Association between the SERPING1 gene and age-related macular degeneration: a two-stage case–control study
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Background Age-related macular degeneration is the most prevalent form of visual impairment and blindness in developed countries. Genetic studies have made advancements in establishing the molecular cause of this disease, identifying mutations in the complement factor H (CFH) gene and a locus on chromosome 10 encompassing the HTRA1/LOC387715/ARMS2 genes. Variants in complement 3 (C3) and an HLA locus containing both factor B and C2 genes have also been implicated. We aimed to identify further genetic risk factors for this disease.Methods We used a case-control study design in a UK sample of patients with age-related macular degeneration (n=479) and controls (n=479) and undertook a low-density screen of 32 genes using 93 single nucleotide polymorphisms (SNPs). Genes were selected as candidates on the basis of potential functional relevance to age-related macular degeneration. Significant initial findings were confirmed by replication in an independent US cohort of 248 unrelated patients with disease and 252 controls, and by high-density genotyping around association signals.Findings The SNP variant rs2511989, located within intron six of the SERPING1 gene, showed highly significant genotypic association with age-related macular degeneration (uncorrected p=4.0x10(-5), corrected p=0.00372). We detected no evidence for association between disease and the other 31 candidate genes. The odds ratio for age-related macular degeneration in rs2511989 G/A heterozygotes compared with wild type G/G homozygotes was 0.63 (95% CI 0.47-0.84). A similar comparison of the A/A homozygotes with the wild type yielded an odds ratio of 0.44 (0.31-0.64). We replicated the observed genotypic association in a US cohort (p=0.008). Furthermore, a secondary high-density genotyping study across the SERPING1 gene region identified five additional SNP variants similarly associated with age-related macular degeneration (rs2244169, rs2511990, rs2509897, rs1005510, and rs2511988).Interpretation Genetic variation in SERPING1 significantly alters susceptibility to age-related macular degeneration. SERPING1 encodes the C1 inhibitor, which has a crucial role in inhibition of complement component 1 (C1) and might implicate the classic pathway of complement activation in this disease.
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Screening of potential functional candidate genes identified an association with an intronic variant within the SERPING1 gene.
“Screening of potential functional candidate genes identified association with an in-tronic variant within the SERPING1 gene (42);”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [42]
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- Authors
- Ennis, S., Jomary, C., Mullins, R., Cree, A., Chen, X., MacLeod, A., Jones, S., Collins, A., Stone, E., & Lotery, A.
- Affiliations
- Southampton General Hospital (GB)
- University of Iowa (US)
- St Thomas' Hospital (GB)
- Corresponding author
- Lotery, Andrew
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 372
- Issue
- 9652
- Pages
- 1828-1834
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC5983350
- OpenAlex
- W2032834555
- Cited by
- 171
- References
- 30
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 2 · 2021: 14 · 2020: 4 · 2019: 4 · 2018: 13 · 2017: 6 · 2016: 8 · 2015: 4 · 2014: 7 · 2013: 10 · 2012: 22
- FWCI
- 23.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Macula Vision Research Foundation
- Wellcome Trust (076169)
- National Eye Institute (R01EY017451, EY016822, R01EY016822, EY017451)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- degeneration, SERPING1, genetic susceptibility, single nucleotide polymorphisms, complement system, genetic risk factors, replication study, complement factor H
- MeSH terms
- Aged, Aged, 80 and over, Complement C1 Inactivator Proteins, Female, Genotype, United Kingdom, Humans, Macular Degeneration, Male, Middle Aged, Case-Control Studies, Polymorphism, Single Nucleotide, Complement C1 Inhibitor Protein
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