Central serous chorioretinopathy (CSCR) is characterized by serous detachment of the central neurosensory retina and it is one of the most common retinal disorders. Various genetic polymorphisms have been associated with CSCR development.
Methods
The aim of our study was to investigate the potential association between ARMS2 (rs10490924) and NR3C2 (rs2070951 and rs5522) genes polymorphisms and CSCR development in a well defined Greek cohort for the first time in literature. We enrolled, in our case-control study, 48 CSCR patients and 137 controls. The ARMS2 (rs10490924) and NR3C2 (rs2070951 and rs5522) genes polymorphisms were analyzed using Polymerase Chain Reaction (PCR) assays.
Results
In our study, we found significant associations between ARMS2rs10490924 and NR3C2rs2070951 single nucleotide polymorphisms and CSCR development. Specifically, the GTrs10490924 genotype frequency of the ARMS2 gene was found to be significantly associated with risk of CSCR and T allele of rs10490924ARMS2 gene was also found to increase risk for CSCR. The genotype frequency GC and CC of rs2070951NR3C2 gene were observed more frequently in CSCR patients than controls and C allele of rs2070951NR3C2 gene was also observed more frequently in CSCR patients than controls. Rs5522 of NR3C2 gene polymorphism was not found to be significantly associated with CSCR.
Conclusion
Our findings showed, for the first time in a Greek population, that SNPs in the ARMS2 and NR3C2 genes are significantly associated with risk of CSCR. The results of this study support the involvement of extracellular matrix (ARMS2 gene) and mineralocorticoid receptor (MR) in the pathogenesis of CSCR.
WangMMunchICHaslerPW, et al.Central serous chorioretinopathy. Acta Ophthalmol2008; 86: 126–145.
2.
KitzmannASPulidoJSDiehlNN, et al.The incidence of central serous chorioretinopathy in Olmsted County, Minnesota, 1980–2002. Ophthalmology2008; 115: 169–173.
3.
DaruichAMatetADiraniA, et al.Central serous chorioretinopathy: recent findings and new physiopathology hypothesis. Prog Retin Eye Res2015; 48: 82–118.
4.
NicholsonBNobleJForooghianF, et al.Central serous chorioretinopathy: update on pathophysiology and treatment. Surv Ophthalmol2013; 58: 103–126.
5.
ReibaldiMCardasciaNLongoA, et al.Standard-fluence versus low-fluence photodynamic therapy in chronic central serous chorioretinopathy: a nonrandomized clinical trial. Am J Ophthalmol2010; 149: 307–315.e2.
6.
GiannopoulosKGazouliMChatzistefanouK, et al.The genetic background of central serous chorioretinopathy: a review on central serous chorioretinopathy genes. J Genomics2021; 9: 10–19.
7.
GemenetziMDe SalvoGLoteryAJ. Central serous chorioretinopathy: an update on pathogenesis and treatment. Eye2010; 24: 1743–1756.
8.
LiewGQuinGGilliesM, et al.Central serous chorioretinopathy: a review of epidemiology and pathophysiology. Clin Experiment Ophthalmol2013; 41: 201–214.
9.
GargSJMaguireJIRegilloCD, et al.Central serous chorioretinopathy. In: WajdaBBagheriN (eds) The wills eye manual: office and emergency room diagnosis and treatment of eye disease. 7th ed. Philadelphia:Wolters Kluwer, 2017, pp. 305–307.
10.
HaimoviciRKohSGagnonDR, et al.Central serous chorioretinopathy case-control study group. Risk factors for central serous chorioretinopathy: a case-control study. Ophthalmology2004; 111: 244–249.
11.
PanCKVailDBhattacharyaJ, et al.The effect of obstructive sleep apnea on absolute risk of central serous chorioretinopathy. Am J Ophthalmol2020; 218: 148–155.
12.
WeeninkACBorsjeRAOosterhuisJA. Familial chronic central serous chorioretinopathy. Ophthalmologica2001; 215: 183–187.
13.
Van DijkEHCSchellevisRLBreukinkMB, et al.Familial central serous chorioretinopathy. Retina2019; 39: 398–407.
14.
SchellevisRLVan DijkEHCBreukinkMB, et al.Exome sequencing in families with chronic central serous chorioretinopathy. Mol Genet Genomic Med2019; 7: e00576.
15.
De JongEKBreukinkMBSchellevisRL, et al.Chronic central serous chorioretinopathy is associated with genetic variants implicated in age related macular degeneration. Ophthalmology2015; 122: 562–570.
16.
Van DijkEHCSchellevisRLVan BergenMGJM, et al.Association of a haplotype in the NR3C2 gene, encoding the mineralocorticoid receptor, with chronic central serous chorioretinopathy. JAMA Ophthalmol2017; 135: 446–451.
17.
HuangTShuYCaiYD. Genetic differences among ethnic groups. BMC Genomics2015; 16: 1093.
18.
YannuzziLA. Central serous chorioretinopathy: a personal perspective. Am J Ophthalmol2010; 149: 361–363.e1.
19.
SahooNKSinghSRRajendranA, et al.Masqueraders of central serous chorioretinopathy. Surv Ophthalmol2019; 64: 30–44.
20.
MikiAKondoNYanagisawaS, et al.Common variants in the complement factor H gene confer genetic susceptibility to central serous chorioretinopathy. Ophthalmology2014; 121: 1067–1072.
21.
HagemanGSAndersonDHJohnsonLV, et al.A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA2005; 102: 7227–7232.
22.
MoschosMMGazouliMGatzioufasZ, et al.Prevalence of the complement factor H and GSTM1 genes polymorphisms in patients with central serous chorioretinopathy. Retina2016; 36: 402–407.
23.
KortvelyEHauckSMDuetschG, et al.ARMS2 Is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degeneration. Invest Ophthalmol Vis Sci2010; 51: 79–88.
24.
KortvelyEUeffingM. Gene structure of the 10q26 locus. A clue to cracking the ARMS2/HTRA1 riddle?Adv Exp Med Biol2016; 854: 23–29.
25.
JakobsdottirJConleyYPWeeksDE, et al.Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet2005; 77: 389–407.
26.
RiveraAFisherSAFritscheLG, et al.Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet2005; 14: 3227–3236.
27.
FritscheLGLoenhardtTJanssenA, et al.Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet2008; 40: 892–896.
28.
KandaAChenWOthmanM, et al.A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA2007; 104: 16227–16232.
29.
MicklischSLinYJacobS, et al.Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator. J Neuroinflamation2017; 14: 4.
30.
YangJLiYChanL, et al.Validation of genome-wide association study (GWAS) identified disease risk alleles with patient-specific stem cell lines. Hum Mol Genet2014; 23: 3445–3455.
31.
SainiJSCorneoBMillerJD, et al.Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell2017; 20: 635–647.e7.
32.
BradleyDTZipfelPFHughesAE. Complement in age-related macular degeneration: a focus on function. Eye (Lond)2011; 25: 683–693.
33.
ZengFZhangMXuY, et al.ARMS2 Interference leads to decrease of proinflammatory mediators. Graefes Arch Clin Exp Ophthalmol2013; 251: 2539–2544.
34.
MohabatiDSchellevisRLVan DijkEHC, et al.Genetic risk factors in acute central serous chorioretinopathy. Retina2019; 39: 2303–2310.
35.
ZennaroMCKeightleyMCKotelevtsevY, et al.Human mineralocorticoid receptor genomic structure and identification of expressed isoforms. J Biol Chem1995; 270: 21016–21020.
36.
FarmanNRafestin-OblinME. Multiple aspects of mineralocorticoid selectivity. Am J Physiol Renal Physiol2001; 280: F181–F192.
37.
ViengchareunSLe MenuetDMartinerieL, et al.The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology. Nucl Recept Signal2007; 5: e012.
38.
ZhaoMCélérierIBousquetE, et al.Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy. J Clin Invest2012; 122: 2672–2679.
39.
ChatziralliIVlachodimitropoulouADaoulaC, et al.Eplerenone in the treatment of central serous chorioretinopathy: a review of the literature. Int J Retina Vitreous2018; 4: 33.
40.
LoteryASivaprasadSO’ConnellA, et al.Eplerenone versus placebo for chronic central serous chorioretinopathy: the VICI RCT. Southampton (UK): NIHR Journals Library, 2021.
41.
DuanJZhangYZhangM. Efficacy and safety of the mineralocorticoid receptor antagonist treatment for central serous chorioretinopathy: a systematic review and meta-analysis. Eye (Lond)2021; 35: 1102–1110.
42.
Carvalho-RecchiaCAYannuzziLANegrӑoS, et al.Corticosteroids and central serous chorioretinopathy. Ophthalmology2002; 109: 1834–1837.
43.
GolestanehNPicaudSMirshahiM. The mineralocorticoid receptor in rodent retina: ontogeny and molecular identity. Mol Vis2002; 8: 221–225.
44.
Behar-CohenFZhaoM. Corticosteroids and the retina: a role for the mineralocorticoid receptor. Curr Opin Neurol2016; 29: 49–54.
45.
ZhaoMValamaneshFCelerierI, et al.The neuroretina is a novel mineralocorticoid target: aldosterone up-regulates ion and water channels in Mϋller glial cells. FASEB J2010; 24: 3405–3415.
46.
MillerWL. The hypothalamic-pituitary-adrenal axis: a brief history. Horm Res Paediatr2018; 89: 212–223.
47.
Van LeeuwenNCaprioMBlayaC, et al.The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, rennin an aldosterone levels. Hypertension2010; 56: 995–1002.
48.
TsaiDCChenSJHuangCC, et al.Epidemiology of idiopathic central serous chorioretinopathy in Taiwan, 2001–2006: a population-based study. PLoS One2013; 8: e66858.
49.
MohabatiDSchellevisRLVan DijkEHC, et al.Genetic risk factors in severe, nonsevere and acute phenotypes of central serous chorioretinopathy. Retina2020; 40: 1734–1741.
