Contreras Alejandra V, Zenteno Juan Carlos, Fernández-López Juan Carlos, Rodríguez-Corona Ulises, Falfán-Valencia Ramcés, Sebastian Leticia, Morales Fabiola, Ochoa-Contreras Daniel, Carnevale Alessandra, Silva-Zolezzi Irma
Instituto Nacional de Medicina Genómica. Mexico City, Mexico.
Department of Genetics and Research Unit, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico ; Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico.
Mol Vis. 2014 Jan 14;20:105-16. eCollection 2014.
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.
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.
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.
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.
评估补体因子H（CFH）、补体成分2和3（C2和C3）、补体因子B（CFB）以及年龄相关性黄斑病变易感性2（ARMS2）的基因变异对墨西哥梅斯蒂索人群年龄相关性黄斑变性（AMD）风险的影响。
分析纳入了282例患有晚期AMD的无血缘关系的墨西哥患者、205例健康对照和280例人群对照。立体眼底图像按照临床年龄相关性黄斑病变系统（CARMS）进行分级。我们设计了一种重测序策略，在96例经过临床评估的个体亚组中，使用带有M13接头的引物对CFH基因的23个外显子进行检测：48例AMD患者和48例年龄及性别匹配的健康对照。使用TaqMan分析对所有患者、健康对照和人群对照中的C3（Arg80Gly和Pro292Leu）、C2（rs547154）、CFB（Leu9His）和ARMS2（Ala69Ser）中的单核苷酸多态性（SNP）进行基因分型。
所有评估个体均为墨西哥梅斯蒂索人，使用224个祖先信息标记并计算F(st)值对其遗传血统进行了验证。CFH重测序揭示了19个SNP以及内含子2剪接受体位点的一个常见变异；从个体基因型推断出的三种CFH单倍型在病例组和对照组之间显示出显著差异。C3（rs1047286，优势比[OR]=2.48，95%置信区间[CI]=1.64 - 3.75，p = 1.59E - 05；rs2230199，OR = 2.15，95% CI = 1.48 - 3.13，p = 6.28E - 05）和ARMS2（rs10490924，OR = 3.09，95% CI = 2.48 - 3.86，p = 5.42E - 23）中的风险等位基因与AMD风险密切相关。C2（rs547154）和CFB（rs4151667）中等位基因的保护作用显示出一种趋势，但在多重检验校正后未显示出显著相关性。
我们的结果表明，ARMS2和C3是墨西哥患者晚期AMD的主要促成因素，而CFH、C2和CFB的作用相对于其他人群较小，这揭示了次要等位基因频率存在显著的种族差异。我们提供的证据表明，CFH基因中的两种特定常见单倍型使个体易患AMD，而另一种单倍型可能会降低该混合人群的疾病风险。
