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F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease.

Tosto G, Fu H, Vardarajan BN, Lee JH, Cheng R, Reyes-Dumeyer D, Lantigua R, Medrano M, Jimenez-Velazquez IZ, Elkind MS, Wright CB, Sacco RL, Pericak-Vance M, Farrer L, Rogaeva E, St George-Hyslop P, Reitz C, Mayeux R - Ann Clin Transl Neurol (2015)

Bottom Line: A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08).Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates.Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.

View Article: PubMed Central - PubMed

Affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York.

ABSTRACT

Objective: In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.

Methods: About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.

Results: A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.

Interpretation: FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.

No MeSH data available.


Related in: MedlinePlus

The expression of Fbxl7 protein in J20 and rTg4510 mice. Protein samples from the cortex and hippocampus of: (A) 10-months-old J20 (n = 5) and control mice (n = 5), (B) 3-month-old rTg4510 (n = 5) and control mice (n = 7), and (C) 8-month-old rTg4510 (n = 2) and control mice (n = 4) were separated in 4–12% Bis-Tris polyacrylamide gels and blotted with mouse primary antibodies against APP/Aβ (6E10), Tau (CP27), Fbxl7, or ACTB. The quantitation of integrated density of Fbxl7 and ACTB in (A–C) was shown in (D–F), respectively. Data are presented as mean ± standard error of Fbxl7/ACTB. *P < 0.05.
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fig02: The expression of Fbxl7 protein in J20 and rTg4510 mice. Protein samples from the cortex and hippocampus of: (A) 10-months-old J20 (n = 5) and control mice (n = 5), (B) 3-month-old rTg4510 (n = 5) and control mice (n = 7), and (C) 8-month-old rTg4510 (n = 2) and control mice (n = 4) were separated in 4–12% Bis-Tris polyacrylamide gels and blotted with mouse primary antibodies against APP/Aβ (6E10), Tau (CP27), Fbxl7, or ACTB. The quantitation of integrated density of Fbxl7 and ACTB in (A–C) was shown in (D–F), respectively. Data are presented as mean ± standard error of Fbxl7/ACTB. *P < 0.05.

Mentions: We quantified the expression of Fbxl7 protein in two transgenic mice models: J20 and rTg4510. Using western blot assay, Fbxl7 protein level in the cortex and hippocampus of 10-month-old J20 mice was found increased by 95% (t-test, P = 0.017) as compared to age-matched control mice (Fig.2A and D). In 3-month-old rTg4510 mice, Fbxl7 protein level was significantly increased by 30% compared to control littermates (t-test, P = 0.024) (Fig.2B and E). Ultimately, Fbxl7 expression was again found increased compared to control mice in 8-month-old rTg4510 mice (38%, P < 0.0001; Fig.2C and F).


F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease.

Tosto G, Fu H, Vardarajan BN, Lee JH, Cheng R, Reyes-Dumeyer D, Lantigua R, Medrano M, Jimenez-Velazquez IZ, Elkind MS, Wright CB, Sacco RL, Pericak-Vance M, Farrer L, Rogaeva E, St George-Hyslop P, Reitz C, Mayeux R - Ann Clin Transl Neurol (2015)

The expression of Fbxl7 protein in J20 and rTg4510 mice. Protein samples from the cortex and hippocampus of: (A) 10-months-old J20 (n = 5) and control mice (n = 5), (B) 3-month-old rTg4510 (n = 5) and control mice (n = 7), and (C) 8-month-old rTg4510 (n = 2) and control mice (n = 4) were separated in 4–12% Bis-Tris polyacrylamide gels and blotted with mouse primary antibodies against APP/Aβ (6E10), Tau (CP27), Fbxl7, or ACTB. The quantitation of integrated density of Fbxl7 and ACTB in (A–C) was shown in (D–F), respectively. Data are presented as mean ± standard error of Fbxl7/ACTB. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554442&req=5

fig02: The expression of Fbxl7 protein in J20 and rTg4510 mice. Protein samples from the cortex and hippocampus of: (A) 10-months-old J20 (n = 5) and control mice (n = 5), (B) 3-month-old rTg4510 (n = 5) and control mice (n = 7), and (C) 8-month-old rTg4510 (n = 2) and control mice (n = 4) were separated in 4–12% Bis-Tris polyacrylamide gels and blotted with mouse primary antibodies against APP/Aβ (6E10), Tau (CP27), Fbxl7, or ACTB. The quantitation of integrated density of Fbxl7 and ACTB in (A–C) was shown in (D–F), respectively. Data are presented as mean ± standard error of Fbxl7/ACTB. *P < 0.05.
Mentions: We quantified the expression of Fbxl7 protein in two transgenic mice models: J20 and rTg4510. Using western blot assay, Fbxl7 protein level in the cortex and hippocampus of 10-month-old J20 mice was found increased by 95% (t-test, P = 0.017) as compared to age-matched control mice (Fig.2A and D). In 3-month-old rTg4510 mice, Fbxl7 protein level was significantly increased by 30% compared to control littermates (t-test, P = 0.024) (Fig.2B and E). Ultimately, Fbxl7 expression was again found increased compared to control mice in 8-month-old rTg4510 mice (38%, P < 0.0001; Fig.2C and F).

Bottom Line: A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08).Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates.Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.

View Article: PubMed Central - PubMed

Affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York.

ABSTRACT

Objective: In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.

Methods: About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.

Results: A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.

Interpretation: FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.

No MeSH data available.


Related in: MedlinePlus