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Research Article| Volume 240, ISSUE 2, P462-467, June 2015

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

  • Author Footnotes
    1 These authors contributed equally and are co-equal first authors.
    Chuanhui Dong
    Footnotes
    1 These authors contributed equally and are co-equal first authors.
    Affiliations
    Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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  • Author Footnotes
    1 These authors contributed equally and are co-equal first authors.
    David Della-Morte
    Footnotes
    1 These authors contributed equally and are co-equal first authors.
    Affiliations
    Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

    Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy

    IRCCS San Raffaele Pisana, Rome, Italy
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  • Ashley Beecham
    Affiliations
    John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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  • Liyong Wang
    Affiliations
    John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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  • Digna Cabral
    Affiliations
    Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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  • Susan H. Blanton
    Affiliations
    John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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  • Ralph L. Sacco
    Affiliations
    Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

    John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

    Department of Epidemiology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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  • Tatjana Rundek
    Correspondence
    Corresponding author. Department of Neurology, Miller School of Medicine, University of Miami, 1120 NW 14th Street, Miami, FL 33136, USA.
    Affiliations
    Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

    Department of Epidemiology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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  • Author Footnotes
    1 These authors contributed equally and are co-equal first authors.

      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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