CFH haplotypes and ARMS2, C2, C3, and CFB alleles show association with susceptibility to age-related macular degeneration in Mexicans.
OBJECTIVE
To evaluate the contribution of genetic variants of complement factor H (CFH), complement component 2 and 3 (C2 and C3), complement factor B (CFB), and age-related maculopathy susceptibility 2 (ARMS2) to age-related macular degeneration (AMD) risk in the Mexican Mestizo population.


METHODS
Analysis included 282 unrelated Mexican patients with advanced AMD, 205 healthy controls, and 280 population controls. Stereoscopic fundus images were graded on the Clinical Age-Related Maculopathy System (CARMS). We designed a resequencing strategy using primers with M13 adaptor for the 23 exons of the CFH gene in a subgroup of 96 individuals clinically evaluated: 48 AMD cases and 48 age- and sex-matched healthy controls. Single nucleotide polymorphisms (SNPs) in C3 (Arg80Gly and Pro292Leu), C2 (rs547154), CFB (Leu9His), and ARMS2 (Ala69Ser) were genotyped in all patients, healthy and population controls using TaqMan assay.


RESULTS
All evaluated individuals were Mexican Mestizos, and their genetic ancestry was validated using 224 ancestry informative markers and calculating F(st) values. The CFH resequencing revealed 19 SNPs and a common variant in the intron 2 splice acceptor site; three CFH haplotypes inferred from individual genotypes, showed significant differences between cases and controls. The risk alleles in C3 (rs1047286, odds ratio [OR]=2.48, 95% confidence interval [CI]=1.64-3.75, p=1.59E-05; rs2230199, OR=2.15, 95% CI=1.48-3.13, p=6.28E-05) and in ARMS2 (rs10490924, OR=3.09, 95% CI=2.48-3.86, p=5.42E-23) were strongly associated with risk of AMD. The protective effect of alleles in C2 (rs547154) and CFB (rs4151667) showed a trend but was not significantly associated after correction for multiple testing.


CONCLUSIONS
Our results show that ARMS2 and C3 are major contributors to advanced AMD in Mexican patients, while the contributions of CFH, C2, and CFB are minor to those of other populations, reveling significant ethnic differences in minor allele frequencies. We provide evidence that two specific common haplotypes in the CFH gene predispose individuals to AMD, while another may confer reduced risk of disease in this admixed population.
Instituto Nacional de Medicina Genómica. Mexico City, Mexico.
Alejandra V
AV
Contreras
Department of Genetics and Research Unit, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico ; Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico.
Juan Carlos
JC
Zenteno
Instituto Nacional de Medicina Genómica. Mexico City, Mexico.
Juan Carlos
JC
Fernández-López
Instituto Nacional de Medicina Genómica. Mexico City, Mexico.
Ulises
U
Rodríguez-Corona
Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
Ramcés
R
Falfán-Valencia
Instituto Nacional de Medicina Genómica. Mexico City, Mexico.
Leticia
L
Sebastian
Instituto Nacional de Medicina Genómica. Mexico City, Mexico.
Fabiola
F
Morales
Asociación Para Evitar la Ceguera en México, Hospital "Dr. Luis Sánchez Bulnes," Mexico City, Mexico.
Daniel
D
Ochoa-Contreras
Instituto Nacional de Medicina Genómica. Mexico City, Mexico.
Alessandra
A
Carnevale
Nutrition and Health Department, Nestlé Research Center, Lausanne, Switzerland.
Irma
I
Silva-Zolezzi
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D003175:Complement C2 / Q000235:genetics*; D003176:Complement C3 / Q000235:genetics*; D011415:Complement Factor B / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008800:Mexico; D016366:Open Reading Frames / Q000235:genetics; D011506:Proteins / Q000235:genetics*
C514392:ARMS2 protein, human; D003175:Complement C2; D003176:Complement C3; D011506:Proteins; D017242:Complement Factor H; D011415:Complement Factor B