NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke

Juan Lorenzo Rodriguez-Flores, Shareef Khalid, Neelroop Parikshak, Asif Rasheed, Bin Ye, Manav Kapoor, Joshua Backman, Farshid Sepehrband, Silvio Alessandro Di Gioia, Sahar Gelfman, Tanima De, Nilanjana Banerjee, Deepika Sharma, Hector Martinez, Sofia Castaneda, David D’Ambrosio, Xingmin A. Zhang, Pengcheng Xun, Ellen Tsai, I-Chun Tsai, Maleeha Zaman Khan, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Khalid Mahmood, Tanvir Us Salam, Muhammad Hussain, Javed Iqbal, Faizan Aslam, Michael N. Cantor, Gannie Tzoneva, John Overton, Jonathan Marchini, Jeffrey G. Reid, Aris Baras, Niek Verweij, Luca A. Lotta, Giovanni Coppola, Katia Karalis, Aris Economides, Sergio Fazio, Wolfgang Liedtke, John Danesh, Ayeesha Kamal, Philippe Frossard, Thomas Coleman, Alan R. Shuldiner () and Danish Saleheen ()
Additional contact information
Juan Lorenzo Rodriguez-Flores: Regeneron Genetics Center
Shareef Khalid: Columbia University
Neelroop Parikshak: Regeneron Genetics Center
Asif Rasheed: Center for Non-Communicable Diseases
Bin Ye: Regeneron Genetics Center
Manav Kapoor: Regeneron Genetics Center
Joshua Backman: Regeneron Genetics Center
Farshid Sepehrband: Regeneron Genetics Center
Silvio Alessandro Di Gioia: Regeneron Pharmaceuticals Inc
Sahar Gelfman: Regeneron Genetics Center
Tanima De: Regeneron Genetics Center
Nilanjana Banerjee: Regeneron Genetics Center
Deepika Sharma: Regeneron Genetics Center
Hector Martinez: Regeneron Pharmaceuticals Inc
Sofia Castaneda: Rye Country Day School
David D’Ambrosio: Regeneron Pharmaceuticals Inc
Xingmin A. Zhang: Regeneron Genetics Center
Pengcheng Xun: Regeneron Pharmaceuticals Inc
Ellen Tsai: University of California at Los Angeles
I-Chun Tsai: Regeneron Pharmaceuticals Inc
Maleeha Zaman Khan: Center for Non-Communicable Diseases
Muhammad Jahanzaib: Center for Non-Communicable Diseases
Muhammad Rehan Mian: Center for Non-Communicable Diseases
Muhammad Bilal Liaqat: Center for Non-Communicable Diseases
Khalid Mahmood: Dow University of Health Sciences and Civil Hospital
Tanvir Us Salam: Lahore General Hospital
Muhammad Hussain: Lahore General Hospital
Javed Iqbal: Allied Hospital
Faizan Aslam: Aziz Fatima Hospital
Michael N. Cantor: Regeneron Genetics Center
Gannie Tzoneva: Regeneron Genetics Center
John Overton: Regeneron Genetics Center
Jonathan Marchini: Regeneron Genetics Center
Jeffrey G. Reid: Regeneron Genetics Center
Aris Baras: Regeneron Genetics Center
Niek Verweij: Regeneron Genetics Center
Luca A. Lotta: Regeneron Genetics Center
Giovanni Coppola: Regeneron Genetics Center
Katia Karalis: Regeneron Genetics Center
Aris Economides: Regeneron Genetics Center
Sergio Fazio: Regeneron Pharmaceuticals Inc
Wolfgang Liedtke: Regeneron Pharmaceuticals Inc
John Danesh: University of Cambridge
Ayeesha Kamal: Aga Khan University
Philippe Frossard: Center for Non-Communicable Diseases
Thomas Coleman: Regeneron Genetics Center
Alan R. Shuldiner: Regeneron Genetics Center
Danish Saleheen: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691 C > T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p = 3.87 × 10−9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p = 7.79 × 10−10). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p = 3.0 × 10−6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-51819-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51819-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-51819-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().