A functional genomics approach in Tanzanian population identifies distinct genetic regulators of cytokine production compared to European population.
Africa
QTL
cytokines
genetic variation
immunogenomics
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 03 2022
03 03 2022
Historique:
received:
14
07
2021
accepted:
24
01
2022
pubmed:
16
2
2022
medline:
3
5
2022
entrez:
15
2
2022
Statut:
ppublish
Résumé
Humans exhibit remarkable interindividual and interpopulation immune response variability upon microbial challenges. Cytokines play a vital role in regulating inflammation and immune responses, but dysregulation of cytokine responses has been implicated in different disease states. Host genetic factors were previously shown to significantly impact cytokine response heterogeneity mainly in European-based studies, but it is unclear whether these findings are transferable to non-European individuals. Here, we aimed to identify genetic variants modulating cytokine responses in healthy adults of East African ancestry from Tanzania. We leveraged both cytokine and genetic data and performed genome-wide cytokine quantitative trait loci (cQTLs) mapping. The results were compared with another cohort of healthy adults of Western European ancestry via direct overlap and functional enrichment analyses. We also performed meta-analyses to identify cQTLs with congruent effect direction in both populations. In the Tanzanians, cQTL mapping identified 80 independent suggestive loci and one genome-wide significant locus (TBC1D22A) at chromosome 22; SNP rs12169244 was associated with IL-1b release after Salmonella enteritidis stimulation. Remarkably, the identified cQTLs varied significantly when compared to the European cohort, and there was a very limited percentage of overlap (1.6% to 1.9%). We further observed ancestry-specific pathways regulating induced cytokine responses, and there was significant enrichment of the interferon pathway specifically in the Tanzanians. Furthermore, contrary to the Europeans, genetic variants in the TLR10-TLR1-TLR6 locus showed no effect on cytokine response. Our data reveal both ancestry-specific effects of genetic variants and pathways on cytokine response heterogeneity, hence arguing for the importance of initiatives to include diverse populations into genomics research.
Identifiants
pubmed: 35167808
pii: S0002-9297(22)00014-3
doi: 10.1016/j.ajhg.2022.01.014
pmc: PMC8948159
pii:
doi:
Substances chimiques
Cytokines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
471-485Informations de copyright
Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Cell Host Microbe. 2018 Aug 8;24(2):308-323.e6
pubmed: 30092202
Nat Immunol. 2018 Mar;19(3):302-314
pubmed: 29476184
Bioinformatics. 2012 Jun 15;28(12):1598-603
pubmed: 22500001
PLoS Genet. 2009 Jul;5(7):e1000562
pubmed: 19609346
Cell. 2019 Mar 21;177(1):26-31
pubmed: 30901543
BMC Evol Biol. 2011 Dec 20;11:368
pubmed: 22185391
BMC Genom Data. 2021 Oct 21;22(1):43
pubmed: 34674637
Am J Respir Crit Care Med. 2008 Oct 1;178(7):710-20
pubmed: 18635889
Am J Epidemiol. 2004 Dec 1;160(11):1033-8
pubmed: 15561982
Tanzan J Health Res. 2011 Dec;13(5 Suppl 1):387-98
pubmed: 26591993
PLoS One. 2012;7(8):e42649
pubmed: 22905157
NPJ Genom Med. 2020 Feb 25;5:5
pubmed: 32140257
Trop Med Int Health. 2017 Apr;22(4):454-464
pubmed: 28072493
BMC Infect Dis. 2010 Mar 07;10:52
pubmed: 20205938
Nat Med. 2016 Aug;22(8):952-60
pubmed: 27376574
Cell. 2016 Oct 20;167(3):643-656.e17
pubmed: 27768888
Genome Res. 2009 May;19(5):826-37
pubmed: 19307593
J Allergy Clin Immunol. 2011 Mar;127(3):701-21.e1-70
pubmed: 21377040
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Cell. 2016 Oct 20;167(3):657-669.e21
pubmed: 27768889
Bioinformatics. 2012 May 15;28(10):1353-8
pubmed: 22492648
Cell. 2016 Nov 3;167(4):1125-1136.e8
pubmed: 27814509
Genes Immun. 2013 Jan;14(1):52-7
pubmed: 23151486
J Steroid Biochem Mol Biol. 1998 Oct;67(2):79-88
pubmed: 9877207
Nat Immunol. 2018 Jul;19(7):776-786
pubmed: 29784908
Cell. 2016 Nov 3;167(4):1111-1124.e13
pubmed: 27814508
Nat Rev Genet. 2014 Jun;15(6):379-93
pubmed: 24776769
Am J Hum Genet. 2016 Jan 7;98(1):22-33
pubmed: 26748514
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
PLoS Genet. 2021 Mar 26;17(3):e1009477
pubmed: 33770075
Nat Immunol. 2012 Jul 19;13(8):722-8
pubmed: 22814351
BMC Res Notes. 2014 Dec 11;7:901
pubmed: 25495213
Nat Rev Genet. 2021 Mar;22(3):137-153
pubmed: 33277640
Nat Immunol. 2012 May 18;13(6):535-42
pubmed: 22610250
Nutrients. 2018 Feb 13;10(2):
pubmed: 29438282
Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2668-73
pubmed: 24550294
PLoS One. 2014 Apr 17;9(4):e95241
pubmed: 24743542
Am J Hum Genet. 2018 May 3;102(5):731-743
pubmed: 29706352
Cell. 2016 Nov 3;167(4):1099-1110.e14
pubmed: 27814507
Am J Hum Genet. 2020 Apr 2;106(4):496-512
pubmed: 32220292
PLoS One. 2012;7(11):e49438
pubmed: 23189146
Sci Rep. 2017 Apr 21;7:46398
pubmed: 28429804
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Bioinformatics. 2007 May 15;23(10):1294-6
pubmed: 17384015
J Exp Med. 2011 Dec 19;208(13):2747-59
pubmed: 22162829
Nat Immunol. 2021 Mar;22(3):287-300
pubmed: 33574617