Genetic variants in LEKR1 and GALNT10 modulate sex-difference in carotid intima-media thickness: A genome-wide interaction study

Background: There is an established sex-difference in carotid artery intima-media thickness (cIMT), a recognized marker of subclinical atherosclerosis. However, the genetic underpinnings of sex-differences in gene-IMT associations are largely unknown. Methods: With a multistage design using 731,037 single nucleotide polymorphisms (SNP), a genome wide interaction study was performed in a discovery sample of 931 unrelated Hispanics, followed by replication in 153 non-Hispanic whites and 257 non-Hispanic blacks. Assuming an additive genetic model, we tested for sex-SNP interactions on cIMT using regression analysis. Results: We did not identify any genome-wide significant SNPs but identified 14 loci with suggestive significance. Specifically, SNP-by-sex interaction was found for rs7616559 within LEKR1 gene (P=3.5E-06 in Hispanic discovery sample, P=0.018 in White, and P=1.3E-06 in combined analysis) and for rs2081015 located within GALNT10 gene (P=4.5E-06 in Hispanic discovery sample, P=0.042 in Blacks, and P=5.3E-07 in combined analysis). For rs7616559 within LEKR1, men had greater cIMT than women in G allele carriers (beta±SE: 0.044±0.007, P=4.2E-09 in AG carriers; beta±SE: 0.064±0.007, P=6.2E-05 in GG carriers). For rs2081015 within GALNT10, men had greater cIMT than women in C allele carriers (beta±SE: 0.022±0.007, P=0.002 in CT carriers; beta±SE: 0.051±0.008, P=3.1E-10 in CC carriers). Conclusions: Our genome-wide interaction analysis reveals multiple loci that may modulate sex difference in cIMT. Of them, genetic variants on LEKR1 and GALNT10 genes have been associated with control of adiposity and weight. Given the consistent findings across different-ethnic groups, further studies are warranted to perform investigations of functional genetic variants in these regions.