IDENTIFICATION OF SUSCEPTIBILITY GENETIC MARKERS FOR PRIMARY OPEN. ANGLE GLAUCOMA IN MALAYS. Rajasunthari T1,Syed Mudassar IB1,Liza ...
IDENTIFICATION OF SUSCEPTIBILITY GENETIC MARKERS FOR PRIMARY OPEN ANGLE GLAUCOMA IN MALAYS Rajasunthari T1, Syed Mudassar IB1, Liza Sharmini AT1, Azhany Y1, Sarina S2, Zilfalil BA2 ,CC Khor3 ,Aung T3 1. Department of Ophthalmology, 2. Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kota Bharu Kelantan, Malaysia, 3. Genome Institute Singapore, National University of Singapore
Introduction
Results
Primary open-angle glaucoma (POAG) is a progressive optic neuropathy characterized by loss of retinal ganglion cells structurally and visual field defect functionally POAG is responsible for 12.3% of global blindness. It is a complex disease with strong evidence of genetic predisposition. Based on single gene analysis, MYOC, OPTN, WDR36,CYP1B1,OPA1 were identified as potential genetic markers for POAG (3) However, these genes were not replicative in other populations(6). Detection of the susceptibility genetic markers is important in understanding this complex disease.
DEMOGRAPHIC DATA
OCULAR PARAMETER
MEAN(SD)
Sex (n,%) Male Female
Corrected IOP(mmHg)
16.6 (3.9)
Central corneal thickness(µm)
519.4 (25.9)
Retinal nerve fiber layer thickness (µm).
66.4(14.7)
Vertical cup disc ratio
0.7 (0.07)
Average cup disc ratio
0.7(0.08)
Rim area (mm2)
0.7(0.3)
Disc area (mm2)
4.2(19.9)
Humphrey visual field analysis Mean deviation Pattern standard deviation
-11.5 (8.7) 7.1 (3.3)
68 (54) 40 (31.7)
Age (year) Mean (SD) Weight ( kg) Mean (SD) Height (cm) Mean (SD) BMI (kg/m2) Mean (SD)
67.3 (8.7) 59.9 (12.4) 156.4 (7.9)
24.5 (4.3)
SYSTEMIC DISEASE
Objective To identify the susceptible genetic markers for Malay patients with POAG To determine the association of the susceptible genetic markers and endophenotype parameters in Malay patients with POAG
Hypertension (n,%)
73 (57.9)
Hyperlipidimea(n,%)
45 (35.7)
Diabetes mellitus (n,%)
43 (34.1)
Cardiovascular diseases (n,%)
16 (12.7)
Methodology
.
● A case control study was conducted involving 108 Malay patients with POAG. ● Venesection was done. DNA was extracted using commercially available DNA extraction kit (Qiagen, Germany). ● Microarray Human Omni Express-12 platform (Illumina,USA) was used for genotyping. Due to financial constraint, we obtained the genetic analysis(controls) from existing database: the Singapore Malay Eye Study (SiMES). ● Genome studio was used to analyze the data. PLINK and R software’s were used for further analysis to get susceptible single nucleotide polymorphisms (SNPs). Inclusion Criteria Confirmed cases of POAG Malay patients Age 40
MALAY PATIENTS WITH CONFIRMED CASE OF POAG(n=108)
Table 2: Endophenotypes
Table 1: Demographic Data
rs1620264
rs2241096
rs8187890 rs1014979
Figure 2 . Manhattan plot of susceptible loci for RNFL Thickness in Malay patients
Figure 1. Manhattan plot of susceptible loci for POAG in Malay patients
Exclusion Criteria Patient who has any other type of Glaucoma Non Malay
OCULAR PARAMETER -IOP
rs190254
rs814836
rs10772847 rs347861
-ONH (VCDR+ RNFL)
VENESECTION
DNA EXTRACTION
MICROARRAY
CONTROL FROM EXISTING DATABASE ( SiMES)
ANALYSIS
Discussion
Figure 3. Manhattan plot of susceptible loci for VCDR in Malay patients
Figure 4. Manhattan plot of susceptible loci for IOP in Malay patients
• Genome-wide association study (GWAS) is a powerful strategy, which has identified numerous loci in many diseases especially in studying complex diseases such as glaucoma. • Two genetic markers; rs1620264 and rs8187890 demonstrated potential role as susceptible loci of POAG in Malay patients. • rs1620264 in KIRREL3 gene, increases the risk to develop POAG by 2.43 folds in Malay patients. To the best of our knowledge, this marker is not found to be associate with any disease yet. • rs8187890 is found in ALDH1A1 gene that is expressed in the anterior lens capsule of patients with pseudoexfoliation glaucoma and trabecular meshwork of POAG patients(10). It is also believed to play a role in oxidative stress (10). rs8187890 increases the susceptibility to develop POAG by 6.23 folds in Malay patients. • rs2241096 (P=9.85× 10e-7) and rs1014979 (P=2.29×10e-5) are found to be associated in determining the RNFL thickness in Malays with POAG. These markers were reported in immune diseases of eye and tumorigenesis of retinoblastoma.(5) • The VCDR of Malay patients with POAG is potentially affected by rs10772847 (P=1.56×10e-6) and rs347861 (P=1.74×10e-5) found to be GWAS significant SNPs. rs347861 was reported to be involve in aqueous humour production.(7) • The IOP may be controlled by intronic SNPS; rs814836 (P=6.58×10e-12) and rs190254 (P=6.58×10e-12) in Malays with POAG.
Conclusion The susceptibility genetic markers; rs1620264 and rs818790 is identified in Malay patients with POAG. rs1620264 of KIRREL3 gene is potentially a novel finding for POAG in Malays. • Genetic marker potentially influence the IOP and ONH parameters including RNFL thickness in Malay patients with POAG.
KELANTAN RESEARCH DAY
th 9
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Acknowledgement
RU Grant 1001/PPSP/812101 and RU Grant 1001/PPSP/910343
Sept 2014
