title: Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.
abstract: OBJECTIVE
  Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.
  
  
  METHODS
  A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.
  
  
  RESULTS
  Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10(-3) and 7.4 × 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10(-4) (odds ratio [OR] = 1.30) and 2.9 × 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10(-3)).
  
  
  CONCLUSIONS
  SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.
authors.affiliation: Cornea Genetic Eye Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Yelena
authors.initials: Y
authors.lastname: Bykhovskaya
authors.forename: Ana Laura Caiado
authors.initials: AL
authors.lastname: Canedo
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: David
authors.initials: D
authors.lastname: Siscovick
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Aldave
authors.forename: Loretta
authors.initials: L
authors.lastname: Szczotka-Flynn
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Yaron S
authors.initials: YS
authors.lastname: Rabinowitz
mesh_terms: D000328:Adult; D000368:Aged; D024062:Collagen Type V / Q000235:genetics* / Q000378:metabolism; D003315:Cornea / Q000378:metabolism / Q000473:pathology*; D019781:Corneal Topography; D004247:DNA / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007640:Keratoconus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D033401:Microscopy, Acoustic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D041623:Tomography, Optical Coherence
chemical_list: C530725:COL5A1 protein, human; D024062:Collagen Type V; D004247:DNA