Genome-Wide Association Study Identifies Novel Genetic Variants Associated with Avascular Necrosis in Sickle Cell Disease

Background:

Avascular necrosis (AVN) is a debilitating complication of sickle cell disease (SCD). The incidence of AVN in individuals with SCD is markedly higher than in the general population, affecting even young children and up to 30% of those over the age of 45. While candidate gene studies have explored genetic associations with AVN in SCD, no genome-wide association studies (GWAS) have been conducted.

Methods:

We performed a GWAS on 405 patients with diagnosis of SCD using data from the screening phase Walk-PHaSST study (NCT00492531). Patients were 12 years or older, median age of 35 years, 53% female, 73% had hemoglobin (Hb) SS, 18% had Hb SC, 4.0% had Hb Sβ + thalassemia, and 4.9% had other SCD forms. All samples had a genotype call rate greater than 95%. SNPs deviating from Hardy-Weinberg equilibrium (P < 0.00001) or with a minor allele frequency less than 0.05 were excluded. Following quality control, 9,874,538 SNPs remained for analysis. genomic inflation factor lambda was 1.023, indicating adequate control for population stratification. We performed multivariable logistic regression analysis (PLINK version 1.9) to investigate the association between SNPs and the presence of AVN of the hip and/or shoulder, adjusting for age, sex, SCD type, alpha-thalassemia, hemoglobin level, hydroxyurea use, and the first 10 principal components.

Results:

There were 88 (21.7%) individuals with AVN of the hip and/or shoulder. Two SNPs on chromosome 1 reached genome-wide significance: rs74436238 (OR=7.43, 95% CI: 3.75-14.70, p=8.11×10^-9) and rs112449951 (OR=6.67, 95% CI: 3.44-12.93, p=1.87×10^-8). These SNPs are in high linkage disequilibrium and located within a long non-coding RNA gene (ENSG00000232537) and an enhancer region (GH01J209266), respectively. The enhancer region is suggested to regulate CAMK1G expression, a gene involved in bone metabolism.

Conclusions:

To the best of our knowledge, this is the first GWAS of AVN to identify a locus that exceeds genome-wide significance threshold. Analyzing a small but well phenotyped cohort of individuals with SCD, we identified a novel locus for AVN on chromosome 1, potentially involving regulatory elements affecting bone metabolism. Further studies in larger cohorts and functional validation are needed to confirm these findings and explore their clinical implications.

Gordeuk:Incyte: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; Novartis: Research Funding; Modus Therapeutics: Consultancy.