TY - JOUR T1 - Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus. JF - Invest Ophthalmol Vis Sci Y1 - 2011 A1 - Burdon, Kathryn P A1 - Macgregor, Stuart A1 - Bykhovskaya, Yelena A1 - Javadiyan, Sharhbanou A1 - Li, Xiaohui A1 - Laurie, Kate J A1 - Muszynska, Dorota A1 - Lindsay, Richard A1 - Lechner, Judith A1 - Haritunians, Talin A1 - Henders, Anjali K A1 - Dash, Durga A1 - Siscovick, David A1 - Anand, Seema A1 - Aldave, Anthony A1 - Coster, Douglas J A1 - Szczotka-Flynn, Loretta A1 - Mills, Richard A A1 - Iyengar, Sudha K A1 - Taylor, Kent D A1 - Phillips, Tony A1 - Montgomery, Grant W A1 - Rotter, Jerome I A1 - Hewitt, Alex W A1 - Sharma, Shiwani A1 - Rabinowitz, Yaron S A1 - Willoughby, Colin A1 - Craig, Jamie E KW - Adult KW - Aged KW - Chromosomes, Human, Pair 7 KW - Corneal Topography KW - Enzyme-Linked Immunosorbent Assay KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Hepatocyte Growth Factor KW - Humans KW - Keratoconus KW - Middle Aged KW - Nucleic Acid Hybridization KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic KW - Sequence Tagged Sites 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.

VL - 52 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22003120?dopt=Abstract ER -