Haplotypes of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 Gene Polymorphisms in Age-Related Macular Degeneration

Hindawi Disease Markers Volume 2019, Article ID 9602949, 11 pages https://doi.org/10.1155/2019/9602949 Research Article Haplotypes of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 Gene Polymorphisms in Age-Related Macular Degeneration Rasa Liutkeviciene , Alvita Vilkeviciute , Greta Gedvilaite , Kriste Kaikaryte, and Loresa Kriauciuniene Neuroscience Institute, Lithuanian University of Health Sciences, Medical Academy, Eiveniu 2, Kaunas LT-50161, Lithuania Correspondence should be addressed to Rasa Liutkeviciene; Received 27 March 2019; Revised 30 June 2019; Accepted 19 August 2019; Published 8 September 2019 Academic Editor: Taina K. Lajunen Copyright © 2019 Rasa Liutkeviciene et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. To determine the impact of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 genotypes on the development of age-related macular degeneration (AMD) in the Lithuanian population. Methods. A total of 916 subjects were examined: 309 patients with early AMD, 301 patients with exudative AMD, and 306 healthy controls. The genotyping of HTRA1 rs11200638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 was carried out using the RT-PCR method. Results. Our study showed that single-nucleotide polymorphisms rs3793784 and rs11200638 were associated with increased odds of early and exudative AMD, and the variant in KCTD10 (rs56209061) was found to be associated with decreased odds of early and exudative AMD development after adjustments for age and gender in early AMD analysis and after adjustments only for age in exudative AMD. The haplotype containing two minor alleles C-A and the G-A haplotype in rs3793784-rs11200638 were statistically significantly associated with an increased risk of exudative AMD development after adjustment for age, while the G-G haplotype showed a protective role against early and exudative AMD and the haplotype C-G in rs3793784-rs11200638 was associated with a decreased risk only of exudative AMD development. Conclusions. Our study identified two markers, rs11200638 and rs3793784, as risk factors for early and exudative AMD, and one marker, rs56209061, as a protective factor for early and exudative AMD development. The haplotypes constructed of rs3793784-rs11200638 were found to be associated with AMD development, as well. 1. Introduction Age-related macular degeneration (AMD) affects the macula (the central part of the retina) and is the most common cause of visual loss in persons over the age of 60 in developed countries [1]. Population estimates have placed the prevalence of AMD approximately from 7% to 10% in adults aged 40-90 yrs. [2–4]. The 10-year incidence of neovascular AMD is 4.1% in persons older than 75 years [5]. In 2002, there were 13.8% blind people due to AMD according to the data of the Lithuanian Medical Social Expertise Commission [6], and it takes second place after glaucoma [6]. AMD is a progressive eye disease that has been linked with several pathological factors, i.e., chronic oxidative stress, autophagy decline, and inflammation [7–9]. However, the full etiology of AMD remains unclear and the treatment options are limited. AMD is a challenging disease to study from a genetic perspective too, because, unlike disorders that exhibit Mendelian inheritance patterns (where one gene and one mutation within that gene is responsible for the phenotype observed in a given family), the development and 2 severity of complex diseases like AMD are influenced by multiple factors. The high prevalence of the disease implies that there is more than one gene or environmental factor as well as interactions among these factors, which influence an individual’s susceptibility to the disease [10]. Early AMD is usually asymptomatic. Early AMD is defined as the presence of drusen and retinal pigmentary abnormalities; late AMD includes dry AMD (geographic atrophy of the retinal pigmentary epithelium in the absence of neovascular AMD) or neovascular AMD (detachment of the retinal pigment epithelium, hemorrhages, and/or scars). AMD is a disease of multifactorial etiology, the development of which is determined by environmental and genetic risk factors. In addition to these factors, various singlenucleotide polymorphisms (SNPs) have been widely reported to be associated with AMD [11]. Genome-wide association studies (GWAS) have confirmed multiple AMD-associated loci. Recently, a large-scale GWAS with thousands of cases and controls reported several additional AMD-associated loci, including rs9621532 near the tissue inhibitor of metalloproteinase 3 (TIMP3) and the synapsin III (SYN3) region of chromosome 22q12.3 [11]. HTRA1, the third gene in the 10q26, is highly conserved among species and has several variants that have consistently been found to be associated with AMD [12–18]. One of the most consistently AMDassociated variants is the SNP rs11200638, located within the putative HTRA1 promoter [15, 17–21]. As the lipid level has been implicated as a major risk factor in AMD [22, 23], GWAS analyze the associations between lipid-trait genes and AMD risk [24–26]. A recent study has shown that two intronic variants rs11066782 and rs11613718 in KCTD10 or potassium channel tetramerisation domain-containing 10 gene were associated with high-density lipoprotein cholesterol (HDL-C) concentrations and with coronary heart disease (CHD) risk [27], while rs2338104 in the KCTD10 gene located in chromosome 12q24 was associated with AMD development [28]. The other intronic variant, rs5620906 in KCTD10, was even related to the advanced AMD subtypes [29]. Today, it is known that the complement system is involved in the pathogenesis of AMD [30]. Therefore, different types of studies were performed to detect the association between CFI polymorphisms and AMD. Numerous researches have shown CFI gene’s role in AMD pathogenesis [31–35]. The CFI gene is located on chromosome 4q25 and encodes complement factor I (FI), which is an important component of the complement system. Factor I is composed of one light and one heavy polypeptide chains held together by disulfide bonds. These chains are encoded by the CFI gene. The light chain has a serine protease domain. The main function of factor I is to cleave C4b and inactivate C3 [36]. Another gene, the Excision Repair Cross-Complementing Group 6 (ERCC6) gene, which is located on human chromosome 10 at q11.23 and has 84,171 bases with 21 exons, may be also associated with AMD. Loss of function mutations in the ERCC6 cause the autosomal recessive disorder Cockayne syndrome, which includes a lot of severe physical and neurologic peculiarities, with premature aging and retinopathy as signs of t (...truncated)