title: Genetic variants in LEKR1 and GALNT10 modulate sex-difference in carotid intima-media thickness: a genome-wide interaction study.
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.
authors.affiliation: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Della-Morte
authors.affiliation: 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.
authors.forename: Ashley
authors.initials: A
authors.lastname: Beecham
authors.affiliation: 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.
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Digna
authors.initials: D
authors.lastname: Cabral
authors.affiliation: 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.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.affiliation: 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.
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Sacco
authors.affiliation: 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. Electronic address: trundek@med.miami.edu.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Rundek
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D002339:Carotid Arteries / Q000000981:diagnostic imaging* / Q000201:enzymology; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D009519:New York City; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D012737:Sex Factors; D044465:White People / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D017350:N-Acetylgalactosaminyltransferases; D011506:Proteins; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000605359:LEKR1 protein, human
keywords: Atherosclerosis; Carotid intima-media thickness; Carotid ultrasonography; Race-ethnicities; Sex-gene interaction