Project Summary Contact lens wear is the leading risk factor for microbial keratitis (MK) in developed countries with a population attributable risk of 65%. Our previous studies have shown that one-third to one-half of soft lenses wearers harbor abnormal microbial bioburden on their lenses or storage cases, including highly pathogenic organisms, yet the vast majority of patients do not experience infection. Therefore, bioburden exposure is necessary but insufficient for susceptibility to contact lens associated MK. This disorder is similar to other infectious diseases where only a fraction of the exposed individuals develop clinical disease, suggesting the importance of the resistance phenotype. Host immunity and its genetic underpinning is critical to comprehending disease etiology, wherein the immune response is a balance between promoting quick and active pathogen clearance vs. allowing for greater tolerance. We propose to test the hypothesis that genomic differences in immune pathways render a contact lens wearer more susceptible to MK by enrolling well defined cases and super-controls in a large-scale genomic study and conduct genotyping utilizing the Infinium ImmunoArray. To increase our ability to detect genetic variants associated with resistance to infection, super-controls will be defined as exposed individuals exhibiting abnormal bioburden on lenses or storage cases, plus behavior known to increase risk for MK, but no history of disease. We will also execute an extended analysis utilizing unphenotyped controls obtained from dbGaP to increase power for our association analyses. In sum, we propose to identify novel loci for contact lens associated MK.