Variants in the β-globin Locus are Associated with Pneumonia in African American Children

Nadine L N Halligan; Sarah C Hanks; Karen Matsuo; Taylor Martins; Sebastian Zöllner; Michael W Quasney; Laura J Scott; Mary K Dahmer

doi:10.1016/j.xhgg.2024.100374

Variants in the β-globin Locus are Associated with Pneumonia in African American Children

HGG Adv. 2024 Oct 22:100374. doi: 10.1016/j.xhgg.2024.100374. Online ahead of print.

Authors

Nadine L N Halligan¹, Sarah C Hanks², Karen Matsuo², Taylor Martins², Sebastian Zöllner³, Michael W Quasney¹, Laura J Scott⁴, Mary K Dahmer⁵

Affiliations

¹ Division of Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI, 48109, USA.
² Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
⁴ Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: ljst@umich.edu.
⁵ Division of Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: ljst@umich.edu.

PMID: 39444160
DOI: 10.1016/j.xhgg.2024.100374

Abstract

In African American adults, the strongest genetic predictor of pneumonia appears to be the A allele of rs334, a variant in the β-globin gene which in homozygous form causes sickle cell disease (SCD). No comparable studies have been done in African American children. We performed genome-wide association analyses of 482 African American children with documented pneumonia and 2048 African American controls using genotypes imputed from two reference panels: 1000 Genomes (1KG) (which contains rs334) and TOPMed (does not contain rs334). Using 1KG imputed genotypes, the most significant variant was rs334 (A allele (OR = 2.76 (2.21-3.74), p=5.9x10^-19); using TOPMed imputed genotypes the most significant variant was rs2226952, found in the β-globin locus control region (G allele (OR =2.14 (1.78-2.57), p = 5.1x10^-16). After conditioning on rs334, the most strongly associated variant in the β-globin locus was rs33930165, (allele T, 1KG: OR=4.09 (2.29-7.29), p=1.7x10^-6; TOPMed: OR=3.58 (2.18-5.90), p=4.7x10^-7), which as a compound heterozygote with rs334 A allele can cause SCD. To compare the power of different sample sets we developed a way to estimate the power of sample sets with different sample sizes, genotype arrays and imputation platforms. Our results suggest that in African American children the strongest genetic determinants of pneumonia are those that increase the risk of SCD.