Variation in RTN3 and PPIL2 genes does not influence platelet membrane beta-secretase activity or susceptibility to alzheimer's disease in the northern Irish population.
Beta-site amyloid precursor protein cleaving enzyme (BACE1) is the rate-limiting enzyme for production of beta-amyloid peptides (Abeta), which are proposed to drive the pathological changes found in Alzheimer's disease (AD). Reticulon 3 (RTN3) is a negative modulator of BACE1 (beta-secretase) proteolytic activity, while peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) positively regulates BACE1 expression. The present study investigated whether there was any association between genetic variation in RTN3 and PPIL2, and either risk for AD, or levels of platelet beta-secretase activity, in a large Northern Irish case-control sample. Four hundred and sixty-nine patients with a diagnosis of probable AD (NINCDS-ADRDA criteria) and 347 control individuals (MMSE > 28/30) were genotyped. SNPs in both genes were selected by downloading genotype data from the International HapMap Project (Phase II) and tags selected using multimarker approach in Haploview, where r (2) > 0.8 and LOD > 3.0. Non-synonymous SNPs of interest were also included. Genotyping was performed by Sequenom iPLEX and TaqMan technologies. Alleles, genotypes and multi-marker haplotypes were tested for association with AD, and platelet beta-secretase activities were measured for a subset of individuals (n = 231). Eight SNPs in RTN3 and 7 in PPIL2 were genotyped. We found no significant associations between allele, genotype or haplotype frequencies and risk of AD. Further, there was no effect of genotype on platelet membrane beta-secretase activity. We conclude that common or potentially functional genetic variation in these BACE1 interacting proteins does not affect platelet membrane beta-secretase activity or contribute to risk of AD in this population.
Carson
Robyn
R
Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, UK.
McKnight
Amy Jayne
AJ
Todd
Stephen
S
Liu
Wei Wei
WW
Heggarty
Shirley
S
Craig
David
D
McGuinness
Bernadette
B
Irvine
G Brent
GB
Passmore
A Peter
AP
Johnston
Janet A
JA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001792:Blood Platelets / Q000201:enzymology; D002352:Carrier Proteins / Q000235:genetics*; D021983:Cyclophilins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009660:Northern Ireland; D044465:White People / Q000235:genetics
D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C476198:RTN3 protein, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D021983:Cyclophilins; C099773:PPIL2 protein, human