TY - JOUR
T1 - Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression
T2 - An association study with mechanistic implications
AU - Allen, Mariet
AU - Zou, Fanggeng
AU - Chai, High Seng
AU - Younkin, Curtis S.
AU - Miles, Richard
AU - Nair, Asha A.
AU - Crook, Julia E.
AU - Pankratz, V. Shane
AU - Carrasquillo, Minerva M.
AU - Rowley, Christopher N.
AU - Nguyen, Thuy
AU - Ma, Li
AU - Malphrus, Kimberly G.
AU - Bisceglio, Gina
AU - Ortolaza, Alexandra I.
AU - Palusak, Ryan
AU - Middha, Sumit
AU - Maharjan, Sooraj
AU - Georgescu, Constantin
AU - Schultz, Debra
AU - Rakhshan, Fariborz
AU - Kolbert, Christopher P.
AU - Jen, Jin
AU - Sando, Sigrid B.
AU - Aasly, Jan O.
AU - Barcikowska, Maria
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Ross, Owen A.
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill R.
AU - Dickson, Dennis W.
AU - Younkin, Steven G.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
Support for this research was provided by the National Institutes of Health grants: National Institute on Aging (R01 032990 to NET and R01 AG018023 to NRG-R and SGY); Mayo Alzheimer’s Disease Research Center: (P50 AG016574 to RCP, DWD, NRG-R, SGY, and NET); Mayo Alzheimer’s Disease Patient Registry: (U01 AG006576 to RCP); National Institute on Aging (AG025711, AG017216, AG003949 to DWD). This project was also generously supported by the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program (to RCP, DWD, NRG-R, and SGY), and by the Palumbo Professorship in Alzheimer’s Disease Research (to SGY). N.E. T. is the recipient of National Institutes of Health (KL2 RR024151), and Siragusa Foundation grants. RJU and ZKW are partially supported by the NIH/NINDS P50 NS072187-01 S2 and NS057567, and Mayo Clinic Florida (MCF) Research Committee CR program. ZKW is also partially supported by NIH/NINDS 1RC2NS070276 and Dystonia Medical Research Foundation.
Funding Information:
N. Graff-Radford, M.D. has served as a consultant to Codman and received grant support from Elan Pharmaceutical Research, Pfizer Pharmaceuticals, Medivation, and Forrest. R.C. Petersen, M.D., Ph.D. has been a consultant to GE Healthcare and Elan Pharmaceuticals, has served on a data safety monitoring board in a clinical trial sponsored by Elan Pharmaceuticals, and a safety monitoring board for Wyeth Pharmaceuticals.
PY - 2012
Y1 - 2012
N2 - Background: Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects). Results: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10 -11-1.9 × 10 -27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003). Conclusion: These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.
AB - Background: Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects). Results: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10 -11-1.9 × 10 -27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003). Conclusion: These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.
KW - Association
KW - Disease risk
KW - GSTO genes
KW - Gene expression
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U2 - 10.1186/1750-1326-7-13
DO - 10.1186/1750-1326-7-13
M3 - Article
C2 - 22494505
AN - SCOPUS:84859517209
SN - 1750-1326
VL - 7
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 13
ER -