NOTCH3 Variants and Risk of Ischemic Stroke

Owen A Ross, Alexandra I. Soto-Ortolaza, Michael G. Heckman, Christophe Verbeeck, Daniel J. Serie, Sruti Rayaprolu, Stephen S. Rich, Michael A. Nalls, Andrew Singleton, Rita Guerreiro, Emma Kinsella, Zbigniew K Wszolek, Thomas G Brott, Robert D Jr. Brown, Bradford B. Worrall, James F Meschia

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background:Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved.Methods:All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS).Results:Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series.Conclusion:Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.

Original languageEnglish (US)
Article numbere75035
JournalPLoS One
Volume8
Issue number9
DOIs
StatePublished - Sep 23 2013

Fingerprint

stroke
Exons
Stroke
exons
Cysteine
CADASIL
Siblings
infarction
mutation
Mutation
odds ratio
cysteine
Testing
Odds Ratio
African Americans
Genes
Amino Acids
Social Adjustment
risk reduction
Alleles

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ross, O. A., Soto-Ortolaza, A. I., Heckman, M. G., Verbeeck, C., Serie, D. J., Rayaprolu, S., ... Meschia, J. F. (2013). NOTCH3 Variants and Risk of Ischemic Stroke. PLoS One, 8(9), [e75035]. https://doi.org/10.1371/journal.pone.0075035

NOTCH3 Variants and Risk of Ischemic Stroke. / Ross, Owen A; Soto-Ortolaza, Alexandra I.; Heckman, Michael G.; Verbeeck, Christophe; Serie, Daniel J.; Rayaprolu, Sruti; Rich, Stephen S.; Nalls, Michael A.; Singleton, Andrew; Guerreiro, Rita; Kinsella, Emma; Wszolek, Zbigniew K; Brott, Thomas G; Brown, Robert D Jr.; Worrall, Bradford B.; Meschia, James F.

In: PLoS One, Vol. 8, No. 9, e75035, 23.09.2013.

Research output: Contribution to journalArticle

Ross, OA, Soto-Ortolaza, AI, Heckman, MG, Verbeeck, C, Serie, DJ, Rayaprolu, S, Rich, SS, Nalls, MA, Singleton, A, Guerreiro, R, Kinsella, E, Wszolek, ZK, Brott, TG, Brown, RDJ, Worrall, BB & Meschia, JF 2013, 'NOTCH3 Variants and Risk of Ischemic Stroke', PLoS One, vol. 8, no. 9, e75035. https://doi.org/10.1371/journal.pone.0075035
Ross OA, Soto-Ortolaza AI, Heckman MG, Verbeeck C, Serie DJ, Rayaprolu S et al. NOTCH3 Variants and Risk of Ischemic Stroke. PLoS One. 2013 Sep 23;8(9). e75035. https://doi.org/10.1371/journal.pone.0075035
Ross, Owen A ; Soto-Ortolaza, Alexandra I. ; Heckman, Michael G. ; Verbeeck, Christophe ; Serie, Daniel J. ; Rayaprolu, Sruti ; Rich, Stephen S. ; Nalls, Michael A. ; Singleton, Andrew ; Guerreiro, Rita ; Kinsella, Emma ; Wszolek, Zbigniew K ; Brott, Thomas G ; Brown, Robert D Jr. ; Worrall, Bradford B. ; Meschia, James F. / NOTCH3 Variants and Risk of Ischemic Stroke. In: PLoS One. 2013 ; Vol. 8, No. 9.
@article{d34e2b2f77354534a930ba50d2381631,
title = "NOTCH3 Variants and Risk of Ischemic Stroke",
abstract = "Background:Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved.Methods:All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS).Results:Sequencing of the 269 SWISS probands identified one (0.4{\%}) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series.Conclusion:Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.",
author = "Ross, {Owen A} and Soto-Ortolaza, {Alexandra I.} and Heckman, {Michael G.} and Christophe Verbeeck and Serie, {Daniel J.} and Sruti Rayaprolu and Rich, {Stephen S.} and Nalls, {Michael A.} and Andrew Singleton and Rita Guerreiro and Emma Kinsella and Wszolek, {Zbigniew K} and Brott, {Thomas G} and Brown, {Robert D Jr.} and Worrall, {Bradford B.} and Meschia, {James F}",
year = "2013",
month = "9",
day = "23",
doi = "10.1371/journal.pone.0075035",
language = "English (US)",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - NOTCH3 Variants and Risk of Ischemic Stroke

AU - Ross, Owen A

AU - Soto-Ortolaza, Alexandra I.

AU - Heckman, Michael G.

AU - Verbeeck, Christophe

AU - Serie, Daniel J.

AU - Rayaprolu, Sruti

AU - Rich, Stephen S.

AU - Nalls, Michael A.

AU - Singleton, Andrew

AU - Guerreiro, Rita

AU - Kinsella, Emma

AU - Wszolek, Zbigniew K

AU - Brott, Thomas G

AU - Brown, Robert D Jr.

AU - Worrall, Bradford B.

AU - Meschia, James F

PY - 2013/9/23

Y1 - 2013/9/23

N2 - Background:Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved.Methods:All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS).Results:Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series.Conclusion:Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.

AB - Background:Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved.Methods:All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS).Results:Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series.Conclusion:Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.

UR - http://www.scopus.com/inward/record.url?scp=84884521546&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884521546&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0075035

DO - 10.1371/journal.pone.0075035

M3 - Article

C2 - 24086431

AN - SCOPUS:84884521546

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e75035

ER -