Keratoconus – Genes and Risk Factors Tuesday 11 th November 2014 A/Professor Paul Baird Ocular Genetics Unit TRANSLATIONAL GENOMICS

Keratoconus – the disease Families Gene studies Other risk factors

mild moderate severe Glasses Contact lenses Toric IOLs X-linking Keratoplasty Corneal transplantation Treatment options and severity of Keratoconus Disease severityTreatment options

 We would like to identify risk factors that influence the disease process - Pre-diagnosis - Disease progression - Response to treatment

Aetiology Eye rubbing Allergy Connective tissue dysfunction Contact lens wear  Twin studies  Familial aggregation studies  Genetic studies Non genetic factors Genetic factors Keratoconus is a Complex disease

Keratoconus study Questionnaire Demographics, Birth history, Ethnicity, Educational Background, Ocular & Medical History, Family history Smoking & Alcohol consumption details DNA Sample Venepuncture 2 x 9ml samples Saliva Biometric Measurement Height, Weight Hip : Waist Participants Eye Exam VA, Refraction, Axial Length, Slit Lamp, Keratometry, OCT, Pentacam Quality of life questionnaire Economic burden questionnaire

Keratoconus study – Genetic studies Questionnaire Demographics, Birth history, Ethnicity, Educational Background, Ocular & Medical History, Family history Smoking & Alcohol consumption details DNA Sample Genetic studies Venepuncture Saliva Biometric Measurement Height, Weight Hip : Waist Participants Eye Exam VA, Refraction, Axial Length, Slit Lamp, Keratometry, OCT, Pentacam Quality of life questionnaire Economic burden questionnaire

Family studies in Keratoconus Families help us to track down keratoconus disease genes

We want to recruit more families where keratoconus is found in multiple family members

Identifying Genes in Keratoconus

Multiple genes implicated Eg: VSX1, SOD1, ILIB, COL4A3, COL4A4, LOX Few of these replicated (small sample size, different methodologies) More robust findings for: Hepatocyte Growth Factor (HGF) gene Genes involved with central corneal thickness (CCT) Currently identifying other genes using a genome wide approach

Age (years) BMI Gender (male) Eye Rubbing Ethnicity Cigarette Smoking Alcohol consumption Diabetes Hypertension Sleep disorder Connective tissue disorder Arthritis Migraine Allergy Hayfever Asthma Eczema Risk Factor Questionnaire

Identify genetic variants/other risk factors of interest associated with disease Incorporate data from patient records -Bioinformatic integration of these data

Keratoconus appears to have multiple genes and risk factors Collecting more individuals and families with keratoconus Exploring the role of the immune system in disease Put these risk factors together to better understand disease and help improve patient care Future Directions