Association of polymorphisms in the Hepatocyte Growth Factor gene promoter with keratoconus

Kathryn Burdon, Stuart Macgregor, Yelena Bykhovskaya, Shahrbanou Javadiyan, Li Xiaohui, Kate Laurie, Dorota Muszynska, Richard Lindsay, Judith Lechner, Talin Haritunians, Anjali Henders, Durga Dash, David Siscovick, Seema Anand, Anthony Aldave, Douglas Coster, Loretta Szczotka-Flynn, Richard Mills, Sudha Iyengar, Kent TaylorAnthony Phillips, G Montgomery, Jerome Rotter, Alex Hewitt, Shiwani Sharma, Yaron Rabinowitz, Colin Willoughby, Jamie Craig

    Research output: Contribution to journalArticlepeer-review

    105 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)8514-8519
    Number of pages6
    JournalInvestigative Ophthalmology and Visual Science
    Issue number11
    Publication statusPublished - Oct 2011


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