title: Effect of genetic variation in LRRTM3 on risk of Alzheimer disease.
abstract: OBJECTIVE
  To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies.
  
  
  METHODS
  First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer's Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker and haplotype analyses. Then we explored the effect of LRRTM3 small-hairpin RNAs on amyloid precursor protein processing.
  
  
  RESULTS
  One single-nucleotide polymorphism in the promoter region (rs16923760; C allele: odds ratio, -0.74, P=.03), and a block of 4 single-nucleotide polymorphisms in intron 2 (rs1925608, C allele: 0.84, P=.04; rs7082306, A allele: 0.75, P=.04; rs1925609, T allele: 1.2, P=.03; and rs10997477, T allele: 0.88, P=.05) were associated with AD in the National Institute on Aging Late-Onset Alzheimer's Disease data set or the Caribbean Hispanic data set. The corresponding haplotypes were also associated with AD risk (.01 < P < .05). In addition, LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing (P < .05 to P < .01) compared with the scrambled small-hairpin RNA condition.
  
  
  CONCLUSIONS
  These complementary findings support the notions that genetic variation in LRRTM3 is associated with AD risk and that LRRTM3 may modulate γ-secretase processing of amyloid precursor protein. Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA. cr2101@columbia.edu
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.forename: Christopher
authors.initials: C
authors.lastname: Conrad
authors.forename: Katherine
authors.initials: K
authors.lastname: Roszkowski
authors.forename: Robert S
authors.initials: RS
authors.lastname: Rogers
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D053318:Apolipoprotein E3 / Q000235:genetics; D017691:Caribbean Region; D016009:Chi-Square Distribution; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism; D006630:Hispanic or Latino / Q000235:genetics; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D000074443:Lysine Acetyltransferase 5; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008609:Mental Status Schedule; D054561:National Institute on Aging (U.S.); D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014481:United States
chemical_list: C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D053318:Apolipoprotein E3; C517878:LRRTM3 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5