Other entities represented in this entry:
DO: 0110026;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33 | {Macular degeneration, age-related, 14, reduced risk of} | 615489 | Digenic dominant | 3 | C2 | 613927 |
| 6p21.33 | {Macular degeneration, age-related, 14, reduced risk of} | 615489 | Digenic dominant | 3 | CFB | 138470 |
A number sign (#) is used with this entry because of evidence that variation at or near the C2 (613927) and CFB (138470) genes on chromosome 6p21 influences susceptibility to age-related macular degeneration.
For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration (ARMD), see 603075.
Because CFH (134370) haplotypes are associated with age-related macular degeneration (ARMD4; 610698), Gold et al. (2006) hypothesized that the same may be true for activators of the same pathway. Gold et al. (2006) screened the CFB (138470) and C2 (613927) genes for genetic variation in 2 independent cohorts comprising approximately 900 individuals with ARMD and approximately 400 matched controls. Haplotype analyses identified a statistically significant common risk haplotype and 2 protective haplotypes. Haplotype H10, consisting of the L9H variant (138470.0003) of CFB and the E318D variant (613927.0004) of C2, and haplotype H7, consisting of the variant in intron 10 (613927.0005) of C2 and the R32Q variant (138470.0004) of CFB, conferred a significantly reduced risk of ARMD (OR = 0.36 and 0.45, respectively). Combined analysis of the C2/CFB haplotypes and CFH variants showed that variation in the 2 loci can predict the clinical outcome in 74% of affected individuals and 56% of controls.
Thakkinstian et al. (2012) reviewed the association of C2/CFB gene polymorphisms with ARMD by pooling data from 19 studies published between 2006 and 2011 for 4 polymorphisms: rs9332739 (613927.0004) and rs547154 (613927.0005) in the C2 gene and rs4151667 (138470.0003) and rs641153 (138470.0004) in the CFB gene. Pooled minor allele frequencies for all 4 SNPs were between 4.7% and 9.6%, except for an Indian population in which the C allele at rs9332739 was the major allele. For the C2 polymorphisms, the minor C allele at rs9332739 and the minor T allele at rs547154 carried estimated relative risks (odds ratios) of 0.55 (95% confidence interval (CI) 0.46, 0.65) and 0.47 (95% CI 0.39, 0.57), respectively. For the CFB polymorphisms, the minor A alleles at rs4151667 and rs614153 carried estimated risks of 0.54 (95% CI 0.45, 0.64) and 0.41 (95% CI 0.34, 0.51), respectively. These allele effects contributed to an absolute lowering of the risk of all AMD in Caucasian populations by 2.0-6.0%.
Fritsche et al. (2013) executed a collaborative genomewide association study, including more than 17,100 advanced ARMD cases and more than 60,000 controls of European and Asian ancestry. They identified 19 loci associated at p less than 5 x 10(-8). These loci showed enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling, and angiogenesis. Fritsche et al. (2013) identified association of the G allele of rs429608, near the C2 and CFB genes on chromosome 6p21.3, with increased risk of age-related macular degeneration (OR 1.74, 95% CI 1.68-1.79, combined p = 4 x 10(-89)).
Fritsche, L. G., Chen, W., Schu, M., Yaspan, B. L., Yu, Y., Thorleifsson, G., Zack, D. J., Arakawa, S., Cipriani, V., Ripke, S., Igo, R. P., Jr., Buitendijk, G. H. S., and 144 others. Seven new loci associated with age-related macular degeneration. Nature Genet. 45: 433-439, 2013. [PubMed: 23455636] [Full Text: https://doi.org/10.1038/ng.2578]
Gold, B., Merriam, J. E., Zernant, J., Hancox, L. S., Taiber, A. J., Gehrs, K., Cramer, K., Neel, J., Bergeron, J., Barile, G. R., Smith, R. T., AMD Genetics Clinical Study Group, Hageman, G. S., Dean, M., Allikmets, R. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nature Genet. 38: 458-462, 2006. [PubMed: 16518403] [Full Text: https://doi.org/10.1038/ng1750]
Thakkinstian, A., McEvoy, M., Chakravarthy, U., Chakrabarti, S., McKay, G. J., Ryu, E., Silvestri, G., Kaur, I., Francis, P., Iwata, T., Akahori, M., Arning, A., Edwards, A. O., Seddon, J. M., Attia, J. The association between complement component 2/complement factor B polymorphisms and age-related macular degeneration: a HuGE review and meta-analysis. Am. J. Epidemiol. 176: 361-372, 2012. [PubMed: 22869612] [Full Text: https://doi.org/10.1093/aje/kws031]