to reßect different ethnic backgrounds, and some of the common variations have been classiÞed into speciÞc mitochondrial haplogroups [146].

Variants in mtDNA appear to inßuence AMD risk. In the Blue Mountain Eye Study, haplogroup H was associated with a reduced prevalence of any AMD (OR 0.75, 95% CI 0.58Ð0.97) and early AMD (OR 0.75, 95% CI 0.57Ð0.98), whereas haplogroups J and U were associated with early AMD only [147]. A U.S. study determined that individuals with the T2 haplogroup were 2.5 times more likely to have advanced AMD than those without the haplogroup (OR 2.54, 95% CI 1.36Ð 4.80) [148]. This Þnding was supported by Canter et al., who found that the mtDNA 4917G polymorphism associated with haplogroup T independently predicted the presence of AMD (OR 2.16, 95% CI 1.21Ð3.91) [149]. Subsequently, PCR analysis of mtDNA from AMD and control donor retinas found that SNPs T16126C and A73G, associated with haplogroups J and T, were more frequent in AMD retinas than in normal retinas [150]. The authors then replicated these associations in blood DNA from 99 cases and 92 controls [150].

The A69S polymorphism in the ARMS2 gene, which has been linked to mitochondrial function in some studies, is strongly associated with AMD [43, 44]. ARMS2 mRNA encoding a 12-kDa protein has been detected in human retina. Cell culture experiments have localized this protein to the mitochondrial outer membrane [47] and speciÞcally to mitochondria in the ellipsoid region of the photoreceptors [151]. These Þndings suggest a functional role for ARMS2 in mitochondrial homeostasis and have led to an attractive hypothesis linking ARMS2 and oxidative stress. Such a connection Þts well with previous reports of an interaction between ARMS2 A69S and cigarette smoking history [152, 153]. The A69S variant plus smoking was shown to confer a higher risk of AMD than either factor alone, suggesting a link between the ARMS2 protein and smoking-induced oxidative stress. The localization of ARMS2 to the mitochondria has been called into question, however, by a recent immunohistologic study that found no colocalization of ARMS2 antibodies and mitochondrial markers and instead reported localization of the ARMS2 protein to the cytosol in cultured RPE cells [48]. Due to potential inconsistencies in antibodies and visualization, further investigation is necessary to conÞrm or refute the relationship between ARMS2 and the mitochondria.

18.5Environmental Exposures and Oxidative Stress

18.5.1Smoking

Strong cumulative evidence demonstrates that smoking is a risk factor for AMD. A 2005 systematic review of 17 cross-sectional, cohort, and caseÐcontrol studies reported that 13 studies found a signiÞcant association between smoking and AMD, demonstrating a two to threefold increase in AMD risk for current smokers

compared to never-smokers [154]. Similarly, in a 2008 meta-analysis of Þve prospective cohort and eight caseÐcontrol studies, ever-smoking was associated with increased AMD risk among both the cohort studies (RR 1.61, 95% CI 1.01Ð 2.57) and the caseÐcontrol studies (RR 1.76, 95% CI 1.56Ð1.99) [155].

Since the publication of these reports, multiple population-based studies have presented new or updated Þndings on the link between AMD and smoking. The Singapore Malay Eye Study reported that current smokers were signiÞcantly more likely to have late AMD (OR 3.79, 95% CI 1.40Ð10.23) and found that this association was even stronger among those who smoked over Þve packs of cigarettes per week (OR 9.35, 95% CI 2.49Ð35.08) [15]. The European EUREYE study showed increased odds of neovascular AMD in current smokers (OR 2.6, 95% CI 1.4Ð4.8) [16], and the Muenster Aging and Retina Study (MARS) reported a threefold higher incidence of AMD in current smokers vs. never-smokers over 30 months (RR 3.25, 95% CI 1.50Ð7.06) [156]. The Los Angeles Latino Eye Study found that ever-smok- ing was associated with a greater risk of neovascular AMD (OR 2.4, 95% CI 1.03Ð 5.4) [17]. Finally the BDES reported that current smokers at baseline were more likely to develop incident early AMD (OR 1.47, 95% CI 1.08Ð1.99) and to progress to later disease stages (OR 1.43, 95% CI 1.05Ð1.94) than were never-smokers during a 15-year follow-up period [18].

Taken together, the reports discussed above provide strong evidence of an important relationship between smoking and AMD, and particularly neovascular AMD. Importantly, the smaller Genetic Factors in AMD Study showed a strong association between AMD and cigarette smoking pack years (p = 0.002) and reported reduced odds of AMD after smoking cessation (p = 0.01) in 435 AMD patients and 280 controls [20]. These results suggest that behavior modiÞcation can reduce the risk of AMD.

A small number of studies have investigated the relationship between smoking and systemic oxidative stress by directly examining the effect of smoking on plasma oxidative stress markers. Moriarty et al. reported that plasma Cys/CySS and GSH/ GSSG redox were more oxidized in 43 smokers than in 78 nonsmokers (p < 0.001 and p = 0.01, respectively) [157]. A subsequent study of 117 Polish patients, classiÞed as smokers or nonsmokers, suggested that cigarette smoking is a strong determinant of plasma homocysteine but not plasma cysteine levels [158]. Further studies are needed to better understand how cigarette smoking inßuences these plasma markers.

As AMD is independently associated with both genetic variants and smoking, several studies have examined the relationship between AMD-associated polymorphisms and smoking. An interaction between the ARMS2 A69S variant and smoking was observed in AMD patients in the USA [152] and Europe [159] but not in Japanese PCV patients [160]. In contrast, the CFH Y402H polymorphism was not found to be associated with smoking in a small American study [161]. These data imply important relationships among ARMS2, smoking-induced oxidative stress, and AMD.