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 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 study15
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
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.