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Four Novel Gene Polymorphisms Cause Nuclear Age Related Cataract in Chinese People

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Four Novel Gene Polymorphisms Cause Nuclear Age Related Cataract in Chinese People Four Novel Gene Polymorphisms Cause Nuclear Age Related Cataract in Chinese People Lin Wang First Aliated Hospital of Harbin Medical University Wencheng Zhao First Aliated Hospital of Harbin Medical University Yongbin Yu First Aliated Hospital of Harbin Medical University ping liu ( [email protected] ) Eye Hospital, The First Affiliated Hospital of Harbin Medical University, Harbin, P.R. China Research article Keywords: nuclear age-related cataract (NARC), single nucleotide polymorphism (SNP), protein structure Posted Date: February 13th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-219650/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/24 Abstract Background More information on genetic variation can be obtained by exon sequencing for the diagnosis of nuclear age-related cataract (NARC). Methods In our present study, genomes of 12 DNA samples were sequenced. The average effective depth was 10× when using Illumina sequencing. After conducting whole-exon sequencing, we further performed depth analysis and spectrum analysis to determine the gene polymorphism sites closely associated with NARC. Results In genes showing single nucleotide polymorphism (SNP), there were 18,699 synonymous mutations and 17,975 missense mutations in the coding region. A total of 4,944 insertions and deletions (indels) were found. Among them, 1329 indels exhibited polymorphism and were further analyzed. Whole-exon sequencing previously showed polymorphism associated with ARC and known pathways associated with protein synthesis and metabolism. Following depth analysis (GO and KEGG analysis), we identied 20 promising candidate genes that were closely related to NARC. We further performed spectrum analysis for 26 polymorphism sites and found that ZNF573 (rs3095726, SNP), ZNF862 (rs62621204, SNP), SYNE3 (rs76499929, indel), and GAS2L2 (rs78557458, SNP) had statistically signicant relationship with NARC. The 3D protein structure showed obvious changes for ZNF573 (rs3095726, SNP) and GAS2L2 (rs78557458, SNP). Conclusions Our ndings provide the basis for further studies and discovery of key genes associated with NARC. Key Messages 1 For studying the pathogenesis of nuclear age-related cataract 2 We found that ZNF573 (rs3095726, SNP), ZNF862 (rs62621204, SNP), SYNE3 (rs76499929, indel), and GAS2L2 (rs78557458, SNP) had statistically signicant relationship with NARC 3 Our ndings provide the basis for further studies and discovery of key genes associated with NARC. Background Age-related cataracts (ARCs) are characterized by visual impairment and lens opacities, and they are the major reason of blindness worldwide [1]. Both genetic variations and environmental factors can lead to ARCs [2]. Various interaction factors have been conrmed to be involved in the complex cataract formation process. Both genetic and environmental factors have been conrmed to be involved in the pathogenesis of ARC [3]. Genetic polymorphism is considered to be an integral part of genetic risk for developing ARC. Many researchers have studied the relationship between genetic polymorphism and ARC sensitivity [4,5]. Alterations in the molecular architecture of lens proteins lead to the development of cataract [1]. The annual worldwide incidence of cataract has been estimated to be 17.7 million [2]. To date, there is no effective pharmacological treatment for cataract because it is an irreversible age-related process [3]. ARCs are classied into cortical cataract, nuclear cataract, and posterior subcapsular cataract (PSC). In cortical cataract, the cytoplasm of mature ber cells are damaged in the outer third of the lens. An increase in light scattering is a characteristic of nuclear cataract with yellow or brown coloration [4]. Furthermore, less than 10% of ARC cases are PSC [5]. We assessed the cataract status of participants and examined their eye structure with slit lamp (Streit BQ-900, Hague; Haag Streit AG, Köniz, Switzerland) [6]. We used the standard lens opacication classication system III (LOCS III) to classify cataract types. On the basis of the standard criterion, we divided the type of cataracts into cortical cataracts (LOCS III score ≥2), nuclear cataracts ((LOCS III score ≥4), or mixed type. In the present study, we analyzed blood samples of patients with nuclear cataract. It is generally believed that genetic factors play an important role in the formation of ARC; however, the exact cause of ARC remains unclear [7]. The etiology of ARC is multifactorial, and both genetic variations and environmental factors are associated with the disease. Genetic factors are closely related to the pathogenesis of ARCs. In twin studies, the heritability of nuclear subtypes was found to be 48% [8] . Genetic variations may increase the sensitivity of lens to environmental risk factors and may be directly involved in the formation of ARC [9] . Through the target enrichment strategy, whole-exome sequencing (WES) is a high-throughput genomic technology that selectively captures the coding region of the genome [10-12]. WES uses oligonucleotide probes that perform selective hybridization [10,12,13], and targeting enrichment is achieved by capturing the entire coding region of the genome. Because exons constitute approximately 2% of the genome [14] , WES technology provides high coverage at low cost [14] with faster speed. After the rst successful application in the discovery of candidate genes for Miller’s syndrome [15], WES has been adopted for investigating a number of complex disorders and Mendelian [16-17]. Page 2/24 WES was used in the NHLBI GO Exome Sequencing Project, Exome Aggregation Consortium (EXAC), and other 1,000 genome projects to identify rare disease- related variants and to classify the variations in the population [18–22]. Since 2011, WES has also been frequently used as a diagnostic tool in clinical genetics laboratories [23–25]. WES is a useful clinical diagnostic tool to identify disease-related variants in patients [26–27]. Currently, to determine whether disease-related mutations in patients are related to mutations in coding regions, researchers are focusing on sequencing exons rather than entire genomes. Recently, several studies have identied variants strongly associated with disease phenotypes [26–27] by successful application of WES technology. Because of the uneven coverage of different WES datasets along the exon length under high-resolution detection, in the variation calling analysis, the impact identication of new variations that may be of clinical signicance. In the present study, we analyzed and determined the key issues related to sequence structure, which lead to low coverage, and systematically studied the different parameters that may affect WES. To date, WES has become a major genetic tool, with over 100,000 exons sequenced in several diagnostic centers [28] . To ll the gap and identify the mutation accurately, it is very important to improve the mapping algorithm and modify the design of target sequence capture technology and estimation of genetic disease heritability. Large numbers of insertions and deletions (indels) and single-nucleotide polymorphisms (SNPs) have been identied using the next-generation sequencing (NGS) technology. In many species and human diseases, short indels are involved in phenotypic diversity and are regarded as the second most common form of genomic variation [29]. It is feasible to identify and study the molecular basis of SNPs and indels for ARC. However, to date, very limited investigations have been reported using the method of whole-genome resequencing for genes related to ARC. The present study aimed to detect polymorphic SNP sites and indels including short indels [1–49 base pairs (bp)] across the whole exon sequence in 8 patients with NARC. In patients with NARC, it is important to identify the differences in SNPs and indels, which result in functional genes. Methods Subjects A total of eight subjects were recruited from the Eye Hospital of Harbin Medical University. All the subjects received comprehensive ophthalmic examinations, including vision, slit lamp microscopy, and ophthalmoscopy. None of the subjects had blood relations (at least not among the four grandparents). All the subjects claimed to be Han (all four grandparents were Han). The study was approved by the institutional review committee, following the principles of the Helsinki declaration, and informed consent was signed by all subjects. Lens opacity grading According to LOCS III, a trained ophthalmologist graded the lens opacity of each right eye as cortical (C), nuclear color (NC), nuclear opalescence (NO), posterior subcapsular (P), or mixed type after pupil dilation with 1% tropicamide. Nuclear ARC group and control group All subjects with NARC were included in this study, and the case and control groups were recruited according to the grading conditions. The following exclusion criteria were used: (1) history of diseases such as tumor, cancer, respiratory disease, kidney disease, or history of diabetes; (2) pseudophakia or aphakia in both eyes; (3) ocular surgery history in either eye; (4) complications with other eye diseases such as fundus diseases, dislocated lens, glaucoma, trauma, high myopia, and uveitis; and (5) under 45 years of age. Blood sample collection and DNA isolation Peripheral blood (12 ml) samples of all subjects (8 disease cases and 4 controls) were collected in EDTA tubes and stored at -80°C before use. DNA was extracted from whole blood cells by using the mammalian
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