Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk

Scott Miners, Zoë van Helmond, Rachel Barker, Peter A. Passmore, Janet A. Johnston, Stephen Todd, Bernadette M. McGuinness, Francesco Panza, Davide Seripa, Vincenzo Solfrizzi, Seth Love, Jonathan A. Prince, Patrick G. Kehoe

Research output: Contribution to journalArticle

Abstract

Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex - levels of total soluble Aβ, oligomeric Aβ1-42, and guanidine-extractable (insoluble) Aβ - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.

Original languageEnglish
Pages (from-to)30-38
Number of pages9
JournalInternational Journal of Molecular Epidemiology and Genetics
Volume3
Issue number1
Publication statusPublished - 2012

Fingerprint

Metalloendopeptidases
Neprilysin
Alzheimer Disease
Membranes
Enzymes
Proteins
Single Nucleotide Polymorphism
Guanidine
Genetic Association Studies
Frontal Lobe
Amyloid
Sweden
Italy
Logistic Models
Odds Ratio
Regression Analysis
Confidence Intervals
Pathology
Brain

Keywords

  • β-amyloid
  • Alzheimer disease
  • Association
  • Gene
  • MME
  • Neprilysin
  • Polymorphism

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Genetics

Cite this

Miners, S., van Helmond, Z., Barker, R., Passmore, P. A., Johnston, J. A., Todd, S., ... Kehoe, P. G. (2012). Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk. International Journal of Molecular Epidemiology and Genetics, 3(1), 30-38.

Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk. / Miners, Scott; van Helmond, Zoë; Barker, Rachel; Passmore, Peter A.; Johnston, Janet A.; Todd, Stephen; McGuinness, Bernadette M.; Panza, Francesco; Seripa, Davide; Solfrizzi, Vincenzo; Love, Seth; Prince, Jonathan A.; Kehoe, Patrick G.

In: International Journal of Molecular Epidemiology and Genetics, Vol. 3, No. 1, 2012, p. 30-38.

Research output: Contribution to journalArticle

Miners, S, van Helmond, Z, Barker, R, Passmore, PA, Johnston, JA, Todd, S, McGuinness, BM, Panza, F, Seripa, D, Solfrizzi, V, Love, S, Prince, JA & Kehoe, PG 2012, 'Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk', International Journal of Molecular Epidemiology and Genetics, vol. 3, no. 1, pp. 30-38.
Miners, Scott ; van Helmond, Zoë ; Barker, Rachel ; Passmore, Peter A. ; Johnston, Janet A. ; Todd, Stephen ; McGuinness, Bernadette M. ; Panza, Francesco ; Seripa, Davide ; Solfrizzi, Vincenzo ; Love, Seth ; Prince, Jonathan A. ; Kehoe, Patrick G. / Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk. In: International Journal of Molecular Epidemiology and Genetics. 2012 ; Vol. 3, No. 1. pp. 30-38.
@article{9a24eb46375f435482717a7f5eaaf52b,
title = "Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk",
abstract = "Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex - levels of total soluble Aβ, oligomeric Aβ1-42, and guanidine-extractable (insoluble) Aβ - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95{\%} confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.",
keywords = "β-amyloid, Alzheimer disease, Association, Gene, MME, Neprilysin, Polymorphism",
author = "Scott Miners and {van Helmond}, Zo{\"e} and Rachel Barker and Passmore, {Peter A.} and Johnston, {Janet A.} and Stephen Todd and McGuinness, {Bernadette M.} and Francesco Panza and Davide Seripa and Vincenzo Solfrizzi and Seth Love and Prince, {Jonathan A.} and Kehoe, {Patrick G.}",
year = "2012",
language = "English",
volume = "3",
pages = "30--38",
journal = "International Journal of Molecular Epidemiology and Genetics",
issn = "1948-1756",
publisher = "e-Century Publishing Corporation",
number = "1",

}

TY - JOUR

T1 - Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk

AU - Miners, Scott

AU - van Helmond, Zoë

AU - Barker, Rachel

AU - Passmore, Peter A.

AU - Johnston, Janet A.

AU - Todd, Stephen

AU - McGuinness, Bernadette M.

AU - Panza, Francesco

AU - Seripa, Davide

AU - Solfrizzi, Vincenzo

AU - Love, Seth

AU - Prince, Jonathan A.

AU - Kehoe, Patrick G.

PY - 2012

Y1 - 2012

N2 - Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex - levels of total soluble Aβ, oligomeric Aβ1-42, and guanidine-extractable (insoluble) Aβ - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.

AB - Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex - levels of total soluble Aβ, oligomeric Aβ1-42, and guanidine-extractable (insoluble) Aβ - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.

KW - β-amyloid

KW - Alzheimer disease

KW - Association

KW - Gene

KW - MME

KW - Neprilysin

KW - Polymorphism

UR - http://www.scopus.com/inward/record.url?scp=84858711606&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858711606&partnerID=8YFLogxK

M3 - Article

C2 - 22493749

AN - SCOPUS:84858711606

VL - 3

SP - 30

EP - 38

JO - International Journal of Molecular Epidemiology and Genetics

JF - International Journal of Molecular Epidemiology and Genetics

SN - 1948-1756

IS - 1

ER -