Genetic Variants Associated With Corneal Biomechanical Properties and Potentially Conferring Susceptibility to Keratoconus in a Genome-Wide Association Study

Abstract

IMPORTANCE Keratoconus is an important cause of visual loss in young adults, but little is known about its genetic causes. Understanding the genetic determinants of corneal biomechanical factors may in turn teach us about keratoconus etiology. OBJECTIVES To identify genetic associations with corneal biomechanical properties and to examine whether these genetic variants are associated with keratoconus. DESIGN, SETTING, AND PARTICIPANTS A stage 1 discovery and replication genome-wide association study (GWAS) of corneal biomechanical properties was performed in 2 cross-sectional populations (6645 participants from the European Prospective Investigation into Cancer and Nutrition [EPIC]-Norfolk Eye Study and 2384 participants from the TwinsUK study). In stage 2, the association of genetic determinants identified in stage 1 with keratoconus was examined in a case-control study. A total of 752 patients with keratoconus were compared with 974 TwinsUK participants (undergoing direct sequencing) or 13 828 EPIC-Norfolk participants (undergoing genotyping and imputation) who were not part of the stage 1 analysis.

Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population

“…Several studies of genetic screening found in the literature have investigated this gene as well as other such as VSX1, LOX, TIMP3, DOCK9, and collagen genes and identified genetic changes that may be related to the disease. Nevertheless, these results alone are not consistent enough to consider these genetic agents as disease-triggering [23,24,[35][36][37][38][39].…”

Molecular Genetics of Keratoconus: Clinical Implications

“…The second stage of the association study involved 752 keratoconus patients as compared with 974 British TwinsUK or 13,828 EPIC-Norfolk. The results showed a likely role in development of keratoconus with 5 associated loci in CH, ANAPC1, ADAMTS8, ADAMTS17, ABCA6, and COL6A1 [36].…”

“…Often, most patients are presented late for ophthalmic consultation and investigations. Prior patients' awareness or notifications of signs and symptoms, genetic testing, if available, would provide diagnosis before symptoms surface [36].…”

“…Apart from corneal morphologic features, a recent GWAS investigated corneal biomechanical properties in an European cohort of 6645 participants and 2384 participants from the British TwinsUK study [36]. The second stage of the association study involved 752 keratoconus patients as compared with 974 British TwinsUK or 13,828 EPIC-Norfolk.…”

“…Notably, genetic studies on the corneal structure, principally central cornea thickness and cornea curvature have successfully mapped keratoconus genes. Corneal properties, as recently exemplified by a successful GWAS on corneal biomechanical properties [36], should provide a basis for genetic research. Rigorous and large multi-center population-based studies, with age-standardized rates, random sampling, progression follow-ups, and accurate and standardized diagnosis, are warranted for better understanding of pathogenesis of keratoconus and for establishment of genetic markers.…”