rs11978267 (IKZF1): Childhood ALL Risk Variant

Key takeaways

• rs11978267, in the IKZF1 gene at chromosome 7p12.2, is one of the strongest known common genetic risk factors for childhood acute lymphoblastic leukemia
• The 7p12.2 locus containing this variant specifically distinguished T-cell ALL from other leukemia subtypes in discovery analyses
• IKZF1 encodes a transcription factor called Ikaros that regulates the development of lymphoid cells, the cell type that becomes cancerous in ALL
• The association has been replicated across large multi-ethnic cohorts including both Latino and non-Latino white children
• A nearby gene, FIGNL1, shows reduced expression linked to this variant across brain, skin, thyroid, and aorta tissues

What the research says rs11978267 is located in chromosomal region 7p12.2 and annotated to IKZF1 (Ikaros family zinc finger protein 1 - a transcription factor governing lymphoid cell differentiation), where it was first identified at P=8.8×10^-¹¹ in a genome-wide scan comparing 317 children with ALL to 17,958 controls PMID 19684603. The variant lies in linkage disequilibrium (a statistical measure of how often two genetic variants are co-inherited) with two nearby DDC gene SNPs (pairwise r²>0.28), and together these 7p12.2 signals distinguished T-cell ALL from B-hyperdiploid, B-other, and ETV6-RUNX1 subtypes at P≤0.020 PMID 19684603. Independent replication confirmed the locus as genome-wide significant in both Latino (1,949 cases, 8,584 controls) and non-Latino white (1,184 cases, 3,551 controls) children in a California cohort, establishing it as one of the most robust susceptibility signals in childhood ALL PMID 29593279.

Reported associations

• Childhood acute lymphoblastic leukemia (ALL): identified at P=8.8×10^-¹¹ in a discovery cohort of 317 European-descent cases and 17,958 controls PMID 19684603
• T-cell ALL subtype: the 7p12.2 locus including rs11978267 distinguished T-cell ALL from all other major subtypes (B-hyperdiploid, B-other, ETV6-RUNX1) at P≤0.020 PMID 19684603
• Childhood ALL (multi-ethnic replication): IKZF1 reached genome-wide significance in both Latino and non-Latino white strata in a California cohort of 3,263 cases and 15,977 controls PMID 29593279
• Childhood ALL (ETV6-RUNX1 study context): IKZF1 named as one of the two highest-scoring susceptibility loci confirmed across independent UK and US childhood ALL studies PMID 22223085

Evidence quality The primary discovery used a relatively modest case sample of 317 children but a large control base of 17,958 individuals, achieving P=8.8×10^-¹¹, well beyond the genome-wide significance threshold of 5×10^-8 PMID 19684603. A separate ETV6-RUNX1-focused GWAS of 419 discovery cases and 474 controls, replicated in 951 cases and 3,061 controls, independently named IKZF1 as one of the two most robustly confirmed childhood ALL risk loci PMID 22223085. Subsequent work in a California cohort of 3,263 cases and 15,977 controls confirmed genome-wide significance across Latino and non-Latino white populations PMID 29593279. No conflicting findings were identified across the provided studies. The T-cell subtype association was reported in a single discovery cohort and has not been separately replicated based on the available evidence.

Tissue-specific expression effects

• FIGNL1 (a gene neighboring IKZF1 on 7p12.2): the alternate allele is associated with reduced expression in multiple brain regions (cerebellar hemisphere, cerebellum, frontal cortex BA9), pituitary gland, both sun-exposed and non-sun-exposed skin, aorta, and thyroid GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.