TY - JOUR
T1 - Association of polymorphisms in the Hepatocyte Growth Factor gene promoter with keratoconus
AU - Burdon, Kathryn
AU - Macgregor, Stuart
AU - Bykhovskaya, Yelena
AU - Javadiyan, Shahrbanou
AU - Xiaohui, Li
AU - Laurie, Kate
AU - Muszynska, Dorota
AU - Lindsay, Richard
AU - Lechner, Judith
AU - Haritunians, Talin
AU - Henders, Anjali
AU - Dash, Durga
AU - Siscovick, David
AU - Anand, Seema
AU - Aldave, Anthony
AU - Coster, Douglas
AU - Szczotka-Flynn, Loretta
AU - Mills, Richard
AU - Iyengar, Sudha
AU - Taylor, Kent
AU - Phillips, Anthony
AU - Montgomery, G
AU - Rotter, Jerome
AU - Hewitt, Alex
AU - Sharma, Shiwani
AU - Rabinowitz, Yaron
AU - Willoughby, Colin
AU - Craig, Jamie
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862833128&partnerID=8YFLogxK
U2 - 10.1167/iovs.11-8261
DO - 10.1167/iovs.11-8261
M3 - Article
SN - 0146-0404
VL - 52
SP - 8514
EP - 8519
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 11
ER -