PURPOSE: 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.
PURPOSE: 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: F Brancati; E M Valente; A Sarkozy; J Fehèr; M Castori; P Del Duca; R Mingarelli; A Pizzuti; B Dallapiccola Journal: J Med Genet Date: 2004-03 Impact factor: 6.318
Authors: H Hutchings; H Ginisty; M Le Gallo; D Levy; F Stoësser; J F Rouland; J L Arné; M H Lalaux; P Calvas; M P Roth; A Hovnanian; F Malecaze Journal: J Med Genet Date: 2005-01 Impact factor: 6.318
Authors: L P Fried; N O Borhani; P Enright; C D Furberg; J M Gardin; R A Kronmal; L H Kuller; T A Manolio; M B Mittelmark; A Newman Journal: Ann Epidemiol Date: 1991-02 Impact factor: 3.797
Authors: Q Li; J Weng; R R Mohan; G L Bennett; R Schwall; Z F Wang; K Tabor; J Kim; S Hargrave; K H Cuevas; S E Wilson Journal: Invest Ophthalmol Vis Sci Date: 1996-04 Impact factor: 4.799
Authors: Michal Kabza; Justyna A Karolak; Malgorzata Rydzanicz; Michał W Szcześniak; Dorota M Nowak; Barbara Ginter-Matuszewska; Piotr Polakowski; Rafal Ploski; Jacek P Szaflik; Marzena Gajecka Journal: Eur J Hum Genet Date: 2017-02-01 Impact factor: 4.246
Authors: Hui Qi; Shrestha Priyadarsini; Sarah E Nicholas; Akhee Sarker-Nag; Jeremy Allegood; Charles E Chalfant; Nawajes A Mandal; Dimitrios Karamichos Journal: J Lipid Res Date: 2017-02-10 Impact factor: 5.922
Authors: Nicholas B Larson; Cecilia Berardi; Paul A Decker; Christina L Wassel; Phillip S Kirsch; James S Pankow; Michele M Sale; Mariza de Andrade; Hugues Sicotte; Weihong Tang; Naomi Q Hanson; Michael Y Tsai; Kent D Taylor; Suzette J Bielinski Journal: Ann Hum Genet Date: 2015-05-22 Impact factor: 1.670
Authors: Srujana Sahebjada; Elsie Chan; Jing Xie; Grant R Snibson; Mark Daniell; Paul N Baird Journal: Int Ophthalmol Date: 2020-11-16 Impact factor: 2.031
Authors: Yi Lu; Veronique Vitart; Kathryn P Burdon; Chiea Chuen Khor; Yelena Bykhovskaya; Alireza Mirshahi; Alex W Hewitt; Demelza Koehn; Pirro G Hysi; Wishal D Ramdas; Tanja Zeller; Eranga N Vithana; Belinda K Cornes; Wan-Ting Tay; E Shyong Tai; Ching-Yu Cheng; Jianjun Liu; Jia-Nee Foo; Seang Mei Saw; Gudmar Thorleifsson; Kari Stefansson; David P Dimasi; Richard A Mills; Jenny Mountain; Wei Ang; René Hoehn; Virginie J M Verhoeven; Franz Grus; Roger Wolfs; Raphaële Castagne; Karl J Lackner; Henriët Springelkamp; Jian Yang; Fridbert Jonasson; Dexter Y L Leung; Li J Chen; Clement C Y Tham; Igor Rudan; Zoran Vatavuk; Caroline Hayward; Jane Gibson; Angela J Cree; Alex MacLeod; Sarah Ennis; Ozren Polasek; Harry Campbell; James F Wilson; Ananth C Viswanathan; Brian Fleck; Xiaohui Li; David Siscovick; Kent D Taylor; Jerome I Rotter; Seyhan Yazar; Megan Ulmer; Jun Li; Brian L Yaspan; Ayse B Ozel; Julia E Richards; Sayoko E Moroi; Jonathan L Haines; Jae H Kang; Louis R Pasquale; R Rand Allingham; Allison Ashley-Koch; Paul Mitchell; Jie Jin Wang; Alan F Wright; Craig Pennell; Timothy D Spector; Terri L Young; Caroline C W Klaver; Nicholas G Martin; Grant W Montgomery; Michael G Anderson; Tin Aung; Colin E Willoughby; Janey L Wiggs; Chi P Pang; Unnur Thorsteinsdottir; Andrew J Lotery; Christopher J Hammond; Cornelia M van Duijn; Michael A Hauser; Yaron S Rabinowitz; Norbert Pfeiffer; David A Mackey; Jamie E Craig; Stuart Macgregor; Tien Y Wong Journal: Nat Genet Date: 2013-01-06 Impact factor: 38.330
Authors: Xiaohui Li; Yelena Bykhovskaya; Yongming G Tang; Yoana Picornell; Talin Haritunians; Anthony J Aldave; Loretta Szczotka-Flynn; Sudha K Iyengar; Jerome I Rotter; Kent D Taylor; Yaron S Rabinowitz Journal: Cornea Date: 2013-05 Impact factor: 2.651