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Two PACG-associated genetic loci linked to PACS, early disease development

Tristan Manalac
18 Feb 2018
A GP who misdiagnosed a patient’s glaucoma - leading to her partial loss of vision - has been suspended by the SMC.

Of the newly identified genetic loci for primary angle-closure glaucoma (PACG), two are significantly associated with primary angle-closure suspect (PACS), indicating involvement in the earlier stages of the disease, a recent Singapore study has shown.

“We conducted a case-control study to examine the association of PACG-related susceptibility loci in participants with PACS,” said researchers, who found that the rs1015213 and rs3739821 single nucleotide polymorphisms (SNPs) were significantly more common in patients with PACS.

“This suggests that these SNPs may be associated with the presence of narrow drainage angles or angle closure, which is the common characteristic across the angle-closure spectrum,” they added.

In a cohort of 2,001 adults with PACS (1,397 Chinese, 604 Indian) and 1,230 controls (943 Chinese, 287 Indian), three of the eight included PACG-related SNPs were significantly associated with PACS status. The rs1015213 SNP, located between the PCMTD1 and ST18 genes on chromosome 8q, was significantly more frequent in Chinese cases vs controls (0.027 vs 0.009; p=0.002; odds ratio [OR], 2.36; 95 percent CI, 1.36–4.11). [Ophthalmology 2018;doi:10.1016/j.ophtha.2017.11.016]

The rs3816415 SNP in the EPDR1 gene (0.15 vs 0.11; p=0.00045; OR, 1.49; 1.19–1.85) and the rs3739821 SNP found between the DPM2 and FAM102A genes (0.32 vs 0.27; p=0.00008; OR, 1.40; 1.18–1.65) were also significantly associated with PACS in the Chinese cases vs controls.

In the Indian cohort, only the rs101513 SNP (0.156 vs 0.113; p=0.056; OR, 1.36; 0.99–1.86) was modestly replicated in cases relative to controls. In contrast, the rs3816415 SNP was less frequent in the cases (0.15 vs 0.15; p=0.54; OR, 0.92; 0.69–1.22), but the trend did not reach statistical significance.

In a meta-analysis of the whole cohort, only two SNPs remained significant. The rs1015213 (OR, 1.55; 1.18–2.04; p=0.002) and rs3739821 (OR, 1.27; 1.12–1.45; p=0.0002) SNPs showed significantly higher frequency in cases than in controls.

“SNPs rs1015213 (located between PCMTD1 and ST18) and rs3739821 at DPM2, which showed positive association results on meta-analysis, are markers for the earliest stage in the angle closure glaucoma disease course and are important for the development of angle closure,” said researchers.

“Further research investigating the genetic variants that are involved in disease progression from PACS to PACG should be performed,” they added.

The researchers obtained the Chinese cohort from the Singapore Chinese Eye Study and recruited additional participants of South Indian ancestry as the replication cohort.

Participants were genotyped for eight SNPs: rs11024102 in the PLEKHA7 gene, rs1015213 in the PCMTD1-ST18 loci, rs3753841 in the COL11A1 gene, rs79394014 in the CHAT gene, rs736893 in the GLIS3 gene, rs3816415 in the EPDR1 gene, rs3739821 in the DPM2-FAM102A loci and rs7494379 in the FERMT2 gene.

“[A] positive association in PACS of a PACG variant likely indicates a genetic predisposition for anatomic angle-closure configuration, the common underlying phenotype for PACS and PACG,” researchers explained.

“Therefore, genetic markers at COL11A1, PLEKHA7, GLIS3, CHAT and FERMT2 that were negative for PACS status in both the Chinese and Indian cohorts seem to be candidates for involvement in latter disease stage or progression from PACS to PACG,” they added.

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