Association of the Hepatocyte Growth Factor Gene with Keratoconus in an Australian Population

Abstract

PurposeA previous study has indicated suggestive association of the hepatocyte growth factor (HGF) gene with Keratoconus. We wished to assess this association in an independent Caucasian cohort as well as assess its association with corneal curvature.ParticipantsKeratoconus patients were recruited from private and public clinics in Melbourne, Australia. Non-keratoconic individuals were identified from the Genes in Myopia (GEM) study from Australia. A total of 830 individuals were used for the analysis including 157 keratoconic and 673 non keratoconic subjects.MethodsTag single nucleotide polymorphisms (tSNPs) were chosen to encompass the hepatocyte growth factor gene as well as 2 kb upstream of the start codon through to 2 kb downstream of the stop codon. Logistic and linear regression including age and gender as covariates were applied in statistical analysis with subsequent Bonferroni correction.ResultsTen tSNPs were genotyped. Following statistical analysis and multiple testing correction, a statistically significant association was found for the tSNP rs2286194 {p = 1.1×10-3 Odds Ratio 0.52, 95% CI - 0.35, 0.77} for keratoconus. No association was found between the 10 tSNPs and corneal curvature.ConclusionsThese findings provide additional evidence of significant association of the HGF gene with Keratoconus. This association does not appear to act through the corneal curvature route.

Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent

“…8 The main statistics used here (allelic test) implicitly assume codominance, and is similar to the additive models assumed in the previous reports. 8,9,13,15 Although some caution is invited in the interpretation of our findings because of the relatively small sample size, the validation of rs2956540:G4C and rs3735520:G4A showing the same effect directions as previous studies in populations of European ancestry adds weight to the existing evidence. 8,9 Although not reaching a statistically significant threshold, the higher MAF of rs1800449:C4T and rs10519694:C4T in controls compared with the KC cases in our study, was consistent with protective effects of these alleles reported in another study using Caucasian case-control panels (Supplementary Table 2).…”

“…13 However, alternative SNPs to those shown statistically significant associations with KC in GWAS were tested. 8,13 LOX enzyme catalyses the final enzymatic reaction required for cross-linking of two basic components of extracellular matrix, collagens and elastin.…”

“…13 However, alternative SNPs to those shown statistically significant associations with KC in GWAS were tested. 8,13 LOX enzyme catalyses the final enzymatic reaction required for cross-linking of two basic components of extracellular matrix, collagens and elastin. Although the underlying mechanism of common variants contributing to the disease development remains unknown, the potential effect could lie in affecting the biologic activity of LOX via tissue specific alternative splicing or regulation of expression.…”

Keratoconus: an inflammatory disorder?

“…57 Association between single-nucleotide polymorphisms in the hepatocyte growth factor (HGF) gene and keratoconus has been found. 58,59 Multiple studies have reported a statistically significant risk of developing keratoconus in patients with polymorphism of the gene in charge of the IL-1β coding (IL-1B-31 T4C and IL-1B-511 C4T); 60,61 nevertheless, a recent study in a different population found no clear relation between the IL-1B gene polymorphism and the receptor antagonist IL-1 (ILRN VNTR) with the possibility of keratoconus development. 62 In vitro studies have found that cultured keratoconus corneal fibroblasts exhibit increased basal generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS).…”

Molecular genetic aspects of keratoconus pathogenesis

“…Кератоконус с крайним истонче-нием роговицы является клиническим признаком редких врождённых заболеваний соединительной ткани с грубыми аномалиями роговицы, таких как синдром хрупкой роговицы (СХР, аутосом-но-рецессивное генерализованное расстройство соединительной ткани) и синдром Элерса -Дан-лоса, вызванных мутацией в полиморфном сайте rs9938149 (С/А) гена ZNF469 (zinc-finger 469) [19]. Эта же мутация ассоциирована с риском изолиро-ванного кератоконуса [1,28]. Всего в гене ZNF469 идентифицировано 12 мутаций, которые вы-зывают СХР.…”