Role of the Complement System in Chronic Central Serous Chorioretinopathy

Abstract

IMPORTANCE To date, several targeted genetic studies on chronic central serous chorioretinopathy (cCSC) have been performed; however, unbiased genome-wide studies into the genetics of cCSC have not been reported. To discover new genetic loci associated with cCSC and to better understand the causative mechanism of this disease, we performed a genome-wide association study (GWAS) on patients with cCSC. OBJECTIVE To discover new genetic loci and pathways associated with cCSC and to predict the association of genetic variants with gene expression in patients with cCSC. DESIGN, SETTING, AND PARTICIPANTS This case-control GWAS was completed in the general community, 3 referral university medical centers, and outpatient care on Europeans individuals with cCSC and population-based control participants. Genotype data was collected from May 2013 to August 2017, and data analysis occurred from August 2017 to November 2017. MAIN OUTCOMES AND MEASURES Associations of single-nucleotide polymorphisms, haplotypes, genetic pathways, and predicted gene expression with cCSC. RESULTS A total of 521 patients with cCSC (median age, 51 years; interquartile range [IQR], 44-59 years; 420 [80.6%] male) and 3577 European population-based control participants (median age, 52 years; IQR, 37-71 years; 1630 [45.6%] male) were included. One locus on chromosome 1 at the complement factor H (CFH) gene reached genome-wide significance and was associated with an increased risk of cCSC (rs1329428; odds ratio [OR], 1.57 [95% CI, 1.38-1.80]; P = 3.12 × 10 −11). The CFH haplotypes H1 and H3 were protective for cCSC (H1: OR, 0.64 [95% CI, 0.

Genome-Wide Association Study to Identify a New Susceptibility Locus for Central Serous Chorioretinopathy in the Japanese Population

“…A recent GWAS with European cohorts demonstrated the most significant association of rs1329428 with chronic CSC. 31 The authors found that some genes involved in the complement system are also significantly associated with CSC, but failed to detect significant association of SLC7A5 with CSC. This might be due to the difference in race since MAF of rs11865049 in Europeans is 0.0310 in the HapMap database and 0.0457 in the 1000 Genomes database, which was less than in Asian cohorts including Japanese.…”

“…Since our study indicated the that OR for the variant rs11865049 was 2.10 in the meta-analysis, the P value of this variant was below a suggestive significance threshold according to the power analysis in a previous report. 31 In addition, it might be a reason why CSC is more prevalent in Asians than in Caucasians. 1,32,33 A recent GWAS study revealed that CFH variants are associated with thickened choroid, which is often observed in CSC.…”

Exome sequencing in families with chronic central serous chorioretinopathy

“…Library preparation of the 52 family members of 12 families collected at the Radboudumc, Nijmegen was performed with the SureSelect XT target enrichment system for Illumina paired‐end multiplex sequencing according to manufacturer's instructions (Version B4, August 2015, Agilent Technologies). Completed libraries were sent to the Department of Genetics of Maastricht University Medical Center+, Maastricht, the Netherlands, where sequencing was performed with eight samples per lane using an Illumina HiSeq2000 with 2*100 bp chemistry, together with a large cohort of 269 sporadic CSC patients (Schellevis et al, submitted).…”

“…Data of all individuals were processed according to the Genome‐Analysis‐Toolkit (GATK) best practices (v3.8) together with the case–control cohort consisting of 269 sporadic cCSC patients and 1,586 population controls (Schellevis et al, submitted) to improve variant calling. Briefly, BAM to FastQC extraction was performed with Picard‐tools (v 1.90), duplicate reads were marked with Picard‐tools, and reads were aligned to the reference genome (GRCh37.p5 with alternate haplotypes excluded) using BWA‐MEM (version v.0.7.12), as described before (Schellevis et al, submitted). Base recalibration was performed and subsequent variant calling was performed with the HaplotypeCaller algorithm.…”

“…Other risk factors include endogenous hypercortisolism, stress, and pregnancy (Daruich et al, ; van Dijk et al, ; Liew et al, ). Moreover, genetic variants that confer risk or are protective for CSC have been identified by genetic association studies in case–control cohorts (de Jong et al, ; Miki et al, ; Moschos et al, ; Schellevis et al, ; Schubert et al, ; van Dijk, Schellevis, Bergen et al, ).…”