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CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD
Open accessAbstract
BACKGROUND: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD--or the relationship between them--is unclear. METHODS AND FINDINGS: We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 x 10(-12)) and odds ratio of 2.14 in US patients from Utah (p = 2.0 x 10(-9)) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD). CONCLUSION: Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.
Overview
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Written from the paper’s full text.
TL;DR
The CFH Y402H variant is associated with advanced AMD in Icelandic and Utah cohorts, and it confers similar risk for soft drusen and both advanced subtypes (geographic atrophy and neovascular AMD). The authors conclude CFH mainly increases risk of soft drusen, with additional genetic and/or environmental factors needed for progression to advanced AMD.
Key findings
- Advanced AMD association was confirmed: Icelandic OR 2.39 (p = 5.9 × 10−12) and Utah OR 2.14 (p = 2.0 × 10−9) in the abstract; subtype ORs were neovascular 2.32, GA 2.27, and mixed GA/neovascular 2.92 in Iceland, and neovascular 2.17 and GA 2.05 in Utah.
- Y402H conferred similar risk of soft drusen and advanced AMD: soft drusen OR 2.52 in Iceland and 2.10 in Utah; no significant association with pigmentary changes; hard drusen showed significant association in Iceland (p = 0.01, OR 1.57) but not Utah, and soft versus hard drusen differed in Iceland (p = 0.011).
- HapMap allele frequencies for CFH Y402H were 39% in Caucasians, 30.7% in Africans, 8.1% in Japanese, and 6.8% in Chinese.
Methods
- Genotyped Icelandic cohort: 581 advanced AMD patients (278 neovascular, 203 GA, 100 mixed) and 435 early AMD patients (220 with soft drusen), compared with 891 population controls or 171 longevous controls; Utah cohort: 322 advanced AMD patients (244 neovascular, 78 GA) and 109 early AMD patients with soft drusen, compared with 203 age-matched controls.
- TaqMan assay for the Icelandic cohort and direct DNA sequencing for the Utah cohort; single-marker association for rs1061170 used Fisher’s exact test (one-sided p for the at-risk allele), with variance adjustment for familial relatedness; ORs and population-attributable risk were calculated under a multiplicative model.
Limitations
- The paper does not present a formal limitations section; it notes that additional genetic and/or environmental factors may be required for progression from soft drusen to advanced AMD, and that other genes remain to be found.
- The discussion states that genotype–phenotype correlation studies are needed in non-Caucasian populations, and the analyzed cohorts were Icelandic and Utah Caucasian populations, limiting generalization.
- Evident from the text: the design is cross-sectional genotype–phenotype association, so it cannot directly establish progression or causality from soft drusen to advanced AMD; the paper also notes the Icelandic GA/neovascular ratio is an open question possibly due to genetic or environmental factors.
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19 Not checked yet · 14 Own result · 11 Own interpretation
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10−12)”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Abstract > Methods and Findings
boostedcorrelationaln = 581 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD).”
- Also stated in: § Discussion · plain
“The effect of the CFH Y402H allele on soft drusen in early AMD is similar to its effect on the advanced forms of AMD, neovascular AMD, and GA.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Abstract > Methods and Findings
boostedcorrelationaln = 581 ·- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A significant difference in CFH Y402H allele frequencies was observed when patients with soft drusen were compared with an unrelated set of patients with hard drusen (p = 0.011).”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In agreement with previous reports [3–19], the Y402H allele confers an OR of 2.32 when comparing Icelandic patients with neovascular AMD to healthy controls.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10−9) with advanced AMD”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Abstract > Methods and Findings
plaincorrelationaln = 431 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“The Y402H variant also contributes to GA, with OR of 2.27.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the variant does not show significant association to pigmentary changes found in early AMD.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The patient group with mixed GA/neovascular AMD gave similar results with OR of 2.92.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, there may be other genes that influence the appearance of hard drusen and pigmentary changes.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, it appears that the Y402H variant in CFH contributes to the increased risk of advanced AMD largely or entirely through its impact on the development of soft drusen as a precursor of advanced AMD.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Soft drusen are usually precursors of both forms of advanced AMD.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Abstract > Conclusion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The addition of markers within the linkage peak led to recent reports by five groups that there is an association between a common missense variant (Y402H) in CFH and AMD in the United States [3,16–19].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Introduction
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the difficulty in explaining the difference in the ratio of the prevalences in neovascular AMD and GA across populations through the CFH variant alone supports the notion that additional genetic or environmental factors contribute to the pathogenesis.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, we conclude that the CFH variant contributes equally to GA and neovascular AMD in our European and US cohorts.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the Y402H allele contributes equally to GA and neovascular AMD in Icelandic patients with advanced AMD (Table 1).”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“However, the question of how the Y402H allele contributes to the different subtypes of AMD has not been properly addressed, owing either to insufficient clinical information or to sample size, as neovascular AMD dominates the patient cohorts in most previously reported studies [3,16–19].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Introduction
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Abstract > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is likely that there are other important genes, yet to be found, that contribute to the risk of advanced AMD, particularly among those who already have soft drusen.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
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In the paper
“This is comparable to the heritability of advanced AMD [37].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
- Not checked yetcites [37] Seddon, 2005, Arch Ophthalmol source
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 13
- Probably not a substantial claim. 14
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the Y402H variant contributes to soft drusen in early AMD, with similar ORs in the Icelandic and Utah study groups of 2.52 and 2.10, respectively (see Tables 1 and 2).”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on the comparison with population controls, the relative risk of the mutation is estimated to be 1.99 with a corresponding estimated population-attributable risk of 0.48.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- The authors state this as an assumption: The multiplicative model holds for interpreting the odds ratio as relative risk and for calculating population-attributable risk.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The allele frequencies for CFH Y402H in Caucasians and Africans were similar, 39% versus 30.7%, while they were much lower in Asians—8.1% in the Japanese and 6.8% in the Chinese.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This CFH variant also confers increased risk although this is not significant when comparing hard drusen to controls in the Utah cohort (see Table 2).”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Iceland we observed significant association (p = 0.01) to hard drusen but with a lower OR (1.57) (Table 1).”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The comparable association to neovascular AMD and GA was replicated in the Utah cohort, giving ORs of 2.17 and 2.05, respectively (Table 2).”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“For example in the Beaver Dam eye study, only 14% of the patients with soft drusen developed AMD over a 10-y period [30].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
- Not checked yetcites [30] Klein, 2002, Ophthalmology source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the prevalence discrepancy between the early and advanced AMD in African Americans is consistent with our hypothesis that CFH Y402H causes soft-drusen formation, but it is not sufficient for progression to advanced AMD.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The allele frequency of Y402H is less (0.31 versus 0.39) in African Americans than in Caucasians.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We have shown that the CFH Y402H allele confers significant risk to neovascular AMD, GA, and soft drusen in early AMD in US and European Caucasian populations.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, in persons of African origin living in United States and Barbados, prevalence of early AMD and soft drusen is slightly lower than in whites, but advanced AMD is rare [34,35].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, we show that the CFH variant is a risk factor for soft drusen, but not for hard drusen or pigmentary changes, per se.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“CFH protein has been detected in choriocapillaris and within soft drusen [3].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Introduction
What the sources say
- Not checked yetcites [3] Hageman, 2005, Proc Natl Acad Sci U S A source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This observation may not be surprising given that soft drusen is comprised, in part, of complement proteins including CFH and its binding partner, complement 3b [20].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
- Not checked yetcites [20] Giannakis, 2003, Eur J Immunol source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Biochemical analysis of drusen have indeed resulted in identification of complement components and inflammatory modulators [2–8].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Introduction
What the sources say
- Not checked yetcites [2] Hageman, 2001, Prog Retin Eye Res source
- Not checked yetcites [3] Hageman, 2005, Proc Natl Acad Sci U S A source
- Not checked yetcites [4] Mullins, 2000, Faseb J source
- Not checked yetcites [5] Mullins, 2001, Eye source
- Not checked yetcites [6] Anderson, 2002, Am J Ophthalmol source
- Not checked yetcites [7] Johnson, 2001, Exp Eye Res source
- Not checked yetcites [8] Crabb, 2002, Proc Natl Acad Sci U S A source
boosted- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Several genome-wide linkage scans for AMD including ours (unpublished data) have found suggestive linkage on chromosome 1q [9–15].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Introduction
What the sources say
- Not checked yetcites [9] Klein, 1998, Arch Ophthalmol source
- Not checked yetcites [10] Weeks, 2001, Am J Ophthalmol source
- Not checked yetcites [11] Majewski, 2003, Am J Hum Genet source
- Not checked yetcites [12] Seddon, 2003, Am J Hum Genet source
- Not checked yetcites [13] Schmidt, 2004, BMC Genet source
- Not checked yetcites [14] Abecasis, 2004, Am J Hum Genet source
- Not checked yetcites [15] Iyengar, 2004, Am J Hum Genet source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The Y402H allele was present in at least 60% of AMD patients with risk ratios of between 2.0 and 3.5 for one risk allele, and with risk ratios of between 3.3 and 7.4 for carriers of two risk alleles.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Introduction
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Numerous epidemiological studies have shown that the prevalence of soft drusen is two to three times greater than that of advanced AMD [33].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
- Not checked yetcites [33] Klein, 2004, Am J Ophthalmol source
boosted- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“As the patient cohort was recruited as families for a linkage analysis, we also repeated the test for association, correcting for the relatedness of the patients by extending a variance-adjustment procedure described previously [24] for sib-ships to apply to general familial relationships.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Methods > Data Analysis
What the sources say
- Not checked yetcites [24] Risch, 1998, Genome Res source
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The 5-y incidence of soft drusen in the Reykjavik Eye Study, a population-based epidemiological study of individuals aged 50 y and older [28,29], was found to be similar to that of the Beaver Dam Eye Study in the US [30], and the Blue Mountains Eye Study in Australia [31].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Consumption of fresh fish and fishliver oil with omega-3 polyunsaturated fatty acids among Icelanders is among the highest in the world [28].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
- Not checked yetcites [28] Jonasson, 2003, Arch Ophthalmol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In the Icelandic population under consideration here, however, GA was found to outnumber neovascular AMD by three to one, as reported in the Reykjavik Eye Study [28,29].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Neovascular AMD outnumbers GA by approximately three to one in both the Beaver Dam Eye Study and the Blue Mountains Eye Study.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Grading was carried out using a standard grid classification suggested by the International Age-Related Maculopathy Epidemiological Study Group for age-related maculopathy and AMD [23].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Methods > Patients
What the sources say
- Not checked yetcites [23] Bird, 1995, Surv Ophthalmol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Interestingly, Seddon et al. [32] reported a trend for decreasing odds of neovascular AMD with increasing amounts of omega-3 and fresh-fish intake.”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
- Not checked yetcites [32] Seddon, 2001, Arch Ophthalmol source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Significant genetic influence in early AMD has been demonstrated in a classical twin study comparing concordance of 226 monozygotic and 280 dizygotic twin pairs, with soft drusen and multiple hard drusen showing strong genetic influences with heritability of 57% and 81%, respectively [36].”
§ CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD > Discussion
What the sources say
- Not checked yetcites [36] Hammond, 2002, Ophthalmology source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Soft drusen are usually precursors of both forms of advanced AMD.
“Soft drusen located between the RPE and Bruch's membrane are usually precursors of both forms of advanced AMD.”
The authors state this as an assumption.
The multiplicative model holds for interpreting the odds ratio as relative risk and for calculating population-attributable risk.
“In the case of population controls and assuming the multiplicative model, in which the risks of the two alleles of the single-nucleotide polymorphism a person carries multiply [25,26], this corresponds to an estimate of the relative risk of the mutation compared to the wild-type.”
“On the basis of the frequency of the at-risk allele and the relative risk, we calculate the population-attributable risk or the reduction in the number of disease cases if the at-risk allele was removed from the population, again assuming the multiplicative model.”
The authors state this as an assumption.
Confidence intervals of relative risks and odds ratios are log-normally distributed.
“Confidence intervals of relative risks and ORs were based on the variance-adjusted tests for association, assuming a log-normal distribution.”
The paper relies on this without support.
The allele frequency of Y402H is less (0.31 versus 0.39) in African Americans than in Caucasians.
“The allele frequency of the Y402H is less (0.31 versus 0.39) in African Americans than in Caucasians.”
The paper relies on this without support.
Soft drusen and pigmentary abnormalities of the RPE are considered to be an early indication of risk of developing advanced AMD.
“Soft drusen and pigmentary abnormalities of the RPE are considered to be an early indication of risk of developing advanced AMD.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“More recently, several studies have found an association between advanced age-related macular degeneration and complement factor H, an integral component of the alternative pathway of complement activation.54–65”
From Age-related macular degeneration (2008) · cites this paper as [63]
Citations
Cites
The International HapMap Project
†The International HapMap Consortium, Genotyping centres: Baylor College of Medicine and ParAllele BioScience, Gibbs, R. A., Belmont, J. W., Hardenbol, P., Willis, T. D., Yu, F., Chinese HapMap Consortium, Yang, H., Ch'ang, L.-Y., et al. (2003) · Nature · doi:10.1038/nature02168 · Cited by 6,057
Self-citationComplement factor H polymorphism in age-related macular degeneration
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J.-Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., et al. (2005) · Science · doi:10.1126/science.1109557 · Cited by 4,492
Complement factor H polymorphism and age-related macular degeneration
Edwards, A. O., Ritter, R., Abel, K. J., Manning, A., Panhuysen, C., & Farrer, L. A. (2005) · Science · doi:10.1126/science.1110189 · Cited by 2,449
Complement factor H variant increases the risk of age-related macular degeneration
Haines, J. L., Hauser, M. A., Schmidt, S., Scott, W. K., Olson, L. M., Gallins, P., Spencer, K. L., Kwan, S. Y., Noureddine, M., Gilbert, J. R., et al. (2005) · Science · doi:10.1126/science.1110359 · Cited by 2,424
Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501536102 · Cited by 1,961
Bird, A. C., Bressler, N. M., Bressler, S. B., Chisholm, I. H., Coscas, G., Davis, M. D., de Jong, P. T. V. M., Klaver, C. C. W., Klein, B. E. K., Klein, R., et al. (1995) · Survey of Ophthalmology · doi:10.1016/s0039-6257(05)80092-x · Cited by 1,926
Hageman, G. (2001) · Progress in Retinal and Eye Research · doi:10.1016/s1350-9462(01)00010-6 · Cited by 1,265
Drusen proteome analysis: an approach to the etiology of age-related macular degeneration
Crabb, J. W., Miyagi, M., Gu, X., Shadrach, K., West, K. A., Sakaguchi, H., Kamei, M., Hasan, A., Yan, L., Rayborn, M. E., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222551899 · Cited by 1,208
The Five-year Incidence and Progression of Age-related Maculopathy
Klein, R., Klein, R., Jensen, S. C., & Meuer, S. M. (1997) · Ophthalmology · doi:10.1016/s0161-6420(97)30368-6 · Cited by 1,154
A role for local inflammation in the formation of drusen in the aging eye
Anderson, D. H., Mullins, R. F., Hageman, G. S., & Johnson, L. V. (2002) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(02)01624-0 · Cited by 1,087
Cited by
Sorted by citations
A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration
Yang, Z., Camp, N. J., Sun, H., Tong, Z., Gibbs, D., Cameron, D. J., Chen, H., Zhao, Y., Pearson, E., Li, X., et al. (2006) · Science · doi:10.1126/science.1133811 · Cited by 796
Self-citationAge-related macular degeneration
de Jong, P. T. V. M. (2006) · New England Journal of Medicine · doi:10.1056/nejmra062326 · Cited by 787
Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts
Gehrs, K. M., Anderson, D. H., Johnson, L. V., & Hageman, G. S. (2006) · Annals of Medicine · doi:10.1080/07853890600946724 · Cited by 650
Immunology of age-related macular degeneration
Ambati, J., Atkinson, J. P., & Gelfand, B. D. (2013) · Nature reviews. Immunology · doi:10.1038/nri3459 · Cited by 606
Age-related macular degeneration
Coleman, H. R., Chan, C.-C., Ferris, F. L., & Chew, E. Y. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61759-6 · Cited by 542
Metadata
- Authors
- Magnusson, K. P., Duan, S., Sigurdsson, H., Petursson, H., Yang, Z., Zhao, Y., Bernstein, P. S., Ge, J., Jonasson, F., Stefansson, E., Helgadottir, G., Zabriskie, N. A., Jonsson, T., Björnsson, A., Thorlacius, T., Jonsson, P. V., Thorleifsson, G., Kong, A., Stefansson, H., Zhang, K., Stefansson, K., & Gulcher, J. R.
- Affiliations
- University of Utah (US)
- Zhongshan Ophthalmic Center, Sun Yat-sen University (CN)
- deCODE Genetics (Iceland) (IS)
- Corresponding author
- Zhang, Kang
- Gulcher, Jeffrey R
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2005-11-29
- Volume
- 3
- Issue
- 1
- Pages
- e5
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC1288033
- OpenAlex
- W2091742941
- Semantic Scholar
- 0e0225f27a97fcd2fe1c5661164e1192004ff2df
- Cited by
- 226
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 8 · 2017: 3 · 2016: 7 · 2015: 9 · 2014: 10 · 2013: 9 · 2012: 18
- FWCI
- 25.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- American Health Assistance Foundation
- Ronald McDonald House Charities
- Deutsches Krebsforschungszentrum
- National Institutes of Health (R01EY14428, M01-RR00064)
- National Eye Institute (R01EY014448, R01EY014428, R01EY14428, R01EY14448, P30EY014800)
- National Center for Research Resources (M01-RR 00064, M01RR000064)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related macular degeneration, complement factor H, soft drusen, geographic atrophy, neovascular AMD, genetic risk factors, disease progression, early AMD
- MeSH terms
- Humans, Iceland, Macular Degeneration, Mutation, Risk Factors, Utah, Retinal Drusen, Odds Ratio, Complement Factor H, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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