Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy.
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.
Conley
Yvette P
YP
Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, PA, USA.
Thalamuthu
Anbupalam
A
Jakobsdottir
Johanna
J
Weeks
Daniel E
DE
Mah
Tammy
T
Ferrell
Robert E
RE
Gorin
Michael B
MB
D000375:Aging; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D003165:Complement System Proteins / Q000502:physiology*; D017931:DNA Primers; D005227:Fatty Acids / Q000096:biosynthesis*; D005787:Gene Frequency; D006801:Humans; D008268:Macular Degeneration / Q000209:etiology / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic
D017931:DNA Primers; D005227:Fatty Acids; D003165:Complement System Proteins