Abstract
Purpose :
45 million Americans wear contact lenses (CL) which are the leading risk factor for microbial keratitis (MK). In CL related MK (CL-MK), a contaminated CL is the vector to transfer organisms to the cornea, but there is a gap in knowledge because only a minority of CL users experience MK (50-130/100,000 annually). The role of genetic susceptibility to CL-MK was proposed based upon candidate gene analysis of several cytokine and immune genes with susceptibility and severity to CL-MK, however, no genome-wide association studies (GWAS) of CL-MK have been conducted. Since the vast majority of MK is bacterial, this study assessed genetic susceptibility using GWAS for CL-bacterial keratitis.
Methods :
We recruited 148 bacterial CL-MK cases and 152 high risk controls who self-identified as White Americans; controls were unaffected despite displaying risky CL habits. Biospecimens were genotyped using the Infinium Global Screening Array v3 (Illumina, CA) and imputed to 8.8 million SNPs for analysis. A GWAS was conducted adjusting for age, age2, sex and population substructure.
Results :
There were 5 prominent hits, including 3 genic variants: CNTN5-rs755779C (OR=2.8, p=2.1x10-6), COL26A1-rs11772848G (OR=3.3, p=2.8x10-6), and MACROD2-rs2423967G (OR=2.5, p=7.9x10-6). The COL26A1 product is an atypical, trimer-forming collagen, whose role in human disease is not well characterized. CNTN5 belongs to the immunoglobulin superfamily, associates with chronic inflammatory conditions, and mouse knockouts display abnormal lymph node morphology. MACROD2 transfers single ADP-ribose groups from target proteins. Bacteria possess very similar ADP ribosyl transferases that act as human endotoxins, and may hijack the MACROD2 cell machinery to exacerbate CL-MK in susceptible individuals.
Conclusions :
Our results show promise in this first GWAS using a narrow definition for CL-MK. Despite modestly significant results due to the limited sample size, after close examination, COL26A1, MACROD2 and CNTN5 may be related to various biological functions underlying CL-MK susceptibility. Knowledge of mechanisms associated with these genes may open novel therapeutic options. Next steps include increasing our sample size for replication and meta-analyses.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.