TNF-α Genetic Predisposition and Higher Expression of Inflammatory Pathway Components in Keratoconus

To date keratoconus (KC) pathogenesis is undefined; however, the involvement of inflammatory pathways in disease development is becoming apparent. In the present study, we investigated the role of a promoter region polymorphism rs1800629 (-308G>A) in the inflammatory pathway component TNF-α and i...

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Published in:	Investigative ophthalmology & visual science Vol. 58; no. 9; pp. 3481 - 3487
Main Authors:	Arbab, Muneeza, Tahir, Saira, Niazi, Muhammad Khizar, Ishaq, Mazhar, Hussain, Alamdar, Siddique, Pir Muhammad, Saeed, Sadia, Khan, Wajid Ali, Qamar, Raheel, Butt, Azeem Mehmood, Azam, Maleeha
Format:	Journal Article
Language:	English
Published:	United States 01-07-2017
Subjects:	Adult Alleles Cytokines - genetics Cytokines - metabolism Enzyme-Linked Immunosorbent Assay Female Genetic Association Studies Genetic Predisposition to Disease Genotype Humans Keratoconus - genetics Keratoconus - metabolism Male Middle Aged Polymerase Chain Reaction Polymorphism, Single Nucleotide Promoter Regions, Genetic RNA, Messenger - genetics Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism
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Summary:	To date keratoconus (KC) pathogenesis is undefined; however, the involvement of inflammatory pathways in disease development is becoming apparent. In the present study, we investigated the role of a promoter region polymorphism rs1800629 (-308G>A) in the inflammatory pathway component TNF-α and its effects on the expression of TNF-α and downstream molecules tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2), v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), and interleukin 6 (IL-6) in KC development. TNF-α promoter polymorphism rs1800629 (-308G>A), was genotyped in 257 sporadic KC patients and 253 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was performed to assess for the -308G>A genotypes. Quantitative polymerase chain reaction (qPCR) was carried out to compare the mRNA expression of TNF-α, TNFR1, TNFR2, RELA, and IL6 in the corneal tissues of 20 KC patients and 20 donor controls. The -308G>A genotype GA was found to be significantly associated with KC development (dominant model [odds ratio (OR) = 6.67 (95% confidence interval [CI] = 4.28-10.42), P < 0.001]) and allele-A (OR = 4.30, 95%CI = 2.93-6.34, P < 0.001). TNF-α serum levels were significantly raised in patients with GA genotype (196.5 ± 69.5 pg/mL) compared to reference genotype GG (21.7 ± 8.2 pg/mL) (P < 0.0001). There was a significant overexpression of TNF-α (P = 0.002), TNFR2 (P = 0.0001), RELA (P = 0.0117), and IL6 (P = 0.0007) in the KC corneal tissues as compared to the control. The GA genotype of the TNF-α -308G>A polymorphism is a significant genetic risk factor for the pathogenesis of KC. Moreover, this single nucleotide polymorphism (SNP) was observed to be associated with deregulated expression of downstream molecules, thus further reinforcing the role of the inflammatory pathway components in the development of KC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1552-5783 1552-5783
DOI:	10.1167/iovs.16-21400