HAGHL genetic variants increase first fracture risk (FFR) in female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime Cohort Study (SJLIFE)
Abstract
10554 Background: Recent genome-wide association studies (GWAS) have reported substantial sex differences in the genetic architectures of bone-related phenotypes. We investigated sex-specific genetic determinants of FFR in survivors of childhood cancer. Methods: We performed sex-combined and sex-stratified GWAS for FFR using Cox regression models fitted on follow-up age in 2,453 long-term (≥5 years) survivors in CCSS with ~5.4 million imputed SNPs (minor allele frequency, MAF≥5%), with self-reported FFR defined by first fracture at any site after diagnosis. Replication analyses were conducted in an independent sample of 1,417 SJLIFE survivors with whole-genome sequencing and clinician-assessed FFR. All models were adjusted for relevant genetic (e.g., ancestry) and clinical (e.g., height, weight, treatment) factors. Results: Sex-combined and male-specific analyses yielded no associations with P < 10−7. Among female CCSS survivors (N = 1,289, 33% ≥1 fractures), we discovered 7 genome-wide significant (P < 5x10−8) SNP-FFR associations with strong evidence of sex effect heterogeneity (P < 7x10−6) across 2 independent loci with no known associations with bone phenotypes. We replicated these associations in SJLIFE (P≤0.05) for 3 coding SNPs in the HAGHL gene (16p13.3), among which rs1406815 showed the strongest association (MAF = 20%, meta-analysis HR = 1.43, P = 8.2x10−9; N = 1,935 women, 35% ≥1 fractures). We observed increased HAGHL SNP effects on FFR that corresponded with…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 1,935 participants or records.
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