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β‐defensins are innate antimicrobial peptides found in a variety of ocular tissues and are critical to the immune response.1,2,3 We present a case of bilateral endophthalmitis and show the carriage of the –44CC genotype in β‐defensin 1. The polymorphism has previously been linked to increased susceptibility to infection.4,5,6,7
An 80‐year‐old man underwent cataract surgery in the right eye complicated by a capsular tear. Within 4 days he returned with a hypopyon, painful loss of vision and reddening of the right eye. Endophthalmitis was diagnosed, an urgent vitreous tap was performed and intravitreal cetazidime and vancomycin were started. Microscopical examination revealed Gram‐positive cocci, but no final growth of organisms. The right eye responded to treatment, but 1 month later a retinal detachment was diagnosed in the same eye. This was surgically repaired without complications. A year later, after an uncomplicated left cataract surgery in another hospital, the patient presented again with endophthalmitis symptoms, including hypopyon, rapid visual loss (hand movements), pain and reddening of the eye. He responded well to intravitreal amikacin and vancomycin treatment. Microscopy was positive for leucocytes but no organisms were seen. Final visual acuities were 6/9 (right) and 6/6 (left).
This gentleman could have had an underlying genetic predisposition to endophthalmitis, given that he had had the same rare complication after ocular surgery on two separate occasions. DNA sequence variants, or polymorphisms, in the β‐defensin gene family may reduce efficacy of defensin activity or production, and predispose an individual to infection. We, therefore, decided to screen two genes of this gene family for polymorphisms.
We examined the promoter, 5′ and 3′ untranslated regions (UTRs) and the coding regions of β‐defensin 1 and 2 (BD1 and BD2), using PCR primers designed to incorporate all previously reported single‐nucleotide polymorphisms (SNPs) in BD2 and 39% of the reported SNPs in BD1. Seven amplicons were produced, sequenced and analysed for new and previously reported sequence variants.
We observed a total of 14 sequence variations: six new and eight previously reported. All new variants were seen in BD2. Seven of the previously reported polymorphisms were in BD1 and one was in BD2 (table 11).
BD1 has been studied extensively and we did not identify any new sequence variants. It is thought to be constitutively expressed in the vitreous, and one of the SNPs we identified, –44G→C, has been previously linked with a predisposition to infection. Two independent studies have shown an association between –44C allele and HIV infection.5,7 Furthermore, Hu et al6 observed an increase in the –44C allele associated with patients having chronic obstructive pulmonary disease when compared with healthy smokers. Jurevic et al4 showed that the –44G allele was protective against high Candida carriage in patients with diabetes and healthy controls. All these studies suggest that carriage of the –44C allele is associated with increased predisposition to disease. Although the function of this particular polymorphism is unknown, its position in the 5′ UTR suggests that it could influence BD1 expression. Possession of either the G or C allele may lead to a variation in defensin levels among individuals. This poses an interesting question as to whether genotyping this locus can predict those at a greater risk of endophthalmitis. A larger study is now underway to determine whether there is a true association between endophthalmitis and carriage of the –44C allele.
BD2 has been less well studied, but is thought to be upregulated in the eye in response to infection/inflammation.3,9 We found six new sequence variants and one previously reported SNP (+319ins9) in BD2. Five of our new sequence changes are in the BD2 promoter region. This region is rich in transcription factor (TF)‐binding sites that are known to play a key role in upregulation of BD2.9 Polymorphisms in this region could render it unresponsive to TF stimuli thereby inhibiting the production of BD2 peptide. Functional work will be necessary to deal with this in more detail.
One has to be very cautious when interpreting and extrapolating findings from a single individual. However, bilateral endophthalmitis is extremely rare and would be more likely to occur in genetically susceptible individuals. Defensins are natural antimicrobial peptides and it is easy to see how a reduction in their production or function could predispose to endophthalmitis. Given the rarity of the condition, large studies on endophthalmitis are difficult, but we hope that by conducting this screening on more individuals we shall determine the role of defensins in susceptibility to this condition, and whether it may be possible to predict those at a greater risk.
Funding: This research was generously supported by The Underwood Trust.
Competing interests: None declared.
This study has been approved by The Central and South Bristol Research Ethics Committee, United Bristol Healthcare NHS Trust, and informed consent has been attained, in accordance with the Declaration of Helsinki.
As the patient has since passed away, informed consent for this work was obtained from the patient's next‐of‐kin. We believe that this, coupled with the complete anonymity of patient within the case report, is sufficient for publication of this work.