ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

被引：70

作者：

Nelson, Peter T. ^{[1
]}

Estus, Steven ^{[2
]}

Abner, Erin L. ^{[2
]}

Parikh, Ishita ^{[2
]}

Malik, Manasi ^{[2
]}

Neltner, Janna H. ^{[2
]}

Ighodaro, Eseosa ^{[2
]}

Wang, Wang-Xia ^{[2
]}

Wilfred, Bernard R. ^{[2
]}

Wang, Li-San ^{[3
]}

Kukull, Walter A. ^{[4
]}

Nandakumar, Kannabiran ^{[5
]}

Farman, Mark L. ^{[2
]}

Poon, Wayne W. ^{[6
]}

Corrada, Maria M. ^{[6
]}

Kawas, Claudia H. ^{[6
]}

Cribbs, David H. ^{[6
]}

Bennett, David A. ^{[7
]}

Schneider, Julie A. ^{[7
]}

Larson, Eric B. ^{[8
]}

Crane, Paul K. ^{[4
]}

Valladares, Otto ^{[3
]}

Schmitt, Frederick A. ^{[2
]}

Kryscio, Richard J. ^{[2
]}

Jicha, Gregory A. ^{[2
]}

Smith, Charles D. ^{[2
]}

Scheff, Stephen W. ^{[2
]}

Sonnen, Joshua A. ^{[9
]}

Haines, Jonathan L. ^{[10
]}

Pericak-Vance, Margaret A. ^{[11
]}

Mayeux, Richard ^{[12
]}

Farrer, Lindsay A. ^{[13
]}

Van Eldik, Linda J. ^{[2
]}

Horbinski, Craig ^{[2
]}

Green, Robert C. ^{[14
]}

Gearing, Marla ^{[15
]}

Poon, Leonard W. ^{[16
]}

Kramer, Patricia L. ^{[17
]}

Woltjer, Randall L. ^{[17
]}

Montine, Thomas J. ^{[4
]}

Partch, Amanda B. ^{[3
]}

Rajic, Alexander J. ^{[6
]}

Richmire, KatieRose ^{[8
]}

Monsell, Sarah E. ^{[4
]}

Schellenberg, Gerard D. ^{[3
]}

Fardo, David W. ^{[18
]}

机构：

[1] Univ Kentucky, Dept Pathol, Div Neuropathol, Sanders Brown Ctr Aging, Lexington, KY 40536 USA

[2] Univ Kentucky, Lexington, KY 40536 USA

[3] Univ Penn, Philadelphia, PA 19104 USA

[4] Univ Washington, Seattle, WA 98195 USA

[5] Mayo Clin, Rochester, MN USA

[6] Univ Calif Irvine, Irvine, CA USA

[7] Rush Univ, Chicago, IL 60612 USA

[8] Grp Hlth Res Inst, Seattle, WA USA

[9] Univ Utah, Salt Lake City, UT USA

[10] Case Western Reserve Univ, Cleveland, OH 44106 USA

[11] Univ Miami, Miami, FL USA

[12] Columbia Univ, New York, NY USA

[13] Boston Univ, Boston, MA 02215 USA

[14] Harvard Univ, Boston, MA 02115 USA

[15] Emory Univ, Atlanta, GA 30322 USA

[16] Univ Georgia, Inst Gerontol, Athens, GA 30602 USA

[17] Oregon Hlth & Sci Univ, Portland, OR 97201 USA

[18] Univ Kentucky, Dept Biostat, Lexington, KY 40536 USA

来源：

ACTA NEUROPATHOLOGICA | 2014年 / 127卷 / 06期

基金：

美国国家卫生研究院;

关键词：

Oldest old; Neuropathology; KATP; CTAGE5; ADGC; Potassium channel; K-ATP CHANNELS; FRONTOTEMPORAL LOBAR DEGENERATION; GENOME-WIDE ASSOCIATION; CENTER NACC DATABASE; ALZHEIMER-DISEASE; CANTU-SYNDROME; TDP-43; IMMUNOREACTIVITY; COGNITIVE IMPAIRMENT; COMMON VARIANTS; CANDIDATE GENES;

D O I：

10.1007/s00401-014-1282-2

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 x 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

引用

页码：825 / 843

页数：19

共 82 条

[1] TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease [J].

Amador-Ortiz, Catalina ;

Lin, Wen-Lang ;

Ahmed, Zeshan ;

Personett, David ;

Davies, Peter ;

Dara, Ranjan ;

Graff-Radford, Neill R. ;

Hutton, Michael L. ;

Dickson, Dennis W. .

ANNALS OF NEUROLOGY, 2007, 61 (05) :435-445

[2] Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration [J].

Amador-Ortiz, Catalina ;

Ahmed, Zeshan ;

Zehr, Cynthia ;

Dickson, Dennis W. .

ACTA NEUROPATHOLOGICA, 2007, 113 (03) :245-252

[3]

[Anonymous], 2013, R: A Language and Environment for Statistical Computing 55

[4] Alzheimer disease pathology and longitudinal cognitive performance in the oldest-old with no dementia [J].

Balasubramanian, Archana B. ;

Kawas, Claudia H. ;

Peltz, Carrie B. ;

Brookmeyer, Ron ;

Corrada, Maria M. .

NEUROLOGY, 2012, 79 (09) :915-921

[5]

Beekly DL, 2004, ALZ DIS ASSOC DIS, V18, P270

[6] The National Alzheimer's Coordinating Center (NACC) database: The uniform data set [J].

Beekly, Duane L. ;

Ramos, Erin M. ;

Lee, William W. ;

Deitrich, Woodrow D. ;

Jacka, Mary E. ;

Wu, Joylee ;

Hubbard, Janene L. ;

Koepsell, Thomas D. ;

Morris, John C. ;

Kukull, Walter A. .

ALZHEIMER DISEASE & ASSOCIATED DISORDERS, 2007, 21 (03) :249-258

[7] Decision rules guiding the clinical diagnosis of Alzheimer's disease in two community-based cohort studies compared to standard practice in a clinic-based cohort study [J].

Bennett, David A. ;

Schneider, Julie A. ;

Aggarwal, Neelum T. ;

Arvanitakis, Zoe ;

Shah, Raj C. ;

Kelly, Jeremiah F. ;

Fox, Jacob H. ;

Cochran, Elizabeth J. ;

Arends, Danielle ;

Treinkman, Anna D. ;

Wilson, Robert S. .

NEUROEPIDEMIOLOGY, 2006, 27 (03) :169-176

[8] Selected Findings from the Religious Orders Study and Rush Memory and Aging Project [J].

Bennett, David A. ;

Wilson, Robert S. ;

Arvanitakis, Zoe ;

Boyle, Patricia A. ;

de Toledo-Morrell, Leyla ;

Schneider, Julie A. .

JOURNAL OF ALZHEIMERS DISEASE, 2013, 33 :S397-S403

[9] STAGING OF ALZHEIMER-RELATED CORTICAL DESTRUCTION [J].

BRAAK, H ;

BRAAK, E ;

BOHL, J .

EUROPEAN NEUROLOGY, 1993, 33 (06) :403-408

[10] Hippocampal Sclerosis of Aging is a Key Alzheimer's Disease Mimic: Clinical-Pathologic Correlations and Comparisons with both Alzheimer's Disease and Non-Tauopathic Frontotemporal Lobar Degeneration [J].

Brenowitz, Willa D. ;

Monsell, Sarah E. ;

Schmitt, Frederick A. ;

Kukull, Walter A. ;

Nelson, Peter T. .

JOURNAL OF ALZHEIMERS DISEASE, 2014, 39 (03) :691-702

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