Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy

Conley, Yvette P.; Thalamuthu, Anbupalam; Jakobsdottir, Johanna; Weeks, Daniel E.; Mah, Tammy; Ferrell, Robert E.; Gorin, Michael B.

doi:10.1093/hmg/ddi204

Cited by 158Retinal Diseases and TreatmentsRetinal Development and DisordersGenetic Associations and Epidemiology

Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy

Conley, Yvette P., Thalamuthu, Anbupalam, Jakobsdottir, Johanna, Weeks, Daniel E., Mah, Tammy, Ferrell, Robert E., Gorin, Michael B.·2005·Human Molecular Genetics

DOI 10.1093/hmg/ddi204

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Abstract

Age-related maculopathy (ARM) is a leading cause of visual impairment in elderly Americans and is a complex genetic disorder. Hypothesized pathways for the etiology of ARM include cholesterol and lipoprotein metabolism and transport, extracellular matrix integrity, oxidative stress and inflammatory/immunologic processes. This study investigates 21 polymorphisms within 15 candidate genes whose products function within these pathways by performing family and case-control genetic association studies using clearly affected familial cases (n=338 families, 796 individuals), clearly affected, unrelated sporadic cases (n=196) and clearly unaffected, unrelated controls (n=120). Two genes demonstrated significant association with ARM status. A Met299Val variant in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene was significantly associated with ARM in the case-control allele (P=0.001), case-control genotype (P=0.001) and case-control family (P<0.0001) tests. A Tyr402His variant in exon 9 in the complement factor H (CFH) gene was also significantly associated with ARM in the case-control allele (P<0.0001), case-control genotype (P<0.0001) and case-control family (P<0.0001) tests. All of these results remain significant after adjusting for false discovery rates to control for the impact of multiple testing. In addition, the CFH variant appears to play a role in exudative and atrophic disease, whereas the ELOVL4 variant may play a greater role in exudative disease in our population. These results support a potential role for multiple pathways in the etiology of ARM, including pathways involved with fatty acid biosynthesis and the complement system.

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Several studies have found an association between advanced age-related macular degeneration and complement factor H.
“More recently, several studies have found an association between advanced age-related macular degeneration and complement factor H, an integral component of the alternative pathway of complement activation.54–65”
From Age-related macular degeneration (2008) · cites this paper as [58]

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Cigarette Smoking Strongly Modifies the Association of LOC387715 and Age-Related Macular Degeneration
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MurineCcl2/Cx3cr1Deficiency Results in Retinal Lesions Mimicking Human Age-Related Macular Degeneration
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CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses
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Lipids, oxidized lipids, oxidation-specific epitopes, and Age-related macular degeneration.
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In vitro C3 deposition on Cryptococcus capsule occurs via multiple complement activation pathways
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The MBL-complex is a significant contributor to thrombogenesis in vivo and in vitro
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Continual Low-Level Activation of the Classical Complement Pathway
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Activation of the alternative complement pathway by extracts of cotton dust
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The Alternative Pathway of Complement Activation
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Authors: Conley, Y. P., Thalamuthu, A., Jakobsdottir, J., Weeks, D. E., Mah, T., Ferrell, R. E., & Gorin, M. B.
Affiliations: University of Pittsburgh (US)
Corresponding author: Conley, Yvette P.
ORCID: Conley, Yvette P.
Thalamuthu, Anbupalam
Weeks, Daniel E.
Mah, Tammy
Gorin, Michael B.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2005-06-01
Volume: 14
Issue: 14
Pages: 1991-2002
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddi204
OpenAlex: W2105155318
Cited by: 158
References: 77
Citations by year: 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 3 · 2016: 2 · 2015: 1 · 2014: 3 · 2013: 9 · 2012: 11
FWCI: 22.93
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Eye Institute (R01EY009859)
Fogarty International Center (D43TW006180)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: age-related maculopathy, genetic association, ELOVL4, complement factor H, fatty acid synthesis, complement system, neovascular age-related macular degeneration, atrophic macular degeneration, candidate genes, family-based association
MeSH terms: Aging, Alleles, Base Sequence, Complement System Proteins, Fatty Acids, Gene Frequency, Humans, Macular Degeneration, Phenotype, Polymorphism, Genetic, Case-Control Studies, DNA Primers

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Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy

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