of rs534125149 and rs201988637 for 14 endpoints with p-value < 1.75 × 10^-5 (PWS) for rs534125149 in FinnGen R6. 95% confidence intervals represented as gray lines.

Fig. 6. Cumulative incidence plots for first event of myocardial infarction in FinnGenR6.

Red line represents carriers (homo- or heterozygous) for either rs534125149 or rs201988637 (n = 17,838), and blue line represent non-carriers (n = 242,567). Hazard ratio and p-value are from cox-proportional hazards model. Dashed lines represent 95% confidence intervals.

Fig. 7. Results for pulse pressure association across all cohorts with splice acceptor variant rs201988637 available (FINRISK, GeneRISK, YFS, EstBB, and UKBB).

Size of the boxes represent the sample size of the cohorts, and the lines the 95% confidence interval. Associations were tested using linear regression, adjusting for age and sex Pulse pressure phenotypes were inverse-rank normalized prior analysis. Source data for the figure is in Supplementary Data 1.