Polymorphisms Of The Complement Factor H Gene In Exudative Age-related Macular Degeneration

Age-related macular degeneration (AMD) is a late-onset, chronic and progressivedegenerative disorder of the macula at the central region of the retina. It is characterized byprogressive destruction of the macula, causing central field visual loss. It is the leading cause ofirreversible visual impairment or blindness in people aged of 65 years or above in developedcountries, affecting about 50 million people worldwide. Its incidence is increasing as the elderlypopulation expands. The exudative AMD, as one of the late stage AMD, accounts for nearly 90%of severe cases in AMD and tends to progress quickly.For such a disorder, no therapy has proven to be broadly effective. Its pathogenesis remainselusive. Risk factors have been linked to AMD, including age, smoking and family history.Recently, a common coding variant (rs1061170, sequence: T1277C; protein: Y402H) in thecomplement factor H gene (CFH) has been reported to have a strong association with thesusceptibility of developing AMD in Caucasians. After that, a series of CFH variants were alsodemonstrated to be associated with AMD, including the I62V, A307A, etc.Chinese is one of the largest ethnic groups in the world, but few data from mutationscreening for AMD in this population was available. Therefore, in order to investigate theassociation between the CFH variants and exudative AMD in ethnic Chinese, we have performeda two-stage, case-control genetic association study in a Chinese population of Hong Kong.In the first stage of the study, we have genotyped 6 representative SNPs in 163 sporadic caseswith exdative AMD and 244 age and sex matched controls, using Taqman genotyping method.We found that the risk allele C in the Y402H SNP was at low frequencies (5.8% in patients and 3.9% in controls) and was not significantly associated with exudative AMD. However, the SNPsrs3753394, rs800292, and rs1329428 were significantly associated with the disease. A haplotypedefined by these SNPs (TGTC) was found to confer a significantly increased likelihood ofexudative AMD with an odds ratio of 1.68 (95% CI: 1.26-2.23).At the second stage of the study, CFH promoter sequence up to-794 and all the 22 exons ofincluding intron-exon boundaries, were screened for any sequence alterations in 163 patients and155 controls, using polymerase chain reaction (PCR) followed by direct DNA sequencing.Fifty-eight sequence changes were identified: 16 were reported SNPs while 42 were novel. Amajor haplotype (T-C-G-G-G-T) defined by the variants-257C＞T, IVS1-36C＞T, I62V, A473A,Q672Q and rs1329428 was detected to confer a 1.63 fold of significantly increased risk forexudatvie AMD (OR: 1.63, 95% CI: 1.18-2.23). Two minor haplotypes containing the Y402H orV837I respectively were detected to confer a trend of risk or protective for the disease. Moreover,fourteen rare variants were detected in eases exclusively and eleven were found only in controls.They could have a minor role on the pathogenesis of exudative AMD though furtherinvestigation is needed.Our study showed that the CFH gene was also a genetic risk factor of exudative AMD inChinese population. However, the pattern of association between the CFH SNPs and AMD wasdifferent from that in Caucasians. These findings were a major advance towards understandingthe genetic risk and pathogenesis of AMD.