May 2010
Volume 51, Issue 5
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Clinical and Epidemiologic Research  |   May 2010
An Ecological Correlation Study of Late Age-Related Macular Degeneration and the Complement Factor H Y402H Polymorphism
Author Affiliations & Notes
  • Bareng A. S. Nonyane
    From the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom;
  • Dorothea Nitsch
    From the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom;
  • John C. Whittaker
    From the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom;
  • Reecha Sofat
    the Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom; and
  • Liam Smeeth
    From the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom;
  • Usha Chakravarthy
    the Centre for Vision and Vascular Science, The Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.
  • Astrid E. Fletcher
    From the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom;
  • Corresponding author: Bareng A. S. Nonyane, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK WC1E 7HT; aletta.nonyane@lshtm.ac.uk
Investigative Ophthalmology & Visual Science May 2010, Vol.51, 2393-2402. doi:10.1167/iovs.09-4228
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      Bareng A. S. Nonyane, Dorothea Nitsch, John C. Whittaker, Reecha Sofat, Liam Smeeth, Usha Chakravarthy, Astrid E. Fletcher; An Ecological Correlation Study of Late Age-Related Macular Degeneration and the Complement Factor H Y402H Polymorphism. Invest. Ophthalmol. Vis. Sci. 2010;51(5):2393-2402. doi: 10.1167/iovs.09-4228.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To investigate whether variation in the distribution of the risk allele frequency of the Y402H single-nucleotide polymorphism (SNP) across various ethnicities and geographic regions reflects differences in the prevalence of late age-related macular degeneration (AMD) in those ethnicities.

Methods.: Published data were obtained via a systematic search. Study samples were grouped into clusters by ethnicity and geographic location and the Spearman correlation coefficient of the prevalence of late AMD and risk allele frequencies was calculated across clusters.

Results.: Across all ethnicities, AMD prevalence was seen to increase with age. Populations of European descent had both higher risk allele frequencies and prevalence of late AMD than did Japanese, Chinese, and Hispanic descendants. Results for African descendants were anomalous: although allele frequency was similar to that in European populations, the age-specific prevalence of late AMD was considerably lower. The correlation coefficient for the association between allele frequency and AMD prevalence was 0.40 (95% confidence interval [CI] = −0.36 to 0.84, P = 0.28) in all populations combined and 0.71 (95% CI = 0.02–0.94, P = 0.04) when people of African descent were excluded.

Conclusions.: Evidence was found at the population level to support a positive association between the Y204H risk allele and the prevalence of AMD after exclusion of studies undertaken on persons of African ancestry. Data in African, Middle Eastern, and South American populations are needed to provide a better understanding of the association of late AMD genetic risk across ethnicities.

Age-related macular degeneration (AMD) is the leading cause of blindness in older people in Western populations. Several lifestyle and environmental risk factors have been identified for AMD, 1 and more recently, genetic variants with strong effects have also been identified. 2 The genetic variants have mainly been studied in people of European origin. In this study, we focused on the single-nucleotide polymorphism (SNP) Y402H in the complement factor H (CFH) gene, which is characterized by a substitution of histidine for tyrosine at codon 402 on the long arm of chromosome 1, region 31 (rs1061170). This SNP is particularly striking because of the strength of its association with late AMD. Odds ratios (ORs) >5 were found for those homozygous for the Y402H risk allele, making this genetic association one of the strongest for a complex disorder yet to be reported. 3  
Although most of the population-based studies reporting the prevalence of late AMD have been undertaken in people of European origin in Western settings, studies are now emerging from other geographic areas. These, along with studies in different ethnic subgroups within Western populations (principally the United States) suggest that there is considerable variation in the distribution of risk alleles of the Y402H SNP 48 and that these variations may in part explain the differences in the prevalence of late AMD in the respective population groups. To our knowledge, no studies have been conducted to examine whether differences in the frequency of this variant between populations or ethnic groups can explain differences in the prevalence of late AMD. We therefore conducted an ecological correlation of the prevalence of late AMD with the frequencies of the Y402H risk allele across ethnic groups and geographic regions. We considered only late AMD because of the differences in classification and grading of early AMD across studies. 
Methods
We systematically searched the literature for studies of the prevalence of late AMD and studies that included representative data on the frequency of Y402H genotypes or alleles in the general population. 
AMD Prevalence
We searched PubMed for relevant articles using the search terms “prevalence” in combination with “age-related macular degeneration” or “AMD,” limiting our search to English language papers. The articles that we deemed eligible were those that clearly confirmed the use of robust systems of fundus grading to determine the diagnosis of AMD 9,10 and reported prevalence of late AMD (either neovascular, geographic atrophy, or a combination of both), by age groups and ethnicity of the sample. The search identified 22 eligible articles, some of which reported prevalence in samples from two or more ethnic groups, resulting in a total of 29 unique samples. The studies reported AMD prevalence using different age ranges starting from as low as 35 to above 90. 
CFH Y402H Polymorphism
We searched PubMed for relevant articles by using the search terms “age-related macular degeneration” and “gene” or “complement factor H” as well as “complement factor H” on its own. We searched for articles on association studies of AMD as well as non-AMD diseases with the Y402H polymorphism. Among these, we included those that reported SNP allele or genotype frequencies of non-AMD cases. Studies were included irrespective of whether Hardy-Weinberg equilibrium (HWE) was observed for the Y402H genotypes in non-AMD cases, since this is not necessarily reflective of poor study design, but may instead be reflective of copy number variation within the complement factor genetic region. 11 Furthermore, in studies in which HWE was observed, the association between the Y402H risk allele and AMD has been shown to be the same as in studies in which HWE was not observed (see, for example, Thakkinstian et al. 12 ). Our search resulted in 50 eligible articles, some of which included two or more samples or samples from more than one ethnic group, hence 67 unique samples. Tables 1 and 2 give general characteristics of the prevalence and Y402H studies that were selected in our search. 
Table 1.
 
General Characteristics of AMD Prevalence Studies Selected
Table 1.
 
General Characteristics of AMD Prevalence Studies Selected
Study Year Study Name Country Ethnicity % Male Mean Age (SD) Sample Size (n) Grading System
Andersen et al. 20 2008 Inuit Greenland Inuit 660 ICSARM
Augood et al. 21 2006 Eureye 7 European countries* European 4753 ICSARM
Chen et al. 22 2008 Shihpai Taiwan Chinese 62.3 71.8 (4.8) 1058 WARMGS
Friedman et al. 23 1999 BES Unites States African 1836
Unites States European 2475 ICSARM
Gupta et al. 24 2007 INDEYE India Indian 1101 WARMGS
Jonasson et al. 25 2006 Reykjavik Iceland Icelandic 48 922 ICSARM
Kawasaki et al. 5 2008 Funagata Japan Japanese 43.8 70.6 (6.8) 1625 WARMGS
Kawasaki et al. 7 2008 Sing Malay Singapore Malay 48.1 58.67 3265 WARMGS
Klein et al. 26 1992 Beaver Dam Unites States European 44.5 4771 WARMGS
Klein et al. 27 2003 CHD Unites States African 363 WARMGS
European 1998
Klein et al. 28 2006 MESA Unites States African 45.1 62.4 (9.9) 1590
Chinese 49.4 62.4 (10) 699
Hispanic 48.1 61.6 (10) 1280 WARMGS
European 48.8 63 (10) 2315
Klein et al. 29 1999 NHANES Unites States African 2129
Hispanic 1925 WARMGS
European 4267
Krishnaiah et al. 4 2005 APES India Indian 47 54 (10.6) 3723
Li et al. 30 2006 Beijing China Chinese 56.1 (10.5) 4376 WARMGS
Mitchell et al. 31 1995 Bluemountain Australia European 43.3 3654 WARMGS
Munoz et al. 32 2005 Proyecto VER Unites States Hispanic 68 2807 WARMGS
Oguido et al. 33 2008 Brazil Japanese 71 483 ICSARM
Oshima et al. 34 2001 Hisayama Japan Japanese 40.1 1486 ICSARM
Schachat et al. 6 1995 Barbados Barbados African 3344 WARMGS
vanNewkirk et al. 35 2000 MVIP Australia European 45 60.2 (12.9) 3271 ICSARM
Varma et al. 36 2004 LALES Unites States Hispanic 42 54.9 (10.7) 5875 WARMGS
Vingerling et al. 37 1995 Rotterdam Netherlands European 40.3 6251 WARMGS
Table 2.
 
General Characteristics of the Y402H Studies Selected
Table 2.
 
General Characteristics of the Y402H Studies Selected
Study Year Country Ethnicity Sample Size* Mean Age Disease† and Study
Baird et al. 38 2006 Australia European 144 70 AMD-MVIP
Brantley et al. 39 2007 Unites States European 189 69.5 AMD-AREDS
Chen et al. 40 2006 China Chinese 244 73.5 AMD
Chowers et al. 41 2008 Israel Israeli 1180 70.8 AMD
Conley et al. 42 2005 Unites States European 210 AMD
DeJong et al. 43 2007 Netherlands European 5066 AMD-Rotterdam
Despriet et al. 44 2006 Netherlands European 3619 AMD
2392
Droz et al. 45 2008 Switzerland European 52 74.9 AMD
Edwards et al. 46 2005 Unites States European 134 AMD
European 68 AMD
Fisher et al. 47 2007 Russia European 151 71 AMD
Fuse et al. 48 2006 Japan Japanese 192 68.6 AMD
Gotoh et al. 49 2006 Japan Japanese 105 60.2 AMD
Gotting et al. 50 2008 German European 189 0 AMD
Grassi et al. 8 2006 Unites States African 75 AMD
European 148
Hispanic 81
Japanese 82
Somali-African 128
Hageman et al. 18 2005 Unites States European 131 78.4 AMD
European 275 68.84
Haines et al. 51 2005 Unites States European 24 69.8 AMD
Jakobsdottir et al. 52 2005 Unites States European 117 AMD
Kaur et al. 19 2006 India Indian 120 63.9 AMD
Kim et al. 53 2008 Korea Koreans 187 AMD
Lau et al. 54 2006 China Chinese 232 AMD
Lee et al. 55 2008 Singapore Chinese 93 AMD
LeFur et al. 56 2008 France European 6348 Dementia
European 642 Alzheimer's
Lin et al. 57 2008 Taiwan Chinese 180 AMD
Magnusson et al. 58 2006 Iceland Icelandic 171 AMD
Icelandic 891 AMD
Unites States European 203 AMD
Maller et al. 59 2006 Unites States European 934 74 AMD-AREDS
Mooijaart et al. 60 2007 Netherlands European 640 Inflammation,
European 552 Cardiovascular-PAMD
Mori et al. 61 2007 Japan Japanese 139 AMD
Narayanan et al. 62 2006 Unites States European 58 72.5 AMD
Ng et al. 63 2008 China Chinese 155 73.1 AMD
Okamoto et al. 64 2006 Japan Japanese 89 AMD
Pai et al. 65 2007 Unites States European 499 65.1 Coronary
European 473 60.3 Heart Disease
Pulido et al. 66 2007 Unites States European 120 Coronary Heart Disease
Rivera et al. 67 2005 Germany European 611 AMD
European 335
Schaumberg et al. 68 2007 Unites States European 1071 60.2 AMD-NHS
Seddon et al. 16 2006 Unites States European 280 AMD
Seitsonen et al. 69 2006 Finland European 105 76.9 AMD
Sepp et al. 70 2006 England European 262 75.8 AMD
Simonelli et al. 71 2001 Italy European 47 0 AMD
Souied et al. 72 2005 France European 91 74.6 AMD
Stark et al. 73 2007 Germany European 56.9 Myocardial Infarction-GMI
973
Tanimoto et al. 74 2007 Japan Japanese 99 73.5 AMD
Tedeschi-Blok et al. 75 2007 Unites States Hispanic 570 AMD-LALES
Uka et al. 76 2006 Japan Japanese 107 AMD
Volcick et al. 77 2008 Unites States African 3010 Atherosclerosis-ARIC
European 8217
Wegscheider et al. 78 2007 Austria European 163 77.5 AMD
Xing et al. 79 2008 Australia European 2381 AMD-Blue Mountains
Xu et al. 80 2008 China Chinese 132 66.1 AMD
Zareparsi et al. 81 2005 Unites States European 275 AMD
Zee et al. 82 2006 Unites States European 335 Cardiovascular diseases-PHS
European 235
European 34
Zetterberg et al. 83 2008 Sweden European 1265 78.6 Alzheimer's
Ziskind et al. 13 2008 South Africa African 98 76 AMD
Analysis
Our hypothesis was that the observed differences in the Y402H risk allele frequencies between ethnicities reflects various prevalence rates of late AMD in these ethnicities. We assumed that the estimates given by the samples in the studies are measures of true allele frequencies and prevalence of late AMD in their respective populations and geographic regions. We thus defined clusters of samples within studies based on both ethnicity and geographic region. For example, people of non-Hispanic European origin living in the United States were categorized in the European-American cluster. For each cluster, mean log-transformed prevalence and mean risk allele frequencies were calculated across all samples, weighted by the sample sizes. Spearman's rank correlation coefficient was calculated. 
Results
The prevalence of late AMD and allele frequency data in our analysis came from independent samples within ethnicities and regions, except for four studies that sampled from the same populations: MVIP (Melbourne Visual Impairment Project), LALES (Los Angeles Latino Eye Study), ProyectoVER (Vision and Eye Research Project), and the Rotterdam Eye Study (Tables 1 and 2). Our selected publications produced 11 clusters on prevalence of AMD and 12 on Y402H studies. Of these, nine clusters had data on both the prevalence and Y402H frequencies. The age groups used in the prevalence studies varied slightly from study to study, and we therefore merged some of these to create three common groups: below 60, between 60 and 69, and above 70 years. 
In the studies on prevalence of late AMD, a clear increase was observed with advancing age but there was a marked variation between studies in the prevalence rates. Most notably, lower rates were observed in Chinese, Japanese, and African Americans. At the other extreme were very high prevalence rates in the Icelandic population, whereas the Greenland Inuit had an overall prevalence that was even 2.5 times higher than that of the Icelandics (Table 3, Fig. 1). 
Table 3.
 
Weighted AMD Prevalence by Age-Group and Cluster and Number of Samples Contributing to Each Estimate
Table 3.
 
Weighted AMD Prevalence by Age-Group and Cluster and Number of Samples Contributing to Each Estimate
Cluster Age <60 Age 60–70 Age 70+ Prevalence Total % (SE)
Samples (n) % (SE) Samples (n) % (SE) Samples (n) % (SE)
African (American and Caribbean) 4 0.28 (0.09) 4 0.29 (0.18) 5 0.47 (0.26) 0.34 (0.12)
Chinese 2 0.14 (0.07) 3 0.32 (0.21) 3 1.67 (0.54) 0.55 (0.16)
European Australia 0 2 0.24 (0.15) 2 3.4 (0.47) 1.13 (0.18)
European Europe* 0 1 0.96 (0.24) 1 4.58 (0.0.37) 2.39 (0.21)
European American 4 0.12 (0.08) 4 0.46 (0.1) 5 2.03 (0.35) 1.18 (0.19)
Hispanic American 4 0.07 (0.04) 4 0.38 (0.22) 4 1.15 (0.36) 0.37 (0.10)
Icelandic 1 0.30 (0.29) 1 1.20 (0.59) 1 10.55 (1.9) 3.47 (0.60)
Indian 2 0.97 (0.22) 2 2.63 (0.45) 2 4.06 (1.14) 1.78 (2.53)
Inuit Greenland 0 1 3.84 (0.94) 1 18.52 (2.4) 9.24 (1.13)
Japanese 2 0.19 (0.14) 2 0.87 (0.39) 2 0.94 (0.39) 0.67 (0.21)
Japanese-Brazilian 0 0 1 1.24 (0.50) 1.24 (0.15)
Malay 1 0.11 (0.08) 1 0.38 (0.22) 1 2.49 (0.58) 0.70 (0.15)
Figure 1.
 
Forest plot of total prevalence across all age groups.
Figure 1.
 
Forest plot of total prevalence across all age groups.
In studies on CFH Y402H allele distribution, low-risk allele frequencies (<1%) were observed in the Japanese, Chinese, and Koreans. In most other populations studied, the allele frequencies were between 36% and 42% (Table 4, Figs. 2, 3). Figure 4 shows a plot of the log transformed, weighted AMD prevalence by age group against the weighted risk allele frequencies. This relationship, across all age groups, is plotted in Figure 5. Only nine clusters are depicted on the graphs because other clusters (Inuit Greenland, South African, Malay, Korean, Israeli, and Japanese-Brazilians) either had prevalence or allele frequency data, but not both, as shown in Tables 3 and 4
Table 4.
 
Weighted Risk Allele Frequencies by Cluster
Table 4.
 
Weighted Risk Allele Frequencies by Cluster
Cluster Samples (n) Weighted Risk Allele Frequency (SE)
African American 3 0.371 (0.008)
African South America 1 0.420 (0.035)
Chinese 6 0.041 (0.011)
European Australia 2 0.361 (0.008)
European Europe 19 0.359 (0.078)
European American 22 0.378 (0.009)
Hispanic American 2 0.170 (0.005)
Icelandic 2 0.383 (0.014)
Indian 1 0.260 (0.028)
Israeli 1 0.356 (0.009)
Japanese 7 0.069 (0.016)
Korean 1 0.065 (0.013)
Figure 2.
 
Forest plot of risk allele frequency for the first 34 studies.
Figure 2.
 
Forest plot of risk allele frequency for the first 34 studies.
Figure 3.
 
Forest plot of the risk allele frequency for the last 33 studies.
Figure 3.
 
Forest plot of the risk allele frequency for the last 33 studies.
Figure 4.
 
Log-transformed AMD prevalence versus risk allele frequencies by age weighted by sample size.
Figure 4.
 
Log-transformed AMD prevalence versus risk allele frequencies by age weighted by sample size.
Figure 5.
 
Log-transformed AMD prevalence across all age groups versus risk allele frequencies weighted by sample size.
Figure 5.
 
Log-transformed AMD prevalence across all age groups versus risk allele frequencies weighted by sample size.
Spearman's rank correlation between weighted AMD prevalence and CFH risk allele frequency was 0.40 (P = 0.28) and after the studies undertaken on persons of African ancestry were excluded, it was 0.71 (P = 0.04). 
Discussion
Overall, our results suggest evidence of a positive association between the prevalence of late AMD and Y402H risk-allele frequency across ethnicities, except in those of African descent. We observed marked differences in both AMD prevalence and allele frequency in different ethnicities and geographic regions. We therefore used an ecological study design to combine evidence of gene–disease association based on published data. To our knowledge, until now, this approach has not been applied to the study of AMD. It provides a useful way of comparing gene–disease associations between ethnicities and geographic regions when large interpopulation-based studies do not exist. The criteria we used to select studies ensured that we included prevalence estimates that were measured using standard diagnostic techniques in different ethnicities. We did not analyze the results by type of late AMD, because not all studies reported prevalence in that way, and therefore we used estimates of any late AMD. 
There are several limitations in our analysis. Only four of the prevalence studies listed in Table 1 had the risk allele frequency derived from the same populations. Most of the studies on the Y402H variant were designed as case–control studies and therefore AMD prevalence was not established within them. Risk allele frequencies were strongly homogeneous within each of the clusters, and therefore it was sensible to cluster study samples in that way. This homogeneity within clusters suggests that, at least for the studies in our analysis, within a given homogenous residential population, a representative sample of genetic information is meaningful for others in the same population. With increased ethnic mixing, populations may be more genetically heterogeneous, and self-reported ethnicity may not reflect this. Ethnic mixing and migration may apply to populations of African origin, but the results of the three African American studies and one South African study show similar allele frequencies. 
It is interesting that the prevalence of late AMD among African descendants does not match their allele frequencies. This mismatch is unlikely to be due to bias in the corresponding prevalence studies, as they have been carefully designed and rigorously implemented. It may be that an association of the Y402H risk allele with late AMD does not exist or is less pronounced in these populations. At present, there are not sufficient data from association studies on those of African ancestry. There is only one study in Africa in which the association between Y204H and AMD (early form) was investigated. 13 The investigators found a nonsignificant odds ratio of 1.56 (95% confidence interval [CI] = 0.75–3.33) for the risk allele, but it was based on a very small sample size. A neighboring deletion allele delCFHR1 confers a protective effect in Europeans. 14 Based on high frequencies of Y402H and delCHFR1 alleles in African Americans, the hypothesis in one study 15 of the complement factor H and related genes was that the effect of these explains the low prevalence of late AMD in African Americans. This notion is in line with what our ecological analysis showed. Further studies are needed in African populations to substantiate this conclusion. It is also plausible that differences between Africans and Europeans in risk factors such as smoking and sunlight may partly explain the lower prevalence of AMD in people of African descent, but at present, there is insufficient evidence to address this point. 
There is a notably high prevalence of late AMD among the Icelandics and the Greenland Inuit. Only one prevalence study was available from each of these two fairly environmentally similar but racially different regions, with sample sizes of 922 and 660 for Iceland and Greenland, respectively. The prevalence estimates in these studies may be imprecise due to small sample sizes, but the response rates for both studies were high (76% and 75%), and so the estimates are unlikely to be biased. The allele frequency for the Icelandic study was 0.38, which is comparable to those of European populations. There may be environmental and lifestyle factors that contribute to such a high prevalence of late AMD in these two populations. 
Differences in observed prevalences within a given cluster may reflect the paucity of people in the very elderly age group in some studies, perhaps due to response bias. (Older people may be less likely to participate for reasons associated with AMD.) Differences between clusters may also have arisen because, in some ethnicities, the proportion of the older age group is lower in the population. A low number of people in the oldest age groups, where AMD rates are the highest, can lead to imprecision in the estimation of the prevalence (i.e., sampling error). More detailed data, such as the mean ages within the age categories, would have enabled us to investigate potential age bias between ethnicities. 
We could not include environmental risk factors that are known to be associated with AMD, such as tobacco smoking, 16,17 because most papers reporting the association of these factors with AMD do not mention the prevalence of the risk factors for the population controls. It is unlikely, however, that even a strong risk factor such as smoking can explain much of the variation in prevalence of AMD. For example, most studies document a lower prevalence of smoking in women, but there is little, if any, variation in prevalence between men and women. In addition, there is no reason to suspect that allele frequency would be related to such environmental factors. We note that the Y402H SNP has been found to be in linkage disequilibrium with other loci on the CFH gene, 18,19 suggesting that there is a haplotype effect. We limited our study to this particular SNP because it is the most widely reported genetic variant in relation to AMD and appears to have very strong effects. We note that there are other genes that increase the risk of development of AMD and that such genes may differ across ethnic groups. 
In conclusion, we found evidence at the population level to support a positive association with the Y204H risk allele and the prevalence of AMD. We highlight the anomalous result of the high-risk allele frequency and the low prevalence of late AMD in African Americans. There are none or very few articles on populations from the African continent or indeed from other regions, such as the Middle East, parts of Asia, and South America. In some of these areas, only the proportion of blindness due to AMD in a population has been reported, rather than prevalence of late AMD among the elderly. This deficiency highlights the need for better reporting of findings from these populations obtained with standard diagnostic techniques to quantify the effects of the Y402H SNP (and other risk genetic variants) on AMD prevalence across ethnicities and regions. 
Footnotes
 Supported by British Heart Foundation (Schillingford) Clinical Training Fellowship FS/07/011 (RS) and by a Wellcome Trust Senior Clinical Fellowship (LS).
Footnotes
 Disclosure: B.A.S. Nonyane, None; D. Nitsch, None; J.C. Whittaker, None; R. Sofat, None; L. Smeeth, None; U. Chakravarthy, None; A.E. Fletcher, None
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Figure 1.
 
Forest plot of total prevalence across all age groups.
Figure 1.
 
Forest plot of total prevalence across all age groups.
Figure 2.
 
Forest plot of risk allele frequency for the first 34 studies.
Figure 2.
 
Forest plot of risk allele frequency for the first 34 studies.
Figure 3.
 
Forest plot of the risk allele frequency for the last 33 studies.
Figure 3.
 
Forest plot of the risk allele frequency for the last 33 studies.
Figure 4.
 
Log-transformed AMD prevalence versus risk allele frequencies by age weighted by sample size.
Figure 4.
 
Log-transformed AMD prevalence versus risk allele frequencies by age weighted by sample size.
Figure 5.
 
Log-transformed AMD prevalence across all age groups versus risk allele frequencies weighted by sample size.
Figure 5.
 
Log-transformed AMD prevalence across all age groups versus risk allele frequencies weighted by sample size.
Table 1.
 
General Characteristics of AMD Prevalence Studies Selected
Table 1.
 
General Characteristics of AMD Prevalence Studies Selected
Study Year Study Name Country Ethnicity % Male Mean Age (SD) Sample Size (n) Grading System
Andersen et al. 20 2008 Inuit Greenland Inuit 660 ICSARM
Augood et al. 21 2006 Eureye 7 European countries* European 4753 ICSARM
Chen et al. 22 2008 Shihpai Taiwan Chinese 62.3 71.8 (4.8) 1058 WARMGS
Friedman et al. 23 1999 BES Unites States African 1836
Unites States European 2475 ICSARM
Gupta et al. 24 2007 INDEYE India Indian 1101 WARMGS
Jonasson et al. 25 2006 Reykjavik Iceland Icelandic 48 922 ICSARM
Kawasaki et al. 5 2008 Funagata Japan Japanese 43.8 70.6 (6.8) 1625 WARMGS
Kawasaki et al. 7 2008 Sing Malay Singapore Malay 48.1 58.67 3265 WARMGS
Klein et al. 26 1992 Beaver Dam Unites States European 44.5 4771 WARMGS
Klein et al. 27 2003 CHD Unites States African 363 WARMGS
European 1998
Klein et al. 28 2006 MESA Unites States African 45.1 62.4 (9.9) 1590
Chinese 49.4 62.4 (10) 699
Hispanic 48.1 61.6 (10) 1280 WARMGS
European 48.8 63 (10) 2315
Klein et al. 29 1999 NHANES Unites States African 2129
Hispanic 1925 WARMGS
European 4267
Krishnaiah et al. 4 2005 APES India Indian 47 54 (10.6) 3723
Li et al. 30 2006 Beijing China Chinese 56.1 (10.5) 4376 WARMGS
Mitchell et al. 31 1995 Bluemountain Australia European 43.3 3654 WARMGS
Munoz et al. 32 2005 Proyecto VER Unites States Hispanic 68 2807 WARMGS
Oguido et al. 33 2008 Brazil Japanese 71 483 ICSARM
Oshima et al. 34 2001 Hisayama Japan Japanese 40.1 1486 ICSARM
Schachat et al. 6 1995 Barbados Barbados African 3344 WARMGS
vanNewkirk et al. 35 2000 MVIP Australia European 45 60.2 (12.9) 3271 ICSARM
Varma et al. 36 2004 LALES Unites States Hispanic 42 54.9 (10.7) 5875 WARMGS
Vingerling et al. 37 1995 Rotterdam Netherlands European 40.3 6251 WARMGS
Table 2.
 
General Characteristics of the Y402H Studies Selected
Table 2.
 
General Characteristics of the Y402H Studies Selected
Study Year Country Ethnicity Sample Size* Mean Age Disease† and Study
Baird et al. 38 2006 Australia European 144 70 AMD-MVIP
Brantley et al. 39 2007 Unites States European 189 69.5 AMD-AREDS
Chen et al. 40 2006 China Chinese 244 73.5 AMD
Chowers et al. 41 2008 Israel Israeli 1180 70.8 AMD
Conley et al. 42 2005 Unites States European 210 AMD
DeJong et al. 43 2007 Netherlands European 5066 AMD-Rotterdam
Despriet et al. 44 2006 Netherlands European 3619 AMD
2392
Droz et al. 45 2008 Switzerland European 52 74.9 AMD
Edwards et al. 46 2005 Unites States European 134 AMD
European 68 AMD
Fisher et al. 47 2007 Russia European 151 71 AMD
Fuse et al. 48 2006 Japan Japanese 192 68.6 AMD
Gotoh et al. 49 2006 Japan Japanese 105 60.2 AMD
Gotting et al. 50 2008 German European 189 0 AMD
Grassi et al. 8 2006 Unites States African 75 AMD
European 148
Hispanic 81
Japanese 82
Somali-African 128
Hageman et al. 18 2005 Unites States European 131 78.4 AMD
European 275 68.84
Haines et al. 51 2005 Unites States European 24 69.8 AMD
Jakobsdottir et al. 52 2005 Unites States European 117 AMD
Kaur et al. 19 2006 India Indian 120 63.9 AMD
Kim et al. 53 2008 Korea Koreans 187 AMD
Lau et al. 54 2006 China Chinese 232 AMD
Lee et al. 55 2008 Singapore Chinese 93 AMD
LeFur et al. 56 2008 France European 6348 Dementia
European 642 Alzheimer's
Lin et al. 57 2008 Taiwan Chinese 180 AMD
Magnusson et al. 58 2006 Iceland Icelandic 171 AMD
Icelandic 891 AMD
Unites States European 203 AMD
Maller et al. 59 2006 Unites States European 934 74 AMD-AREDS
Mooijaart et al. 60 2007 Netherlands European 640 Inflammation,
European 552 Cardiovascular-PAMD
Mori et al. 61 2007 Japan Japanese 139 AMD
Narayanan et al. 62 2006 Unites States European 58 72.5 AMD
Ng et al. 63 2008 China Chinese 155 73.1 AMD
Okamoto et al. 64 2006 Japan Japanese 89 AMD
Pai et al. 65 2007 Unites States European 499 65.1 Coronary
European 473 60.3 Heart Disease
Pulido et al. 66 2007 Unites States European 120 Coronary Heart Disease
Rivera et al. 67 2005 Germany European 611 AMD
European 335
Schaumberg et al. 68 2007 Unites States European 1071 60.2 AMD-NHS
Seddon et al. 16 2006 Unites States European 280 AMD
Seitsonen et al. 69 2006 Finland European 105 76.9 AMD
Sepp et al. 70 2006 England European 262 75.8 AMD
Simonelli et al. 71 2001 Italy European 47 0 AMD
Souied et al. 72 2005 France European 91 74.6 AMD
Stark et al. 73 2007 Germany European 56.9 Myocardial Infarction-GMI
973
Tanimoto et al. 74 2007 Japan Japanese 99 73.5 AMD
Tedeschi-Blok et al. 75 2007 Unites States Hispanic 570 AMD-LALES
Uka et al. 76 2006 Japan Japanese 107 AMD
Volcick et al. 77 2008 Unites States African 3010 Atherosclerosis-ARIC
European 8217
Wegscheider et al. 78 2007 Austria European 163 77.5 AMD
Xing et al. 79 2008 Australia European 2381 AMD-Blue Mountains
Xu et al. 80 2008 China Chinese 132 66.1 AMD
Zareparsi et al. 81 2005 Unites States European 275 AMD
Zee et al. 82 2006 Unites States European 335 Cardiovascular diseases-PHS
European 235
European 34
Zetterberg et al. 83 2008 Sweden European 1265 78.6 Alzheimer's
Ziskind et al. 13 2008 South Africa African 98 76 AMD
Table 3.
 
Weighted AMD Prevalence by Age-Group and Cluster and Number of Samples Contributing to Each Estimate
Table 3.
 
Weighted AMD Prevalence by Age-Group and Cluster and Number of Samples Contributing to Each Estimate
Cluster Age <60 Age 60–70 Age 70+ Prevalence Total % (SE)
Samples (n) % (SE) Samples (n) % (SE) Samples (n) % (SE)
African (American and Caribbean) 4 0.28 (0.09) 4 0.29 (0.18) 5 0.47 (0.26) 0.34 (0.12)
Chinese 2 0.14 (0.07) 3 0.32 (0.21) 3 1.67 (0.54) 0.55 (0.16)
European Australia 0 2 0.24 (0.15) 2 3.4 (0.47) 1.13 (0.18)
European Europe* 0 1 0.96 (0.24) 1 4.58 (0.0.37) 2.39 (0.21)
European American 4 0.12 (0.08) 4 0.46 (0.1) 5 2.03 (0.35) 1.18 (0.19)
Hispanic American 4 0.07 (0.04) 4 0.38 (0.22) 4 1.15 (0.36) 0.37 (0.10)
Icelandic 1 0.30 (0.29) 1 1.20 (0.59) 1 10.55 (1.9) 3.47 (0.60)
Indian 2 0.97 (0.22) 2 2.63 (0.45) 2 4.06 (1.14) 1.78 (2.53)
Inuit Greenland 0 1 3.84 (0.94) 1 18.52 (2.4) 9.24 (1.13)
Japanese 2 0.19 (0.14) 2 0.87 (0.39) 2 0.94 (0.39) 0.67 (0.21)
Japanese-Brazilian 0 0 1 1.24 (0.50) 1.24 (0.15)
Malay 1 0.11 (0.08) 1 0.38 (0.22) 1 2.49 (0.58) 0.70 (0.15)
Table 4.
 
Weighted Risk Allele Frequencies by Cluster
Table 4.
 
Weighted Risk Allele Frequencies by Cluster
Cluster Samples (n) Weighted Risk Allele Frequency (SE)
African American 3 0.371 (0.008)
African South America 1 0.420 (0.035)
Chinese 6 0.041 (0.011)
European Australia 2 0.361 (0.008)
European Europe 19 0.359 (0.078)
European American 22 0.378 (0.009)
Hispanic American 2 0.170 (0.005)
Icelandic 2 0.383 (0.014)
Indian 1 0.260 (0.028)
Israeli 1 0.356 (0.009)
Japanese 7 0.069 (0.016)
Korean 1 0.065 (0.013)
×
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