title: Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.
abstract: OBJECTIVE
  Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.
  
  
  METHODS
  Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.
  
  
  RESULTS
  The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).
  
  
  CONCLUSIONS
  Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.
authors: Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia. kathryn.burdon@flinders.edu.au
authors: Kathryn P
authors: KP
authors: Burdon
authors: Stuart
authors: S
authors: Macgregor
authors: Yelena
authors: Y
authors: Bykhovskaya
authors: Sharhbanou
authors: S
authors: Javadiyan
authors: Xiaohui
authors: X
authors: Li
authors: Kate J
authors: KJ
authors: Laurie
authors: Dorota
authors: D
authors: Muszynska
authors: Richard
authors: R
authors: Lindsay
authors: Judith
authors: J
authors: Lechner
authors: Talin
authors: T
authors: Haritunians
authors: Anjali K
authors: AK
authors: Henders
authors: Durga
authors: D
authors: Dash
authors: David
authors: D
authors: Siscovick
authors: Seema
authors: S
authors: Anand
authors: Anthony
authors: A
authors: Aldave
authors: Douglas J
authors: DJ
authors: Coster
authors: Loretta
authors: L
authors: Szczotka-Flynn
authors: Richard A
authors: RA
authors: Mills
authors: Sudha K
authors: SK
authors: Iyengar
authors: Kent D
authors: KD
authors: Taylor
authors: Tony
authors: T
authors: Phillips
authors: Grant W
authors: GW
authors: Montgomery
authors: Jerome I
authors: JI
authors: Rotter
authors: Alex W
authors: AW
authors: Hewitt
authors: Shiwani
authors: S
authors: Sharma
authors: Yaron S
authors: YS
authors: Rabinowitz
authors: Colin
authors: C
authors: Willoughby
authors: Jamie E
authors: JE
authors: Craig
mesh_terms: D000328:Adult; D000368:Aged; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D019781:Corneal Topography; D004797:Enzyme-Linked Immunosorbent Assay; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000235:genetics*; D006801:Humans; D007640:Keratoconus / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016324:Sequence Tagged Sites
chemical_list: C066855:HGF protein, human; D017228:Hepatocyte Growth Factor