Abstract B073: Leveraging genomic diversity identifies additional germline risk loci in SMAD6 for Langerhans cell histiocytosis
Authors: Shetty Priya B. , Peckham-Gregory Erin , Stricker Erik , Lin Howard , Scull Brooks , Ehli Erik , Davis Christel , McClain Kenneth , Lupo Philip , Allen Carl , Scheurer Michael 
Published: December 2023

Abstract
Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate with recurrent, mutually exclusive somatic activating mutations in MAPK pathway genes in ~85% of LCH lesions; however, germline risk factors remain largely unknown. A SEER analysis reported that incidence of high-risk LCH was higher in Hispanic populations than non-Hispanic populations, and lowest in non-Hispanic Black populations. Our group reported that Hispanic mothers/couples were more likely to have children with LCH compared to non-Hispanic white mothers/couples. In the first GWAS of LCH, our group identified and validated a risk variant in SMAD6 associated with a 3-fold increase in risk. Our current objective is to leverage the genomic diversity of our patient population to identify additional SMAD6 LCH risk loci. Methods: Cases diagnosed with LCH were recruited at Texas Children’s Hospital (n=466). Targeted sequencing of SMAD6 was conducted among cases with ~200x coverage at the Avera Institute of Human Genetics. We accessed aggregate-level SMAD6 sequence data in SMAD6 from a median of 15,694 non-cancer controls in gnomAD v2.1.1. Fisher’s exact test was applied to 154 SMAD6 variants (Bonferroni critical P-value of 3.2 x 10-4) to assess association between SMAD6 variation and case status. Analyses were conducted with SAS and population genetics were assessed in Ensembl. Results: In this case-control analysis, 49 variants were significantly associated with LCH risk, including our previous risk locus. Leveraging population genetics, we found that the top 4 SNPs have low MAF globally (range 2-9%) but are enriched (MAF range 15-23%) in Hispanic/Latinx populations (MXL, CLM, PEL). The top two hits are in high LD in some of the Hispanic/Latinx and Black (ASW) populations (r2: MXL= 0.71, ASW = 1.0, PEL = 0.92), but not globally. The third SNP is in high LD with the peak SNP in these populations, as well (r2: MXL= 0.28, ASW = 0.83, PEL = 0.51). The fourth hit, which is our previously identified risk locus, has moderate LD with the peak SNP in Hispanic/Latinx populations (r2: MXL= 0.31, CLM = 0.3, PEL = 0.13). Conversely, the LD between the 1st and 5th SNPs was low globally and within different populations. Conclusion: We identified additional support for the role of SMAD6 variation in LCH susceptibility across and within diverse ancestral populations. These findings suggest that the top four SMAD6 variants identified in this study vary in how they function as independent signals across populations, especially in Hispanic/Latinx patients. The 5th hit in SMAD6 appears to be the next independent variant across all populations. These results indicate that there are common risk variants across populations and ancestry-specific variants for LCH, which may contribute to the differences in ancestry-specific LCH risk. Broadly, our work emphasizes the benefits of leveraging in, rather than adjusting out, the genomic richness of diverse patient populations.
Citation Format: Priya B. Shetty, Erin Peckham-Gregory, Erik Stricker, Howard Lin, Brooks Scull, Erik Ehli, Christel Davis, Kenneth McClain, Philip Lupo, Carl Allen, Michael Scheurer. Leveraging genomic diversity identifies additional germline risk loci in SMAD6 for Langerhans cell histiocytosis [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B073.