Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype

Reecha Sofat, Juan P Casas, Andrew R Webster, Alan C Bird, Samantha S Mann, John R W Yates, Anthony T Moore, Tiina Sepp, Valentina Cipriani, Catey Bunce, Jane C Khan, Humma Shahid, Anand Swaroop, Gonçalo Abecasis, Kari E H Branham, Sepideh Zareparsi, Arthur A Bergen, Caroline C W Klaver, Dominique C Baas, Kang ZhangYuhong Chen, Daniel Gibbs, Bernhard H F Weber, Claudia N Keilhauer, Lars G Fritsche, Andrew Lotery, Angela J Cree, Helen L Griffiths, Shomi S Bhattacharya, Li L Chen, Sharon A Jenkins, Tunde Peto, Mark Lathrop, Thierry Leveillard, Michael B Gorin, Daniel E Weeks, Maria Carolina Ortube, Robert E Ferrell, Johanna Jakobsdottir, Yvette P Conley, Mati Rahu, Johan H Seland, Gisele Soubrane, Fotis Topouzis, Jesus Vioque, Laura Tomazzoli, Ian Young, John Whittaker, Usha Chakravarthy, Paulus T V M de Jong, Liam Smeeth, Astrid Fletcher, Aroon D Hingorani

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


BACKGROUND: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.

METHODS: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry.

RESULTS: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.

CONCLUSION: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

Original languageEnglish
Pages (from-to)250-62
Number of pages13
JournalInternational Journal of Epidemiology
Issue number1
Publication statusPublished - Feb 2012


  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Complement Factor H
  • European Continental Ancestry Group
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Macular Degeneration
  • Male
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Smoking
  • Journal Article
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype'. Together they form a unique fingerprint.

Cite this