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However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and\/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the <jats:italic>CFH-CFHR5<\/jats:italic> region on chromosome 1q32  (Chr1 locus)\u00a0and <jats:italic>ARMS2\/HTRA1<\/jats:italic> gene on chromosome 10q26 \u00a0(Chr10 locus).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>By refining associations within the <jats:italic>CFH-CFHR5<\/jats:italic> locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant <jats:italic>CFH<\/jats:italic> I62V (rs800292) and genetic deletion of <jats:italic>CFHR3\/1<\/jats:italic>. Haplotypes based on <jats:italic>CFH<\/jats:italic> I62V, a <jats:italic>CFHR3\/1<\/jats:italic> deletion tagging SNP and the risk variant <jats:italic>CFH<\/jats:italic> Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of <jats:italic>CFH-CFHR5<\/jats:italic> haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk\/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the <jats:italic>ARMS2\/HTRA1<\/jats:italic> locus is also mitigated by combinations of <jats:italic>CFH-CFHR5<\/jats:italic> haplotypes, with Chr10\u00a0risk variants essentially neutralized by protective <jats:italic>CFH<\/jats:italic>-<jats:italic>CFHR5<\/jats:italic> haplotypes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our study highlights the importance of considering protective <jats:italic>CFH-CFHR5<\/jats:italic> haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by <jats:italic>CFH-CFHR5<\/jats:italic> risk haplotypes may also be effective when AMD is driven by <jats:italic>ARMS2\/HTRA1<\/jats:italic> risk variants.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40246-021-00359-8","type":"journal-article","created":{"date-parts":[[2021,9,25]],"date-time":"2021-09-25T20:02:32Z","timestamp":1632600152000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2\/HTRA1 loci"],"prefix":"10.1186","volume":"15","author":[{"given":"Chris M.","family":"Pappas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-7748","authenticated-orcid":false,"given":"Moussa A.","family":"Zouache","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacie","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin D.","family":"Faust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill L.","family":"Hageman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandi L.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burt T.","family":"Richards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory S.","family":"Hageman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,25]]},"reference":[{"key":"359_CR1","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1001\/archopht.122.4.564","volume":"122","author":"DS Friedman","year":"2004","unstructured":"Friedman DS, O\u2019Colmain BJ, Mu\u00f1oz B, Tomany SC, McCarty C, de Jong PTVM, et al. 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