Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease

Stephanie Ioannou; Ashley Beecham; Lissette Gomez; Ryan Dauer; Nidah Khakoo; Lauren Pascual; Maria Quintero; Joanna Lopez; James S. Leavitt; Norma Solis; Mailenys Ortega; Amar R. Deshpande; David H. Kerman; Siobhan Proksell; Esther A. Torres; Talin Haritunians; Dalin Li; Maria T. Abreu; Dermott P.B. McGovern; Jacob L. McCauley; Oriana M. Damas

doi:10.1016/j.cgh.2024.07.032

Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease

Stephanie Ioannou, Ashley Beecham, Lissette Gomez, Ryan Dauer, Nidah Khakoo, Lauren Pascual, Maria Quintero, Joanna Lopez, James S. Leavitt, Norma Solis, Mailenys Ortega, Amar R. Deshpande, David H. Kerman, Siobhan Proksell, Esther A. Torres, Talin Haritunians, Dalin Li, Maria T. Abreu, Dermott P.B. McGovern, Jacob L. McCauleyOriana M. Damas

Research output: Contribution to journal › Article › peer-review

Abstract

Background and Aims: The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds. Methods: We performed a multicenter, retrospective cohort study comprising 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1∗05; their ancestral origin (European, African, or Amerindian); and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, in exposed patients. Results: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15, which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15∗4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1∗05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1∗05 in the European allele subset. Conclusions: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian/Alaska Native ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1∗05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with inflammatory bowel disease.

Original language	English
Pages (from-to)	1008-1018.e7
Journal	Clinical Gastroenterology and Hepatology
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.cgh.2024.07.032
State	Published - May 2025
Externally published	Yes

Keywords

Crohn's Disease
Hispanic/Latine
Inflammatory Bowel Disease
Pharmacogenomics
Ulcerative Colitis

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10.1016/j.cgh.2024.07.032

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Ioannou, S., Beecham, A., Gomez, L., Dauer, R., Khakoo, N., Pascual, L., Quintero, M., Lopez, J., Leavitt, J. S., Solis, N., Ortega, M., Deshpande, A. R., Kerman, D. H., Proksell, S., Torres, E. A., Haritunians, T., Li, D., Abreu, M. T., McGovern, D. P. B., ... Damas, O. M. (2025). Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology, 23(6), 1008-1018.e7. https://doi.org/10.1016/j.cgh.2024.07.032

@article{a81084403572431fbec683af9afd7475,

title = "Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease",

abstract = "Background and Aims: The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds. Methods: We performed a multicenter, retrospective cohort study comprising 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1∗05; their ancestral origin (European, African, or Amerindian); and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, in exposed patients. Results: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15, which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15∗4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1∗05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1∗05 in the European allele subset. Conclusions: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian/Alaska Native ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1∗05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with inflammatory bowel disease.",

keywords = "Crohn's Disease, Hispanic/Latine, Inflammatory Bowel Disease, Pharmacogenomics, Ulcerative Colitis",

author = "Stephanie Ioannou and Ashley Beecham and Lissette Gomez and Ryan Dauer and Nidah Khakoo and Lauren Pascual and Maria Quintero and Joanna Lopez and Leavitt, {James S.} and Norma Solis and Mailenys Ortega and Deshpande, {Amar R.} and Kerman, {David H.} and Siobhan Proksell and Torres, {Esther A.} and Talin Haritunians and Dalin Li and Abreu, {Maria T.} and McGovern, {Dermott P.B.} and McCauley, {Jacob L.} and Damas, {Oriana M.}",

note = "Publisher Copyright: {\textcopyright} 2025 AGA Institute",

year = "2025",

month = may,

doi = "10.1016/j.cgh.2024.07.032",

language = "English",

volume = "23",

pages = "1008--1018.e7",

journal = "Clinical Gastroenterology and Hepatology",

issn = "1542-3565",

publisher = "W.B. Saunders",

number = "6",

}

Ioannou, S, Beecham, A, Gomez, L, Dauer, R, Khakoo, N, Pascual, L, Quintero, M, Lopez, J, Leavitt, JS, Solis, N, Ortega, M, Deshpande, AR, Kerman, DH, Proksell, S, Torres, EA, Haritunians, T, Li, D, Abreu, MT, McGovern, DPB, McCauley, JL & Damas, OM 2025, 'Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease', Clinical Gastroenterology and Hepatology, vol. 23, no. 6, pp. 1008-1018.e7. https://doi.org/10.1016/j.cgh.2024.07.032

TY - JOUR

T1 - Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease

AU - Ioannou, Stephanie

AU - Beecham, Ashley

AU - Gomez, Lissette

AU - Dauer, Ryan

AU - Khakoo, Nidah

AU - Pascual, Lauren

AU - Quintero, Maria

AU - Lopez, Joanna

AU - Leavitt, James S.

AU - Solis, Norma

AU - Ortega, Mailenys

AU - Deshpande, Amar R.

AU - Kerman, David H.

AU - Proksell, Siobhan

AU - Torres, Esther A.

AU - Haritunians, Talin

AU - Li, Dalin

AU - Abreu, Maria T.

AU - McGovern, Dermott P.B.

AU - McCauley, Jacob L.

AU - Damas, Oriana M.

PY - 2025/5

Y1 - 2025/5

N2 - Background and Aims: The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds. Methods: We performed a multicenter, retrospective cohort study comprising 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1∗05; their ancestral origin (European, African, or Amerindian); and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, in exposed patients. Results: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15, which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15∗4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1∗05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1∗05 in the European allele subset. Conclusions: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian/Alaska Native ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1∗05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with inflammatory bowel disease.

AB - Background and Aims: The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds. Methods: We performed a multicenter, retrospective cohort study comprising 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1∗05; their ancestral origin (European, African, or Amerindian); and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, in exposed patients. Results: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15, which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15∗4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1∗05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1∗05 in the European allele subset. Conclusions: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian/Alaska Native ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1∗05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with inflammatory bowel disease.

KW - Crohn's Disease

KW - Hispanic/Latine

KW - Inflammatory Bowel Disease

KW - Pharmacogenomics

KW - Ulcerative Colitis

UR - http://www.scopus.com/inward/record.url?scp=85204797575&partnerID=8YFLogxK

U2 - 10.1016/j.cgh.2024.07.032

DO - 10.1016/j.cgh.2024.07.032

M3 - Article

C2 - 39181428

AN - SCOPUS:85204797575

SN - 1542-3565

VL - 23

SP - 1008-1018.e7

JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

IS - 6

ER -

Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease

Abstract

Keywords

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