Age related macular degeneration (AMD) was one of the five main causes of vision impairment in the combined study of the Melbourne Visual Impairment Project (MVIP) and the Blue Mountains Eye Study (BMES).1
A higher dietary intake of lutein/zeaxanthin was significantly associated with lower risk of having exudative age related macular degeneration in the Eye Disease Case‐Control Study, but there was no association between lutein/zeaxanthin (LZ) intake and either early or neovascular age related maculopathy in the combined prospective US study.2,3 Also, a higher fish intake has been associated with a lower risk of progression to advanced AMD among those with low (below median) linoleic acid intake, whereas there was no significant association among those with higher linoleic acid intake.4
The aim of this paper is to examine the association of AMD with dietary intake of the carotenoids lutein/zeaxanthin in conjunction with linoleic acid intake in the follow up population based sample of the MVIP.
Methods
Study design
Of 3040 permanent residents recruited in 1992–4, 2594 (85%) of them attended the follow up examinations in 1997–9.5 At both time points of the study, participants signed an informed consent and underwent a standard procedure including an ophthalmic examination and an interview regarding socioeconomic and demographic characteristics, historic and current symptoms of eye diseases, medical history, and medication use. The follow up survey also included a food frequency questionnaire (FFQ).
AMD detection
AMD was diagnosed by either clinical or photographic examinations.5 Features of AMD were graded according to the Wisconsin Age‐Related Maculopathy Grading System, and AMD was classified according to an international classification system.5 Neovascular AMD included (i) subretinal fibrous scars or (ii) serous or haemorrhagic detachment of the retinal pigment epithelium (RPE) or sensory retina; intraretinal, or subretinal or sub‐RPE haemorrhages. Atrophic AMD included the presence of at least 175 μm in diameter visible choroidal vessels in the central areolar zone of RPE atrophy in the absence of signs of neovascular AMD.5 Early AMD was defined in the absence of signs of late (neovascular or atrophic) AMD. International classification (IC) early AMD was defined as the presence of soft distinct, soft indistinct, or reticular drusen, or the presence of any pigmentary abnormalities.5 We also used the Wisconsin definition of early AMD in the BMES or the Beaver Dam Eye Study (BDES), where early AMD was defined as the presence of soft indistinct or reticular drusen in field‐2 fundus photograph or the presence of any soft drusen and retinal pigmentary abnormalities in the same field.5
Nutritional analysis
We used the FFQ developed and validated by the Cancer Council Victoria that includes 13 different fruit items and 25 vegetable items with 10 frequency options from never to three or more times per day for each item.6 We used the method of Willett to calculate the energy adjusted LZ intake.7 Briefly, we first fitted the simple linear regression of the logarithm of the nutrient intake on the logarithm of total energy intake. Next we calculated the difference between the observed and expected values of the logarithm of the nutrient intake and added to this the predicted logarithm of nutrient intake at the population mean of the logarithm of energy intake. Then we exponentiated this quantity to obtain the energy adjusted nutrient score.
Statistical analysis
All statistical analyses were conducted with Statistical Analysis System. The odds ratios were adjusted for age, smoking duration (⩾40 years versus <40 years), and body mass index. Use of ACE inhibitors and cholesterol lowering medication were not associated with AMD in this sample and were not included in further analyses, although they were significant for predicting AMD in the baseline MVIP.8 We explored the interaction between LZ intake and an indicator of low (below median) linoleic acid intake. A test with a p value less than 0.05 was considered to be significant.
Results
Of 2594 participants who attended the follow up examination, 2448 (94.3%) had macular assessment, 2322 (89.5%) completed dietary questionnaires, 2345 (90.4%) had smoking data, and 2144 (83%) had body mass index data. Of 2448 participants who had macular assessment, 1760 (71.9%) had photographic macular assessment. We also excluded one participant with a large outlier for daily LZ intake, leaving 1972 participants with a complete record for smoking duration, body mass index, dietary intake, and macular assessment to be included in the analyses (table 1).
Table 1 Participants' characteristics (n = 1972).
| Continuous variable | Mean (SD) |
|---|---|
| Age (years) | 61.9 (10.5) |
| Body mass index (kg/m2) | 26.2 (4.5) |
| Daily energy intake (kJ) | 7441 (2804) |
| Daily linoleic acid intake (g) | 9.4 (5.2) |
| Daily LZ intake (μg) | 803 (414) |
| Adjusted daily LZ intake (μg) | 788 (371) |
| Daily fat intake (g) | 66.1 (30.2) |
| Adjusted daily fat intake (g) | 61.0 (11.4) |
| Categorical variable | No (%) |
| Female | 1038 (53) |
| Number of years smoked >40 | 173 (8.8) |
| Taking an ACE inhibitor (1971*) | 299 (15) |
| Taking blood cholesterol lowering medication (1964*) | 52 (2.7) |
| Taking supplement (s) (1931*) | 409 (21) |
| AMD (International classification) | |
| Late | 36 (1.8%) |
| Early | 421 (21%) |
| None | 1515 (77%) |
| AMD (Wisconsin) | |
| Late | 36 (1.8%) |
| Early | 147 (7.5%) |
| None | 1789 (91%) |
| Daily LZ intake (μg/4.18 MJ) | Median |
| 1st quintile | 213 |
| 2nd quintile | 328 |
| 3rd quintile | 440 |
| 4th quintile | 562 |
| 5th quintile | 801 |
*Number of complete records for the corresponding variable.
Among those with daily linoleic acid intake ⩾7.17 mg the risk of having late AMD with either grading increased up to fivefold for 1 mg increase in adjusted daily LZ intake, and up to threefold for 1 mg increase in crude daily LZ intake. Also the risk of having early AMD with either grading significantly increased with higher adjusted daily LZ intake. These results are strengthened with the exclusion of participants taking supplements (table 2).
Table 2 The odds ratios adjusted for age, smoking, and body mass index and stratified by the daily linoleic acid intake.
| Any AMD | Early AMD | Late AMD | ||||
|---|---|---|---|---|---|---|
| OR (95% CI) | p Value | OR (95% CI) | p Value | OR (95% CI) | p Value | |
| All participants: | ||||||
| International classification AMD | ||||||
| Daily linoleic acid intake ⩾7.17 g | 0.70 (0.44 to 1.13) | 0.142 | 0.77 (0.47 to 1.25) | 0.296 | 0.15 (0.03 to 0.69) | 0.014 |
| Crude daily LZ intake (mg) (DLAI <7.17 g) | 1.02 (0.66 to 1.57) | 0.944 | 1.09 (0.70 to 1.69) | 0.713 | 0.27 (0.04 to 1.70) | 0.163 |
| Crude daily LZ intake (mg) (DLAI ⩾7.17 g) | 1.42 (1.03 to 1.94) | 0.030 | 1.34 (0.97 to 1.86) | 0.075 | 3.16 (1.28 to 7.79) | 0.013 |
| Wisconsin AMD | ||||||
| Daily linoleic acid intake ⩾7.17 g | 0.41 (0.20 to 0.80) | 0.010 | 0.48 (0.23 to 1.02) | 0.057 | 0.15 (0.04 to 0.65) | 0.011 |
| Crude daily LZ intake (mg) (DLAI <7.17 g) | 0.54 (0.26 to 1.09) | 0.087 | 0.60 (0.28 to 1.28) | 0.191 | 0.26 (0.04 to 1.55) | 0.140 |
| Crude daily LZ intake (mg) (DLAI ⩾7.17 g) | 1.60 (1.03 to 2.47) | 0.037 | 1.41 (0.86 to 2.31) | 0.168 | 2.83 (1.24 to 6.45) | 0.013 |
| International classification AMD | ||||||
| Daily linoleic acid intake ⩾7.17 g | 0.62 (0.38 to 1.04) | 0.069 | 0.70 (0.42 to 1.18) | 0.185 | 0.10 (0.02 to 0.54) | 0.007 |
| Adjusted daily LZ intake (mg) (DLAI <7.17 g) | 1.04 (0.68 to 1.57) | 0.870 | 1.11 (0.73 to 1.69) | 0.636 | 0.30 (0.06 to 1.66) | 0.170 |
| Adjusted daily LZ intake (mg) (DLAI ⩾7.17 g) | 1.74 (1.18 to 2.57) | 0.005 | 1.61 (1.08 to 2.40) | 0.020 | 5.50 (1.70 to 17.8) | 0.005 |
| Wisconsin AMD | ||||||
| Daily linoleic acid intake ⩾7.17 g | 0.35 (0.17 to 0.73) | 0.005 | 0.44 (0.20 to 0.97) | 0.041 | 0.11 (0.02 to 0.51) | 0.005 |
| Adjusted daily LZ intake (mg) (DLAI <7.17 g) | 0.71 (0.37 to 1.35) | 0.298 | 0.82 (0.42 to 1.62) | 0.571 | 0.29 (0.06 to 1.51) | 0.142 |
| Adjusted daily LZ intake (mg) (DLAI ⩾7.17 g) | 2.44 (1.43 to 4.17) | 0.001 | 2.13 (1.19 to 3.83) | 0.011 | 4.72 (1.60 to 13.9) | 0.005 |
| Excluding those who took supplements: | ||||||
| International classification AMD | ||||||
| Daily linoleic acid intake ⩾7.17 g | 0.56 (0.33 to 0.96) | 0.037 | 0.64 (0.37 to 1.12) | 0.117 | 0.12 (0.02 to 0.58) | 0.009 |
| Crude daily LZ intake (mg) (DLAI <7.17 g) | 0.94 (0.56 to 1.58) | 0.817 | 1.03 (0.61 to 1.75) | 0.906 | 0.27 (0.04 to 1.91) | 0.190 |
| Crude daily LZ intake (mg) (DLAI ⩾7.17 g) | 1.68 (1.18 to 2.39) | 0.004 | 1.59 (1.10 to 2.28) | 0.013 | 3.65 (1.37 to 9.76) | 0.010 |
| Wisconsin AMD | ||||||
| Daily linoleic acid intake ⩾7.17 g | 0.35 (0.16 to 0.78) | 0.010 | 0.46 (0.19 to 1.11) | 0.083 | 0.12 (0.03 to 0.56) | 0.007 |
| Crude daily LZ intake (mg) (DLAI <7.17 g) | 0.61 (0.27 to 1.40) | 0.244 | 0.75 (0.31 to 1.82) | 0.526 | 0.26 (0.04 to 1.71) | 0.160 |
| Crude daily LZ intake (mg) (DLAI ⩾7.17 g) | 2.04 (1.26 to 3.30) | 0.004 | 1.85 (1.08 to 3.15) | 0.025 | 3.15 (1.30 to 7.59) | 0.011 |
| International classification AMD | ||||||
| Daily linoleic acid intake ⩾7.17 g | 0.50 (0.28 to 0.89) | 0.018 | 0.58 (0.32 to 1.05) | 0.070 | 0.08 (0.01 to 0.49) | 0.006 |
| Adjusted daily LZ intake (mg) (DLAI <7.17 g) | 1.04 (0.64 to 1.68) | 0.870 | 1.14 (0.70 to 1.86) | 0.604 | 0.32 (0.05 to 1.97) | 0.219 |
| Adjusted daily LZ intake (mg) (DLAI ⩾7.17 g) | 2.27 (1.46 to 3.53) | <0.001 | 2.11 (1.35 to 3.32) | 0.001 | 6.39 (1.71 to 23.9) | 0.006 |
| Wisconsin AMD | ||||||
| Daily linoleic acid intake ⩾ 7.17 g | 0.32 (0.14 to 0.75) | 0.009 | 0.44 (0.17 to 1.12) | 0.085 | 0.09 (0.02 to 0.47) | 0.005 |
| Adjusted daily LZ intake (mg) (DLAI <7.17 g) | 0.86 (0.41 to 1.79) | 0.684 | 1.08 (0.5 to 2.36) | 0.842 | 0.30 (0.05 to 1.73) | 0.179 |
| Adjusted daily LZ intake (mg) (DLAI ⩾7.17 g) | 3.17 (1.74 to 5.77) | <0.001 | 2.88 (1.5 to 5.54) | 0.002 | 5.18 (1.59 to 16.9) | 0.007 |
DLAI, daily linoleic acid intake.
Comment
Our study showed a possible protection of high LZ intake on AMD among those with low level of linoleic acid intake. Thus, our results would not contradict that significant protection of higher LZ intake on AMD in the Eye Disease Case‐Control Study if the daily linoleic acid intake median in this US study were similar to that of only 4.9 g in another US study of 261 AMD patients.2,4
The main strengths of our study are the relatively large, population based sample, two different definitions of AMD, the use of a comprehensive ophthalmological examination, and the FFQ validated by the Cancer Council Victoria. The daily LZ intake mean was 914 μg in the BMES while it was 803 μg in the MVIP.9 Furthermore, our quintile medians (μg/4.18 MJ) were from 29% to 36% lower than the population based BDES (table 1).10 The LZ intakes in other volunteer case‐control studies that were from three to five times higher in each quintile than the population based intakes clearly show a “healthy volunteer bias”.2,3 Limitations of this study include cross sectional data, a possibility of selection bias because of loss of follow up, and the problem of 24% cumulative missing data.
In our study there was a harmful effect of higher LZ intake on AMD among those with high level of linoleic acid intake. Based on these data LZ supplementation could not be recommended.
Acknowledgements
The Melbourne Visual Impairment Project was supported, in part, by grants from: National Health and Medical Research Council, Canberra, Australia; Jack Brockhoff Foundation, Melbourne, Australia; Ansell Ophthalmology Foundation, Melbourne, Australia; Eye, Ear, Nose and Throat Research Institute; Edols Bequest; Appel Family Bequest; Hugh Williamson Foundation and Ian Potter Foundation.
Footnotes
Competing interests: None declared.
Ethics approval: The protocol of the study was approved by the Human Research and Ethics Committee of the Royal Victorian Eye and Ear Hospital.
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