CFB R32Q - GET-Evidence

Curation:
Currentness:

CFB R32Q

(CFB Arg32Gln)


Short summary

This variant is associated with a significant protective effect — individuals with this variant are about half as likely to have age-related macular degeneration. Appears to be an additive effect, with homozygotes having a stronger protective effect.

Variant evidence
Computational -
Functional -
Case/Control 5

Case/control data is very high significance

See Gold B et al. 2006 (16518403), Maller J et al. 2006 (16936732).

Familial -
 
Clinical importance
Severity 3
Treatability 2
Penetrance 3

Assuming a lifetime risk of 10%, we estimate a 5-6% attributable reduced risk of disease (total risk of 4-5%) — but this number may be too high, see below.

See Gold B et al. 2006 (16518403), Maller J et al. 2006 (16936732), unpublished research (below).

 

Impact

Moderate clinical importance, Likely protective

(The "moderate clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

dominant

Summary of published research, and additional commentary

Notably, both Gold et al. and Maller et al. use controls that strongly exclude signs of disease — without knowing what fraction of the total population would have fallen into case and control groups it is difficult to predict the overall impact of this variant on disease. That said, the frequency of the variant allele in European controls from both papers (0.111 and 0.102) is very close to the allele frequency in European populations as recording in dbSNP (HapMap-CEU: 0.125, PGA-EUROPEAN-PANEL: 0.107).

Using their numbers, if we assume controls represent the general population and the cases represent disease which has an average lifetime risk of 10% in the general population, we would estimate a reduced risk of 5-6% (total risk of 4-5%). Because these cases were extreme version of the disease, however, the effect may actually be more modest.

Allele frequency

  • CA @ chr6:32022157: 11.7% (15/128) in GET-Evidence
  • Frequency shown in summary reports: 11.7% (15/128)

Publications
 

Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT; AMD Genetics Clinical Study Group, Hageman GS, Dean M, Allikmets R. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006 Apr;38(4):458-62. Epub 2006 Mar 5. PubMed PMID: 16518403.

This association study in individuals of European descent investigated variants associated with age-related macular degeneration and first reported the protective effect for the R32Q allele. Affected individuals consisted of unrelated individuals with clinically documented AMD, while controls did not show any distinguishing signs of macular disease and had no family history of the disease. The first cohort had highly significant numbers, 44/1096 case alleles vs. 61/550 control alleles (case+: 44, case-: 1,052, cont+: 61, cont-: 489). This produces an odds ratio of 0.335 and p = 9 * 10^-9.

This is reported to be replicated in a second cohort, but it’s unclear what the numbers from this cohort are — table 2 supposedly combines numbers from both, but the number of controls for R32Q in table 2 (269 controls, 538 alleles) is less than the number of controls in table 1 (275 controls, 550 alleles) but more than the number of control individuals the text describes for the second cohort (114 controls, 228 alleles).

Although they do not report specific numbers, the authors cite statistically significant results for both homozygous and heterozygous individuals and propose a codominant effect.

Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, Seddon JM. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006 Sep;38(9):1055-9. Epub 2006 Aug 27. PubMed PMID: 16936732.

This study compares individuals diagnosed with advanced age-related macular degeneration to controls of at least 60-years of age and without any early signs of the disease. The frequency of the allele in cases 0.045, and 0.102 in controls, implying a protective effect for this variant. This had a p-value of 5.5 * 10^-13.

Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009 May;50(5):2044-53. Epub 2008 Dec 30. PubMed PMID: 19117936.

Provides a model for combining variants including this one.

Genomes
 

hu034DB1

 

hu0D879F

 

hu43860C

 

hu604D39

 

hu9385BA

 

huBEDA0B

 

GS18501 - var-GS18501-1100-36-ASM
het A @ chr6:32022159

 

GS18504 - var-GS18504-1100-36-ASM
het A @ chr6:32022159

 

GS18505 - var-GS18505-1100-36-ASM
het A @ chr6:32022159

 

GS19017 - var-GS19017-1100-36-ASM
het A @ chr6:32022159

 

GS19026 - var-GS19026-1100-36-ASM
het A @ chr6:32022159

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr6:32022159

 

Other external references
 

    dbSNP
  • rs641153
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the CFB gene
    Atypical Hemolytic-Uremic Syndrome
    CFB-Related Atypical Hemolytic-Uremic Syndrome
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CFB
    PolyPhen-2
  • Score: 0.01 (benign)
    Web search results (92 hits -- see all)
  • Protective effect of complement factor B and complement ...
    The R32Q variant of CFB was significantly associated with protection ... The minor alleles at CC2 rs547154 and CFB R32Q are present in 4% of cases versus ...
    www.ncbi.nlm.nih.gov/pubmed/17576744
  • C3 R102G polymorphism increases risk of age-related macular ...
    Because C3, CFH, and CFB all operate within the same biological pathway, the ... LOC387715, and the R32Q variant in CFB was estimated using logistic regression, ...
    hmg.oxfordjournals.org/cgi/content/full/17/12/1821
  • Protective effect of complement factor B and complement ...
    The R32Q variant of CFB was significantly associated with protection from AMD in ... Therefore, CFB R32Q is associated with AMD regardless of genotype at CC2 E318D. ...
    hmg.oxfordjournals.org/cgi/content/full/16/16/1986
  • Further assessment of the Complement Component 2 and Factor B ...
    ... associated with AMD, in particular CFB R32Q and CC2 rs547154, both of which ... of LD within the extended CC2/CFB region, variation within SKIV2L may exert a ...
    intl.iovs.org/cgi/content/abstract/iovs.08-2275v1
  • Further Assessment of the Complement Component 2 and Factor B ...
    In contrast, CC2 and CFB, paralogous genes separated by 500 base pairs on ... Both of the previous studies reported rs641153 (CFB R32Q) to be significantly associated with AMD. ...
    www.iovs.org/cgi/content/full/50/2/533
  • Publication details :: Cambridge Neuroscience
    ... associated with AMD, in particular CFB R32Q and CC2 rs547154, both of which share strong linkage ... SNPs across the extended CC2/CFB region for genotyping, to measure ...
    neuroscience.cam.ac.uk/publications/pubInfo.php?...
  • C3 R102G polymorphism increases risk of age-related macular ...
    C3 R102G polymorphism increases risk of age-related macular degeneration. ... CFH Y402H, LOC387715 A69S, and CFB R32Q, the effect of R102G remained strong ...
    www.ncbi.nlm.nih.gov/pubmed/18325906
  • Smoking and other risk factors for coronary heart-disease in ...
    BioInfoBank Library :: Smoking and other risk factors for coronary heart-disease in British civil servants. Plasma fibrinogen concentration predicts the risk of ...
    lib.bioinfo.pl/pmid:62262
  • . T
    rs641153 R32Q (CFB) G. A 94.6% 5.4% 0.0% 2.7% 85.1% 14.9% 0.0% 7.5% 0.03. C3 gene. 68 35 9 ... R32W (CFB) R32Q (CFB) 0.134 * Because the homozygous risk genotype ...
    plosone.org/article/fetchSingleRepresentation.action?...
  • AMD Risk Calculator ::: MyVisionTest.com
    Calculate risk of progression to advanced macular degeneration ... or heterozygous for complement factor B (CFB) R32Q (rs641153), the nonsynonymous coding single nucleotide ...
    www.myvisiontest.com/riskcalc.php

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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