NOTCH3 variants and risk of ischemic stroke.

[cadasil]

Mutations within the NOTCH 3 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 NOTCH 3 variation not involving cysteine residues and mutations in exons 25 -33 in ischemic stroke remains unresolved .All 33 exons of NOTCH 3 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 ).Sequencing of the 269 SWISS probands identified one (0 .4 %) with small vessel type stroke carrying a known CADASIL mutation (p .R 558 C ; Exon 11 ). Of the 19 common NOTCH 3 variants identified , the only variant significantly associated with ischemic stroke after multiple testing adjustment was p .R 1560 P (rs 78501403 ; 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 .T 101 T (rs 3815188 ; Exon 3 ) was associated with an increased risk of small -vessel stroke (OR : 1 .56 , P =0 .008 ) and p .P 380 P (rs 61749020 ; 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 .Cysteine-affecting NOTCH 3 mutations are rare in patients with typical ischemic stroke , however our observation that common NOTCH 3 variants may be associated with risk of ischemic stroke warrants further study .