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APOE transports cholesterol for luteinizing hormone (LH)-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (<jats:italic>LHB<\/jats:italic>) and its receptor (<jats:italic>LHCGR<\/jats:italic>) have not been tested for their association with AD, we scored AD and age-matched control samples for <jats:italic>APOE<\/jats:italic> genotype and 14 polymorphisms of <jats:italic>LHB<\/jats:italic> and <jats:italic>LHCGR<\/jats:italic>. Thirteen gene-gene interactions between the loci of <jats:italic>LHB<\/jats:italic>, <jats:italic>LHCGR<\/jats:italic>, and <jats:italic>APOE<\/jats:italic> were associated with AD. The most strongly supported of these interactions was between an <jats:italic>LHCGR<\/jats:italic> intronic polymorphism (rs4073366; lhcgr2) and <jats:italic>APOE<\/jats:italic> in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the <jats:italic>APOE<\/jats:italic> \u03b54 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR) = 3.08(95%confidence interval: 1.37, 6.91)], \u03b54-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38); p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an <jats:italic>APOE<\/jats:italic> \u03b54 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions.<\/jats:p>","DOI":"10.1186\/1471-2350-9-37","type":"journal-article","created":{"date-parts":[[2008,4,26]],"date-time":"2008-04-26T06:13:23Z","timestamp":1209190403000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E \u03b54 allele"],"prefix":"10.1186","volume":"9","author":[{"given":"Ryan J","family":"Haasl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M Reza","family":"Ahmadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sivan Vadakkadath","family":"Meethal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carey E","family":"Gleason","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sterling C","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Asthana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L","family":"Bowen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig S","family":"Atwood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2008,4,25]]},"reference":[{"key":"331_CR1","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.phrs.2003.11.018","volume":"50","author":"L Bertram","year":"2004","unstructured":"Bertram L, Tanzi RE: The current status of Alzheimer's disease genetics: what do we tell the patients?. 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