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R. Sharafieh, A. Child, M. Sarfarazi; Targeted Gene Association Studies of Primary Open Angle Glaucoma (POAG) at the GLC1B Locus. Invest. Ophthalmol. Vis. Sci. 2009;50(13):893.
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Combined genetic linkage data from 4 different research groups suggests that the GLC1B locus may be limited to a region of 6.6 Mb on 2q11-q12 that harbors a total of 37 genes. We aim to use targeted association studies to identify genes that are more likely to be responsible for this phenotype.
The HapMap database was used to select highly polymorphic SNP markers from within the 37 candidate genes. The study included 380 British subjects (190 POAG and 190 normal controls). SNP genotyping was carried out with the ABI-SNaPshot Multiplex System and direct DNA sequencing was performed on an ABI-3100 machine. The genotypic data was tabulated for all subjects and statistical evaluation was carried out with SNP-STAT and PLINKS programs.
Genotypic data was generated in two stages. The discovery phase used 95 POAG subjects that included 30 probands from families with prior consistent linkage to the GLC1B locus. Our initial statistical analysis showed that genotypic or allelic association studies were significant for only 6 of the 37 genes investigated. The confirmation phase used additional 95 POAG and a total of 190 matched normal control subjects. These 380 subjects were genotyped for SNP markers mapping to these 6 genes (RNF149, CREG2, IL1RL1, TBC1D8, C2orf29, PDCL3). This new round of case/control association study revealed only one SNP (rs13151 in RNF149 gene) which was statistically significant (p=0.0077; OR=1.75). We sequenced this gene in 98 POAG families and observed 19 variations. The only sequence change in exon-1 (N139S) did not segregate in the two original families identified in. Selection of additional SNP markers from other regions of these 37 genes and generation of their genotypic data in the same group of POAG and normal subjects are now in progress.
The combined analysis of genetic linkage data with targeted gene association studies is an accelerating method to identify candidate genes from a large candidate region. The application of this method to the GLC1B locus is being further investigated.
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