Publications by authors named "G Chichua"

8 Publications

MICROENVIRONMENT ALTERATIONS IN CONJUNCTIVAL NEOPLASTIC LEOSIONS WITH DIFFERENT PROLIFERATION-APOPTOTIC CHARACTERISTICS.

Georgian Med News 2021 Jun(315):152-159

2Tbilisi State Medical University, Georgia.

Different studies indicate that tumor infiltrating lymphocytes (TILs) and tumor associated neutrophils (TANs) play an important role during the progression of malignant tumors. We have analysed the distribution of tumor associated neutrophils (TANs) and tumor infiltrating lymphocytes (TILs) in different conjunctival lesions, with different proliferation and apoptotic characteristics. The distribution of TILs and TANs were evaluated in standard haematoxylin and eosin (H&E) stained sections using the digital pathology software QuPathin normal conjunctiva, actinic keratosis, pterigea, conjunctival intraepithelial neoplasias (CoIN1-3) and conjunctival squamous cell carcinoma (CSCC). In addition, the expression of following markers were investigated using standard immunohistochemistry: Ki67, Bcl2, p53, CD3, CD8 and Foxp3. The study results indicated that the number of TILs and TANs are significantly increased during the progression of conjunctival intraepithelial lesions. Also, the number of TILs and TANs significantly correlate with higher proliferation index, lower apoptotic index and the p53 mutation status.
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June 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

NEW GENETIC MARKERS ASSOCIATED WITH SUSCEPTIBILITY TO EXFOLIATION SYNDROME AMONG GEORGIAN POPULATION.

Georgian Med News 2019 Sep(294):41-45

2Chichua Medical Center Mzera, LLC, Tbilisi, Georgia.

The aim of this study was to identify susceptibility variants of CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A genes for Exfoliation Syndrome (XFS) and Exfoliation Glaucoma (XFG) by a case-control association study approach among Georgian population. Self-reported Georgian subjects were recruited between 2015 and 2017 at a specialized ophthalmic center. Patients underwent detailed ophthalmic examination to diagnose or exclude Exfoliation Syndrome and Exfoliation Glaucoma. Patients underwent peripheral blood sampling. Genome-Wide Association Study (GWAS) was performed using Illumina OmniExpress Microarray (USA). One hundred and thirty-two XFS patients (including XFG-affected individuals) and 199 healthy subjects were included into the study. Six genes CACNA1A rs4926244, POMP rs7329408, TMEM136 rs11827818, AGPAT1 rs3130283, RBMS3 rs12490863 and SEMA6A rs10072088 variants were identified. The A alleles of SEMA6A and POMP genes are likely the risk factors of disease development in Georgians with p=0.001; OR= 1.8, 95% CI 1.2676 to 2.6973 and p=0.001; OR=1.6, 95% CI 0.9931 to 2.5634, respectively. SEMA6A homozygotes have 4 times greater risk compared to normal individuals, with p<0.004; OR=4.0, 95% CI 1.1531 to 13.9903. The G allele of CACNA1A in homozygous state increases the risk up to 3-fold with p<0.05, OR=3.15, 95% CI 0.9275 to 10.6658. The A alleles of SEMA6A and POMP increased XFG susceptibility more than 3 times (p=0.04; OR= 3.4; 95% CI: 1.2676 to 2.6973 and p=0.02; OR= 2.7; 95% CI: 0.9931 to 2.5634, respectively). Three high-risk genes have been identified in connection to XFS in Georgian population. Two genes are relevant to XFG. Three other previously described genes are not associated with the disease development.
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September 2019

LOXL1 GENE VARIANTS IN ASSOCIATION WITH EXFOLIATION SYNDROME IN GEORGIAN POPULATION.

Georgian Med News 2019 Jan(286):32-36

Chichua Medical Center Mzera, LLC, Tbilisi; David Tvildiani Medical University, Tbilisi, Georgia.

The aim of this study was to identify susceptibility variants of LOXL1 gene for Exfoliation Syndrome and Exfoliation Glaucoma by a case-control association study approach in Georgian population. Self-reported Georgian subjects were recruited between 2015 and 2017 at a specialized ophthalmic center. Patients underwent detailed ophthalmic examination to diagnose or exclude Exfoliation Syndrome (XFS) and Exfoliation Glaucoma (XFG). Patients underwent peripheral blood sampling. Genome-Wide Association Study (GWAS) was performed using Illumina OmniExpress Microarray. One hundred and thirty-two XFS patients and 195 healthy subjects were included into the study. Four LOXL1 variants were identified: rs2165241, rs3825942 (G153A), rs4886776 (R141L) and rs8042039 (G153D). Allele A of rs2165241 and allele G of rs3825942 are likely the main risk factors of disease development in Georgians with p=0.0001; OR= 5.8; 95% CI: 1.9986-16.9372 and p=0.002; OR=4.6; 95% CI: 1.7531-12.3146, respectively, both present in 96% of affected patients. The above-mentioned alleles are also encountered in more than 80% of healthy individuals. Two other SNPs have been described for the first time in exfoliation patients, though they appear to have no effect on the disease development in Georgian population. Two high-risk alleles of LOXL1 gene have been identified in Georgian population. As these SNPs are also very prevalent in healthy subjects, further studies are needed to identify the genetic mechanisms of exfoliation syndrome and exfoliation glaucoma.
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January 2019

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Nat Genet 2017 07 29;49(7):993-1004. Epub 2017 May 29.

Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
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http://dx.doi.org/10.1038/ng.3875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685441PMC
July 2017
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