GENOME-WIDE ASSOCIATION STUDY OF NON-CRISIS PAIN IN PATIENTS WITH SICKLE CELL DISEASE
7 affiliations
- 1Universidade de São Paulo (USP), São Paulo, SP, Brazil
- 2Fundação Hemominas (FH), Belo Horizonte, MG, Brazil
- 3Fundação de Hematologia e Hemoterapia de Pernambuco (Hemope), Recife, PE, Brazil
- 4Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil
- 5UCSF Benioff Children's Hospital Oakland, United States
- 6Vitalant, United States
- 7Pró-Sangue, São Paulo, SP, Brazil
Abstract
Background: Pain is one of the most common and disabling manifestations of sickle cell disease (SCD), significantly affecting patients' quality of life. While several genetic variants have been associated with pain phenotypes in SCD, the biological mechanisms underlying chronic non-crisis pain remain incompletely understood. Previous studies have reported associations between acute pain and variants in genes such as ICAM1, COMT, DRD3, and NR3C1, whereas ADRB2 and S100B have been implicated in persistent pain outside vaso-occlusive crises. Methods: Whole-genome sequencing (WGS) data from Brazilian individuals with HbSS or HbSβ⁰ genotypes, aged over 12 years, were analyzed. Chronic non-crisis pain was defined by continuous use of analgesic medication for at least 30 consecutive days during the year preceding enrollment. A genome-wide association study (GWAS) was conducted using a logistic mixed-effects model adjusted for genetic ancestry and relatedness among participants. Results: Three single-nucleotide variants (SNVs) demonstrated suggestive evidence of association with chronic non-crisis pain, with p-values ranging from approximately 10 -8 to 10 -7 . The strongest association signals were observed within DPP10, a gene involved in neuronal excitability and pain regulation. Additional candidate loci were identified in GRAMD1C and TLR4, genes previously linked to inflammatory responses, vaso-occlusive complications, and acute chest syndrome in individuals with SCD. Conclusions: Our findings identify promising genetic loci associated with susceptibility to chronic non-crisis pain in sickle cell disease. These results contribute to a better understanding of the genetic architecture of pain in SCD and may support future studies aimed at identifying biomarkers and developing personalized therapeutic strategies.
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BibTeX
@article{ozahata2026genomewide,
title = {{GENOME-WIDE ASSOCIATION STUDY OF NON-CRISIS PAIN IN PATIENTS WITH SICKLE CELL DISEASE}},
author = {Mina CINTHO OZAHATA and Carlos Henrique PASSOS and André ROLIM BELISáRIO and Alessandra FERRAZ and Ester CERDEIRA SABINO and Shannon KELLY and Brian CUSTER and Carla Luana DINARDO},
journal = {Hematology, Transfusion and Cell Therapy},
year = {2026},
month = oct,
doi = {10.1016/j.htct.2026.106654},
url = {https://doi.org/10.1016/j.htct.2026.106654},
note = {CC BY},
}
RIS
TY - JOUR
TI - GENOME-WIDE ASSOCIATION STUDY OF NON-CRISIS PAIN IN PATIENTS WITH SICKLE CELL DISEASE
AU - Mina CINTHO OZAHATA
AU - Carlos Henrique PASSOS
AU - André ROLIM BELISáRIO
AU - Alessandra FERRAZ
AU - Ester CERDEIRA SABINO
AU - Shannon KELLY
AU - Brian CUSTER
AU - Carla Luana DINARDO
PY - 2026
DA - 2026/10/23
JO - Hematology, Transfusion and Cell Therapy
DO - 10.1016/j.htct.2026.106654
UR - https://doi.org/10.1016/j.htct.2026.106654
AB - Background: Pain is one of the most common and disabling manifestations of sickle cell disease (SCD), significantly affecting patients' quality of life. While several genetic variants have been associated with pain phenotypes in SCD, the biological mechanisms underlying chronic non-crisis pain remain incompletely understood. Previous studies have reported associations between acute pain and variants in genes such as ICAM1, COMT, DRD3, and NR3C1, whereas ADRB2 and S100B have been implicated in persistent pain outside vaso-occlusive crises. Methods: Whole-genome sequencing (WGS) data from Brazilian individuals with HbSS or HbSβ⁰ genotypes, aged over 12 years, were analyzed. Chronic non-crisis pain was defined by continuous use of analgesic medication for at least 30 consecutive days during the year preceding enrollment. A genome-wide association study (GWAS) was conducted using a logistic mixed-effects model adjusted for genetic ancestry and relatedness among participants. Results: Three single-nucleotide variants (SNVs) demonstrated suggestive evidence of association with chronic non-crisis pain, with p-values ranging from approximately 10 -8 to 10 -7 . The strongest association signals were observed within DPP10, a gene involved in neuronal excitability and pain regulation. Additional candidate loci were identified in GRAMD1C and TLR4, genes previously linked to inflammatory responses, vaso-occlusive complications, and acute chest syndrome in individuals with SCD. Conclusions: Our findings identify promising genetic loci associated with susceptibility to chronic non-crisis pain in sickle cell disease. These results contribute to a better understanding of the genetic architecture of pain in SCD and may support future studies aimed at identifying biomarkers and developing personalized therapeutic strategies.
SN - 2531-1379
SN - 2531-1387
ER -