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Originally published In Press as doi:10.1167/iovs.08-2020 on June 14, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4760-4764.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2020
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Lysosome-Related Genes Are Regulated in the Orbital Fat of Patients with Graves’ Ophthalmopathy

Mei-Hsiu Chen,1,2 Shu-Lang Liao,3 Ming-Hong Chen,4 Pei-Ling Tsou,5 Mei-Ju Shih,3 Tien-Chun Chang,5,6 and Lee-Ming Chuang1,5,6

1From the Graduate Institute of Clinical Medicine, National Taiwan University Medical College, Taipei, Taiwan; the 2Department of Internal Medicine, Far-Eastern Memorial Hospital, Taipei, Taiwan; the 3Departments of Ophthalmology and 5Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; and the 4Institute of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan.

PURPOSE. The molecular mechanism involved in the hypertrophy of the orbital fat in patients with Graves’ ophthalmopathy or thyroid eye disease (TED) remains unclear. Comparison of genome-wide expression profiles may help in the search for the gene sets involved in TED.

METHODS. Twenty-five orbital adipose tissue specimens were obtained, from which the RNA was isolated. Four of the tissue specimens (from four individuals, two with TED and two control subjects) were subjected to cDNA microarray analysis. The data were analyzed by the gene set enrichment analysis (GSEA) to survey the biological pathways involved in the pathogenesis of TED. Messenger RNA levels of some top-ranked genes in GSEA-selected pathways are validated by quantitative PCR (QPCR).

RESULTS. The expression of specific gene sets related to lytic vacuoles, lysosomes, and vacuoles were different between the specimens obtained from patients with TED and control subjects (P < 0.001). These three gene sets overlapped. For QPCR, four top-ranked genes were selected from these overlapping gene sets and another one that related to visual failure, using 21 independent samples of patients with TED (n = 15) and control subjects (n = 6). The results showed that ceroid-lipofuscinosis, neuronal 2, late infantile (CLN2; P = 0.044) and ceroid-lipofuscinosis, neuronal 3, juvenile (CLN3, which related to visual failure; P = 0.012) were significantly downregulated in the orbital fat of patients with TED. The expression of the β subunit of hexosaminidase A (HEXB) was reduced as well, but the change did not reach statistical significance (P = 0.058).

CONCLUSIONS. Lysosome-related genes, such as CLN2, CLN3, and HEXB, may be involved in the pathogenesis of adipose tissue hypertrophy in TED.






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