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

Author

Listed:
  • Juan Lorenzo Rodriguez-Flores

    (Regeneron Genetics Center)

  • Shareef Khalid

    (Columbia University
    Center for Non-Communicable Diseases)

  • 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
    Center for Non-Communicable Diseases)

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.

Suggested Citation

  • 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 D, 2024. "NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51819-3
    DOI: 10.1038/s41467-024-51819-3
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    References listed on IDEAS

    as
    1. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
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