Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

To investigate whether dietary nutrients can reduce the genetic risk of early age-related macular degeneration (AMD) conferred by the genetic variants CFH Y402H and LOC387715 A69S in a nested case-control study.Methods: For 2167 individuals (Ն55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes.Results: Five hundred seventeen participants developed early AMD. Significant synergy indices supported the possibility of biological interaction between CFH Y402H and zinc, ␤-carotene, lutein/zeaxanthin, and eicosapentaenoic/docosahexaenoic acid (EPA/DHA) and between LOC387715 A69S and zinc and EPA/DHA (all P Ͻ.05). Homozygotes of CFH Y402H with dietary intake of zinc in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of ␤-carotene, lutein/zeaxanthin, and EPA/DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. Carriers of LOC387715 A69S with the highest intake of zinc and EPA/DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all P trends Ͻ.05).Conclusions: High dietary intake of nutrients with antioxidant properties reduces the risk of early AMD in those at high genetic risk. Therefore, clinicians should provide dietary advice to young susceptible individuals to postpone or prevent the vision-disabling consequences of AMD.

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status, has been reported. We present a pooled analysis (n=21,160) demonstrating associations between late AMD and APOε4 (OR=0.72 per haplotype; CI: 0.65–0.74; P=4.41×10−11) and APOε2 (OR=1.83 for homozygote carriers; CI: 1.04–3.23; P=0.04), following adjustment for age-group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR=1.54; CI: 1.38–1.72; P=2.8×10−15) and atrophic (OR=1.38; CI: 1.18–1.61; P=3.37×10−5) AMD but not early AMD (OR=0.94; CI: 0.86–1.03; P=0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyondε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ(2) for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ(2) for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.

The findings imply that cataract surgery increases the risk of dry AMD, particularly in homozygous CFH Y402H carriers. The risk of AMD progression should be considered before recommending cataract surgery to patients with cataract and early AMD.

Objective-To investigate the association between variants in the complement component 5 (C5) gene and age-related macular degeneration (AMD).Design-Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study).Participants-A total of 2599 AMD cases and 3458 ethnically matched controls.Methods-Fifteen single nucleotide polymorphisms (SNPs) spanning the C5 gene were initially genotyped in 375 cases and 199 controls from the Netherlands (The AMRO-NL study population). Replication testing of selected SNPs was performed in the Rotterdam Study (NL) and study populations from Southampton, United Kingdom (UK) and New York, United States (US).Main Outcome Measures-Early and late stages of prevalent and incident AMD, graded according to (a modification of) the international grading and classification system of AMD. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptOphthalmology. Author manuscript; available in PMC 2011 March 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptResults-Significant allelic or genotypic associations between eight C5 SNPs and AMD were found in the AMRO-NL study and this risk appeared independently of CFH Y402H, LOC387715 A69S, age and gender. None of these findings could be confirmed consistently in three replication populations.Conclusions-Although the complement pathway, including C5, plays a crucial role in AMD, and the C5 protein is present in drusen, no consistent significant associations between C5 SNPs and AMD were found in all studies. The implications for genetic screening of AMD are discussed.

Background and Purpose-Age-related macular degeneration (AMD) and stroke are both frequent diseases in the elderly.A link between AMD and stroke has been suggested, because both disorders have many risk factors in common. The aim of this study was to investigate the association between AMD and stroke and the subtypes cerebral infarction and intracerebral hemorrhage in the general elderly population. Methods-This study was part of the population-based Rotterdam Study and included 6207 participants aged Ն55 years who were stroke-free at baseline (1990 to 1993). Signs of AMD were assessed on fundus photographs at baseline and at regular follow-up examinations and were categorized in 5 stages (0 to 4) representing an increasing severity. Late AMD (Stage 4) was subdivided into dry and wet AMD. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed using time-dependent Cox regression models adjusted for age, sex, and potential confounders. Results-During a median follow-up of 13.6 years, 726 participants developed a stroke (397 cerebral infarction, 59intracerebral hemorrhage, 270 unspecified). Late AMD was associated with an increased risk of any stroke (hazard ratio, 1.56; 95% CI, 1.08 to 2.26) due to a strong association with intracerebral hemorrhage (hazard ratio, 6.11; 95% CI, 2.34 to 15.98). In contrast, late AMD was not associated with cerebral infarction. Earlier AMD stages were not associated with risk of stroke or any of its subtypes. Conclusions-We found that late AMD is strongly associated with intracerebral hemorrhage, but not with cerebral infarction, in the general elderly population. (Stroke. 2011;42:2138-2142.)

We studied differences in cause-specific mortality between highly integrated first- and second-generation Indonesians and native Dutch. We used the municipal population registers and cause-of-death registry to estimate rate ratios via Poisson regression analyses. Although overall mortality levels were similar, cause-of-death patterns varied between Indonesian migrants and native Dutch; the similar levels in overall mortality coincided with the high degree of integration of Indonesians within Dutch society. The differences in cause-of-death patterns may reflect persistent influences of country of origin and migration history.