Highlights
- •We analyzed genetic sex-difference in cIMT a marker of subclinical atherosclerosis.
- •Genome wide interaction study was performed in a sample from NOMAS.
- •Sex–SNP interactions on cIMT was tested using regression analysis.
- •LEKR1 and GALNT10 genes influenced sex-specific development of cIMT.
- •Our study reveals multiple loci that may modulate sex difference in cIMT.
Abstract
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.
Keywords
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Article info
Publication history
Published online: April 15, 2015
Accepted:
April 13,
2015
Received in revised form:
March 27,
2015
Received:
January 7,
2015
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
