{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:36:42Z","timestamp":1790789802737,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,3,20]],"date-time":"2015-03-20T00:00:00Z","timestamp":1426809600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,3,20]],"date-time":"2015-03-20T00:00:00Z","timestamp":1426809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although various risk factors have been identified for the development of age-related macular degeneration (AMD), risk factors of early AMD have been relatively under studied. We aimed to investigate AMD risk factors by evaluating multiple factors in association with large drusen, an important component of AMD, simultaneously. In a community-based cross-sectional survey in Japan, 971 large drusen cases and 3,209 controls were compared for 65 variables, including systemic, environmental and genetic factors. The association and the effect size of each factor were evaluated with logistic regression analysis using a backward-elimination approach. Multivariate analyses identified a significant association in serum calcium level (odds ratio [OR] = 0.932, <jats:italic>P<\/jats:italic> = 1.05 \u00d7 10<jats:sup>\u22123<\/jats:sup>), <jats:italic>ARMS2<\/jats:italic> A69S (rs10490924) genotype (OR = 1.046, <jats:italic>P<\/jats:italic> &lt; 0.001), <jats:italic>Chlamydia pneumoniae<\/jats:italic> IgG (OR = 1.020, <jats:italic>P<\/jats:italic> = 0.0440) and age (OR = 1.013, <jats:italic>P<\/jats:italic> &lt; 0.001) for large drusen. Hypocalcemia was observed in 7.2% of large drusen cases and in 5.5% of controls (<jats:italic>P<\/jats:italic> = 0.0490). <jats:italic>C. pneumoniae<\/jats:italic> infections was more frequent in large drusen cases (56.4%) than in conrols (51.7%, <jats:italic>P<\/jats:italic> = 0.00956). These results suggest that calcium, <jats:italic>ARMS2<\/jats:italic> genotype, <jats:italic>C. pneumonia<\/jats:italic> infection and age are significant factors in the development of the early stages of AMD.<\/jats:p>","DOI":"10.1038\/srep09345","type":"journal-article","created":{"date-parts":[[2015,3,20]],"date-time":"2015-03-20T10:13:33Z","timestamp":1426846413000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Calcium, ARMS2 Genotype and Chlamydia Pneumoniae Infection in Early Age-Related Macular Degeneration: a Multivariate Analysis from the Nagahama Study"],"prefix":"10.1038","volume":"5","author":[{"given":"Isao","family":"Nakata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Yamashiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahisa","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Akagi-Kurashige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Miyake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akitaka","family":"Tsujikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiko","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagahisa","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Nagahama Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,3,20]]},"reference":[{"key":"BFsrep09345_CR1","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1056\/NEJMra062326","volume":"355","author":"PT de Jong","year":"2006","unstructured":"de Jong, P. T. Age-related macular degeneration. N Engl J Med 355, 1474\u201385 (2006).","journal-title":"N Engl J Med"},{"key":"BFsrep09345_CR2","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.preteyeres.2005.11.002","volume":"25","author":"RE Hogg","year":"2006","unstructured":"Hogg, R. E. & Chakravarthy, U. Visual function and dysfunction in early and late age-related maculopathy. Prog Retin Eye Res 25, 249\u201376 (2006).","journal-title":"Prog Retin Eye Res"},{"key":"BFsrep09345_CR3","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1001\/archopht.123.11.1570","volume":"123","author":"FL Ferris","year":"2005","unstructured":"Ferris, F. L. et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 123, 1570\u20134 (2005).","journal-title":"Arch Ophthalmol"},{"key":"BFsrep09345_CR4","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1016\/j.ajo.2011.05.008","volume":"152","author":"S Day","year":"2011","unstructured":"Day, S., Acquah, K., Lee, P. P., Mruthyunjaya, P. & Sloan, F. A. Medicare costs for neovascular age-related macular degeneration, 1994-2007. Am J Ophthalmol 152, 1014\u201320 (2011).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep09345_CR5","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1001\/archopht.1996.01100140716016","volume":"114","author":"W Smith","year":"1996","unstructured":"Smith, W., Mitchell, P. & Leeder, S. R. Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 114, 1518\u201323 (1996).","journal-title":"Arch Ophthalmol"},{"key":"BFsrep09345_CR6","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/j.ajo.2013.06.007","volume":"156","author":"I Nakata","year":"2013","unstructured":"Nakata, I. et al. Prevalence and characteristics of age-related macular degeneration in the Japanese population: the nagahama study. Am J Ophthalmol 156, 1002\u20131009.e2 (2013).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep09345_CR7","doi-asserted-by":"publisher","first-page":"7227","DOI":"10.1073\/pnas.0501536102","volume":"102","author":"GS Hageman","year":"2005","unstructured":"Hageman, G. S. et al. A common haplotype in the complement regulatory gene factor H (HF1\/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102, 7227\u201332 (2005).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep09345_CR8","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/ng1750","volume":"38","author":"B Gold","year":"2006","unstructured":"Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38, 458\u201362 (2006).","journal-title":"Nat Genet"},{"key":"BFsrep09345_CR9","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1167\/iovs.11-8468","volume":"53","author":"I Nakata","year":"2012","unstructured":"Nakata, I. et al. Significance of C2\/CFB Variants in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in a Japanese Population. Invest Ophthalmol Vis Sci 53, 794\u20138 (2012).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"BFsrep09345_CR10","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1001\/archopht.118.3.351","volume":"118","author":"L Hyman","year":"2000","unstructured":"Hyman, L., Schachat, A. P., He, Q. & Leske, M. C. Hypertension, cardiovascular disease and age-related macular degeneration. Age-Related Macular Degeneration Risk Factors Study Group. Arch Ophthalmol 118, 351\u20138 (2000).","journal-title":"Arch Ophthalmol"},{"key":"BFsrep09345_CR11","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1001\/archopht.121.6.785","volume":"121","author":"JM Seddon","year":"2003","unstructured":"Seddon, J. M., Cote, J., Davis, N. & Rosner, B. Progression of age-related macular degeneration: association with body mass index, waist circumference and waist-hip ratio. Arch Ophthalmol 121, 785\u201392 (2003).","journal-title":"Arch Ophthalmol"},{"key":"BFsrep09345_CR12","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1016\/j.ophtha.2006.09.033","volume":"114","author":"JS Tan","year":"2007","unstructured":"Tan, J. S., Mitchell, P., Smith, W. & Wang, J. J. Cardiovascular risk factors and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology 114, 1143\u201350 (2007).","journal-title":"Ophthalmology"},{"key":"BFsrep09345_CR13","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1001\/archopht.125.10.1396","volume":"125","author":"SS Boekhoorn","year":"2007","unstructured":"Boekhoorn, S. S., Vingerling, J. R., Witteman, J. C., Hofman, A. & de Jong, P. T. C-reactive protein level and risk of aging macula disorder: The Rotterdam Study. Arch Ophthalmol 125, 1396\u2013401 (2007).","journal-title":"Arch Ophthalmol"},{"key":"BFsrep09345_CR14","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S0161-6420(02)01565-8","volume":"110","author":"R Klein","year":"2003","unstructured":"Klein, R. et al. Early age-related maculopathy in the cardiovascular health study. Ophthalmology 110, 25\u201333 (2003).","journal-title":"Ophthalmology"},{"key":"BFsrep09345_CR15","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1016\/j.ophtha.2003.11.010","volume":"111","author":"SC Tomany","year":"2004","unstructured":"Tomany, S. C. et al. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology 111, 1280\u20137 (2004).","journal-title":"Ophthalmology"},{"key":"BFsrep09345_CR16","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1111\/j.1600-0420.2005.00492.x","volume":"83","author":"H Buch","year":"2005","unstructured":"Buch, H. et al. Risk factors for age-related maculopathy in a 14-year follow-up study: the Copenhagen City Eye Study. Acta Ophthalmol Scand 83, 409\u201318 (2005).","journal-title":"Acta Ophthalmol Scand"},{"key":"BFsrep09345_CR17","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1073\/pnas.1114759108","volume":"108","author":"JH Park","year":"2011","unstructured":"Park, J. H. et al. Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants. Proc Natl Acad Sci U S A 108, 18026\u201331 (2011).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep09345_CR18","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/S0161-6420(97)30368-6","volume":"104","author":"R Klein","year":"1997","unstructured":"Klein, R., Klein, B. E., Jensen, S. C. & Meuer, S. M. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 104, 7\u201321 (1997).","journal-title":"Ophthalmology"},{"key":"BFsrep09345_CR19","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1086\/444437","volume":"77","author":"J Jakobsdottir","year":"2005","unstructured":"Jakobsdottir, J. et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 77, 389\u2013407 (2005).","journal-title":"Am J Hum Genet"},{"key":"BFsrep09345_CR20","doi-asserted-by":"publisher","first-page":"5914","DOI":"10.1167\/iovs.10-5554","volume":"51","author":"H Hayashi","year":"2010","unstructured":"Hayashi, H. et al. CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 51, 5914\u20139 (2010).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"BFsrep09345_CR21","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1001\/archopht.121.4.478","volume":"121","author":"MV Kalayoglu","year":"2003","unstructured":"Kalayoglu, M. V., Galvan, C., Mahdi, O. S., Byrne, G. I. & Mansour, S. Serological association between Chlamydia pneumoniae infection and age-related macular degeneration. Arch Ophthalmol 121, 478\u201382 (2003).","journal-title":"Arch Ophthalmol"},{"key":"BFsrep09345_CR22","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1136\/bjo.87.5.523","volume":"87","author":"O Ishida","year":"2003","unstructured":"Ishida, O. et al. Is Chlamydia pneumoniae infection a risk factor for age related macular degeneration? Br J Ophthalmol 87, 523\u20134 (2003).","journal-title":"Br J Ophthalmol"},{"key":"BFsrep09345_CR23","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1093\/aje\/kwi130","volume":"161","author":"L Robman","year":"2005","unstructured":"Robman, L. et al. Exposure to Chlamydia pneumoniae infection and progression of age-related macular degeneration. Am J Epidemiol 161, 1013\u20139 (2005).","journal-title":"Am J Epidemiol"},{"key":"BFsrep09345_CR24","first-page":"683","volume":"28","author":"RJ Ulshafer","year":"1987","unstructured":"Ulshafer, R. J., Allen, C. B., Nicolaissen, B. & Rubin, M. L. Scanning electron microscopy of human drusen. Invest Ophthalmol Vis Sci 28, 683\u20139 (1987).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"BFsrep09345_CR25","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1039\/C4MT00058G","volume":"6","author":"JM Flinn","year":"2014","unstructured":"Flinn, J. M., Kakalec, P., Tappero, R., Jones, B. & Lengyel, I. Correlations in distribution and concentration of calcium, copper and iron with zinc in isolated extracellular deposits associated with age-related macular degeneration. Metallomics 6, 1223\u20138. (2014).","journal-title":"Metallomics"},{"key":"BFsrep09345_CR26","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1111\/j.1365-2265.2012.04353.x","volume":"77","author":"R Goswami","year":"2012","unstructured":"Goswami, R. et al. Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism. Clin Endocrinol (Oxf) 77, 200\u20136 (2012).","journal-title":"Clin Endocrinol (Oxf)"},{"key":"BFsrep09345_CR27","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1007\/s00417-005-1169-y","volume":"243","author":"MV Kalayoglu","year":"2005","unstructured":"Kalayoglu, M. V. et al. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 243, 1080\u201390 (2005).","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"BFsrep09345_CR28","doi-asserted-by":"publisher","first-page":"4007","DOI":"10.1167\/iovs.06-1434","volume":"48","author":"L Robman","year":"2007","unstructured":"Robman, L. et al. Exposure to Chlamydia pneumoniae infection and age-related macular degeneration: the Blue Mountains Eye Study. Invest Ophthalmol Vis Sci 48, 4007\u201311 (2007).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"BFsrep09345_CR29","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.ajo.2004.03.018","volume":"138","author":"DM Miller","year":"2004","unstructured":"Miller, D. M. et al. The association of prior cytomegalovirus infection with neovascular age-related macular degeneration. Am J Ophthalmol 138, 323\u20138 (2004).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep09345_CR30","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.1038\/eye.2008.422","volume":"23","author":"P Haas","year":"2009","unstructured":"Haas, P. et al. Complement factor H gene polymorphisms and Chlamydia pneumoniae infection in age-related macular degeneration. Eye (Lond) 23, 2228\u201332 (2009).","journal-title":"Eye (Lond)"},{"key":"BFsrep09345_CR31","first-page":"35","volume":"140","author":"R Klein","year":"2005","unstructured":"Klein, R. et al. Systemic markers of inflammation, endothelial dysfunction and age-related maculopathy. Am J Ophthalmol 140, 35\u201344 (2005).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep09345_CR32","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1001\/jama.296.3.301","volume":"296","author":"DD Despriet","year":"2006","unstructured":"Despriet, D. D. et al. Complement factor H polymorphism, complement activators and risk of age-related macular degeneration. JAMA 296, 301\u20139 (2006).","journal-title":"JAMA"},{"key":"BFsrep09345_CR33","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S0002-9394(02)01624-0","volume":"134","author":"DH Anderson","year":"2002","unstructured":"Anderson, D. H., Mullins, R. F., Hageman, G. S. & Johnson, L. V. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134, 411\u201331 (2002).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep09345_CR34","first-page":"944","volume":"19","author":"JH Chen","year":"2013","unstructured":"Chen, J. H. et al. No association of age-related maculopathy susceptibility protein 2\/HtrA serine peptidase 1 or complement factor H polymorphisms with early age-related maculopathy in a Chinese cohort. Mol Vis 19, 944\u201354 (2013).","journal-title":"Mol Vis"},{"key":"BFsrep09345_CR35","doi-asserted-by":"publisher","first-page":"e53830","DOI":"10.1371\/journal.pone.0053830","volume":"8","author":"EG Holliday","year":"2013","unstructured":"Holliday, E. G. et al. Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. PLoS One 8, e53830 (2013).","journal-title":"PLoS One"},{"key":"BFsrep09345_CR36","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1136\/bjo.85.10.1153","volume":"85","author":"Y Oshima","year":"2001","unstructured":"Oshima, Y. et al. Prevalence of age related maculopathy in a representative Japanese population: the Hisayama study. Br J Ophthalmol 85, 1153\u20137 (2001).","journal-title":"Br J Ophthalmol"},{"key":"BFsrep09345_CR37","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1016\/j.ophtha.2009.04.017","volume":"116","author":"M Yasuda","year":"2009","unstructured":"Yasuda, M. et al. Nine-year incidence and risk factors for age-related macular degeneration in a defined Japanese population the Hisayama study. Ophthalmology 116, 2135\u201340 (2009).","journal-title":"Ophthalmology"},{"key":"BFsrep09345_CR38","first-page":"684","volume":"87","author":"GL Brinkman","year":"1963","unstructured":"Brinkman, G. L. & Coates, E. O. The effect of bronchitis, smoking and occupation on ventilation. Am Rev Respir Dis 87, 684\u201393 (1963).","journal-title":"Am Rev Respir Dis"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep09345","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep09345.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep09345.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T19:49:53Z","timestamp":1672948193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep09345"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,20]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,8,14]]}},"alternative-id":["BFsrep09345"],"URL":"https:\/\/doi.org\/10.1038\/srep09345","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,20]]},"assertion":[{"value":"11 November 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 March 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9345"}}