Abstract
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study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European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 × 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. Published by Oxford University Press on behalf of the International Epidemiological Association
| Original language | English |
|---|---|
| Article number | dyr204 |
| Pages (from-to) | 250-262 |
| Number of pages | 13 |
| Journal | International Journal of Epidemiology |
| Volume | 41 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Feb 2012 |
Bibliographical note
Funding Information: This work was supported by a Medical Research Council Biomarkers Award G0601354. R.S. was supported by a British Heart Foundation (Schillingford) Clinical Training Fellowship (FS/07/011). A.D.H. was supported by British Heart Foundation Senior Fellowship (FS 05/125). V.C. is funded by a grant from the Guide Dogs for the Blind Association. A.M., A.W. and J.Y. receive funding from the UK Department of Health’s NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The views expressed in the publication are those of the authors and not necessarily those of the Department of Health. The Moorfields Study in addition was funded by the Medical Research Council (Award number G0000682), the Mercer Fund (Fight for Sight UK). L.S. holds a Wellcome Trust Senior Research Fellowship. EUREYE was funded by EUQLK6-CT-1999-02094. B.H.F.W. is supported by grants from the German Research Foundation (WE1259/18-1, WE1259/19-1), the Ruth and Milton Steinbach Foundation, New York and the Alcon Research Institute, Fort Worth. Cambridge AMD Study was funded by Grant G0000067 from the Medical Research Council, UK. AS and GA received funding from the NIH EY-016862, AS received funding from Macula Vision Research Foundation and the Harold Falls Professorship. A.A.B. is supported by the ANVVB, the Netherlands Macula Fund and the LSBS. The Pittsburgh Study was funded by the National Institutes of Health grant NIH R01 EY9859, Research for Prevent Blindness, New York, and the American Health Assistance Foundation and the Harold and Pauline Price Endowed Professorship (to Professor Gorin) at University of California, Los Angeles. Andrew Lotery is funded by the Macular Vision Research Foundation, The British Council for Prevention of Blindness and the Macular Disease Society. Mati Rahu is funded by the Estonian Ministry of Education and Science (target funding 01921112s02 and SF0940026s07). A.D.H. has provided non-remunerated advice to GlaxoSmithKline and London Genetics and has received honoraria for speaking at educational meetings on cardiovascular risk which have been donated in whole or part to charity. J.W. is 90% employed at GlaxoSmithKline whilst retaining a 10% appointment at the London School of Hygiene and Tropical Medicine. P.T.V.M. de.J. and B.H.F.W. have unrestricted research awards from Alcon.Other keywords
- Age-related macular degeneration (AMD)
- Complement factor H gene
- Meta-ananlysis