Genetic associations with carotid intima-media thickness link to atherosclerosis with sex-specific effects in sub-Saharan Africans

Abstract

Atherosclerosis precedes the onset of clinical manifestations of cardiovascular diseases (CVDs). We used carotid intima-media thickness (cIMT) to investigate genetic susceptibility to atherosclerosis in 7894 unrelated adults (3963 women, 3931 men; 40 to 60 years) resident in four sub-Saharan African countries. cIMT was measured by ultrasound and genotyping was performed on the H3Africa SNP Array. Two new African-specific genome-wide significant loci for mean-max cIMT, SIRPA (p = 4.7E-08), and FBXL17 (p = 2.5E-08), were identified. Sex-stratified analysis revealed associations with one male-specific locus, SNX29 (p = 6.3E-09), and two female-specific loci, LARP6 (p = 2.4E-09) and PROK1 (p = 1.0E-08). We replicate previous cIMT associations with different lead SNPs in linkage disequilibrium with SNPs primarily identified in European populations. Our study find significant enrichment for genes involved in oestrogen response from female-specific signals. The genes identified show biological relevance to atherosclerosis and/or CVDs, sex-differences and transferability of signals from non-African studies.

Fig. 1. Genetic association with cIMT in sub-Saharan Africans (7894 participants).

A QQ-plot for the combined dataset GIF = 0.997. B Manhattan plot showing the −log10-transformed two-tailed P-value of each SNP from the GWAS for Mean-Max cIMT on the Y-axis and base-pair positions along the chromosomes on the X-axis. Adjustment was made for age, sex and 8 PCs. The red line indicates Bonferroni-corrected genome-wide significance (p < 5E-08); the blue line indicates the threshold for suggestive association (p < 1E-05).

Fig. 2. Regional association plots for selected top SNPs showing genetic associations with mean-max cIMT.

A Regional association plot of the FBXL17 region in the combined dataset. B Plot of the SIRPA region in the combined dataset. C Regional association plot of the PROK1 region in the female-specific dataset. D Regional association plot of the LARP6/UACA region female-specific dataset. E Regional association plot of the MAP3K7 region in the male-specific dataset. F Regional association plot of the SNX29 region in the male-specific dataset. For each locus, the plots show the −log10-transformed p-value of each SNP on the y-axis and base-pair positions along the chromosomes on the X-axis. Genes overlapping the locus are displayed below the plot. SNPs are coloured by their LD value r² (generated from the study population) with the lead SNP in the region shown as a purple diamond.

Fig. 3. Miami plot showing female and male-specific associated p-values for mean-max cIMT.

The −log10-transformed two-tailed P-value of each SNP from the GWAS for Mean-Max cIMT on the Y-axis (Adjusted for age and 5 PCs for each sex) and base-pair positions along the chromosomes on the X-axis. On top are the results for female-specific analysis (n = 3963) and on the bottom the results for the male-specific analysis (n = 3931). The red line indicates Bonferroni-corrected genome-wide significance (p < 5 × 10⁻⁸).

Fig. 4. Genotype plots for genetic associations of rs115473055 stratified by menopausal status.

A Pre-menopausal women (n = 1245), B Post-menopausal women (n = 1108) with cIMT. Bounds of boxes represent 1st and 3rd quintiles, bars represent 95th percentiles, mean.