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Table. 
Risk of Age-Related Macular Degeneration per Unit Increase and per Tertile of Lipoprotein-Associated Phospholipase A2 Activity
Risk of Age-Related Macular Degeneration per Unit Increase and per Tertile of Lipoprotein-Associated Phospholipase A2 Activity
1.
Tjoelker  LWWilder  CEberhardt  C  et al.  Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature 1995;374 (6522) 549- 553PubMedArticle
2.
Rader  DJ Inflammatory markers of coronary risk. N Engl J Med 2000;343 (16) 1179- 1182PubMedArticle
3.
Boekhoorn  SSVingerling  JRWitteman  JCHofman  Ade Jong  PT C-reactive protein level and risk of aging macula disorder: the Rotterdam Study. Arch Ophthalmol 2007;125 (10) 1396- 1401PubMedArticle
4.
Hofman  ABreteler  MMvan Duijn  CM  et al.  The Rotterdam Study: objectives and design update. Eur J Epidemiol 2007;22 (11) 819- 829PubMedArticle
5.
Oei  HHvan der Meer  IMHofman  A  et al.  Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation 2005;111 (5) 570- 575PubMedArticle
Research Letters
March 9, 2009

Lipoprotein-Associated Phospholipase A2 and Risk of Age-Related Macular Degeneration: The Rotterdam Study

Arch Ophthalmol. 2009;127(3):340-341. doi:10.1001/archophthalmol.2009.8

Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a predictor of coronary heart disease and stroke. It is a calcium-independent serine lipase produced predominantly by macrophages, and it co-travels with circulating low-density lipoprotein. Its biological role is controversial. Initial reports suggested anti-inflammatory properties because of its ability to hydrolyze platelet-activating factor and to remove polar phospholipids in modified low-density lipoprotein.1 Conversely, recent studies indicated a proinflammatory role of Lp-PLA2 mediated by its reaction products (lysophosphatidylcholine and oxidized free fatty acids). Lipoprotein-associated phospholipase A2 is an inflammatory marker and can directly promote atherogenesis.2 The potential clinical benefit associated with Lp-PLA2 inhibition or its use as an inflammatory marker provides a rationale for this study. Because inflammation, atherosclerosis, and other cardiovascular risk factors are associated with age-related macular degeneration (AMD), the aim of this study was to examine associations between baseline plasma levels of Lp-PLA2 and risk of AMD.

Methods

A case-cohort design was used within the Rotterdam Study, a population-based prospective cohort study in the elderly. The methods of the Rotterdam Study have been described elsewhere.3,4 From the 6418 participants at risk for AMD at baseline, a random subcohort of 1648 individuals was drawn. Baseline examinations were performed between March 1990 and September 1993 and were followed by 3 follow-up examinations every 2 to 3 years. Plasma aliquots prepared from nonfasting blood samples were collected at baseline and stored at −80°C. The Lp-PLA2 activity was measured with a high-throughput radiometric activity assay as described previously5 and was expressed as nanomoles of platelet-activating factor hydrolyzed per minute per milliliter of plasma sample. We tested for differences in baseline characteristics (age, sex, smoking, C-reactive protein level, body mass index [calculated as weight in kilograms divided by height in meters squared], systolic and diastolic blood pressures, and total and high-density lipoprotein cholesterol levels) between the subcohort and the remainder of the Rotterdam Study participants using analysis of covariance for continuous variables and logistic regression for discrete variables adjusting for age and sex. The Mann-Whitney U test was used for the C-reactive protein level because its distribution was skewed. Likewise, we tested for differences between AMD cases and noncases. We used Cox proportional hazards models to compute hazard ratios adjusted for age, sex, and high-density lipoprotein level (SPSS version 15.0 statistical software; SPSS, Inc, Chicago, Illinois). We did not stratify for type of AMD because of the small number of participants with late AMD. The Erasmus Medical Center Ethics Committee approved the study, which complies with the Declaration of Helsinki. All of the participants gave written informed consent.

Results

Characteristics of the subcohort were similar to those of the remaining population of the Rotterdam Study with a few minor exceptions. Participants of the subcohort as compared with the remaining population were younger (mean age, 68.5 vs 69.2 years, respectively) and had lower systolic blood pressure (mean, 138.0 vs 139.8 mm Hg, respectively). Participants with AMD as compared with those without AMD were older (mean age, 68.7 vs 66.5 years, respectively), were more often male (46.3% vs 38.5%, respectively), and had higher high-density lipo protein levels (mean, 55 vs 52 mg/dL, respectively [to convert to millimoles per liter, multiply by 0.0259]). No other differences existed between those with AMD and those without AMD. During follow-up (mean, 6.9 years), 164 cases with incident AMD (139 with early AMD, 25 with late AMD) were identified. The fully adjusted hazard ratio per unit increase of Lp-PLA2 activity was 1.00 (95% confidence interval, 0.99-1.02). Compared with the lowest tertile of Lp-PLA2 activity, the hazard ratio for the second tertile was 1.19 (95% confidence interval, 0.81-1.73) and the hazard ratio for the third tertile was 1.04 (95% confidence interval, 0.69-1.57) (P for trend = .85) (Table).

Comment

We found no association between plasma levels of Lp-PLA2 and incident AMD. Because of the small number of participants with late AMD, the possibility of an effect on late AMD cannot be ruled out. If confirmed in other studies, our findings suggest that Lp-PLA2 levels are not an important risk factor for AMD despite the partly inflammatory pathogenesis of AMD.

Correspondence: Dr Vingerling, Department of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000CA Rotterdam, the Netherlands (j.vingerling@erasmusmc.nl).

Financial Disclosure: None reported.

Funding/Support: This study was supported by unrestricted grants from GlaxoSmithKline and Topcon Europe BV and by grants from the following institutions: Netherlands Organization for Scientific Research, Blindenhulp, and OOG, the Hague, the Netherlands; Optimix, Blindenpenning, and Prins Bernhard Cultuurfonds, Amsterdam, the Netherlands; Neyenburgh, Bunnik, the Netherlands; Physico Therapeutic Institute, Swart van Essen, Sint Laurens Institute, Bevordering van Volkskracht, Rotterdamse Blindenbelangen Association, and Van Leeuwen Van Lignac, Rotterdam, the Netherlands; kfHein, Utrecht, the Netherlands; and Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn, the Netherlands.

Role of the Sponsor: The sponsors or funding organizations had no involvement in the design or conduct of this research.

Additional Contributions: Yun-Fu Hu and Rena Vora, GlaxoSmithKline, developed the high-throughput radiometric activity assay for Lp-PLA2.

References
1.
Tjoelker  LWWilder  CEberhardt  C  et al.  Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature 1995;374 (6522) 549- 553PubMedArticle
2.
Rader  DJ Inflammatory markers of coronary risk. N Engl J Med 2000;343 (16) 1179- 1182PubMedArticle
3.
Boekhoorn  SSVingerling  JRWitteman  JCHofman  Ade Jong  PT C-reactive protein level and risk of aging macula disorder: the Rotterdam Study. Arch Ophthalmol 2007;125 (10) 1396- 1401PubMedArticle
4.
Hofman  ABreteler  MMvan Duijn  CM  et al.  The Rotterdam Study: objectives and design update. Eur J Epidemiol 2007;22 (11) 819- 829PubMedArticle
5.
Oei  HHvan der Meer  IMHofman  A  et al.  Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation 2005;111 (5) 570- 575PubMedArticle
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