Avery Ulrich

Date of Award

Spring 2022

Document Type

Open Access Thesis

Department

Epidemiology and Biostatistics

First Advisor

Alyssa Clay-Gilmour

Abstract

Background Acute Myeloid Leukemia (AML) is a blood cancer that affects ~70,000 people each year in the US. The Fat Mass and Obesity (FTO) gene on chromosome 16 has been reported to be associated with obesity, solid tumor cancers (lung, renal, breast, prostate, pancreatic, endometrial), and more recently with hematologic malignancies, like AML. In this thesis, we test the hypothesis that inherited variants within the FTO gene are associated with an increased risk of AML. Methods Using the DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after Blood and Marrow Transplantation), a well-powered genome-wide association study consisting of 2 cohorts of BMT recipients with acute leukemias and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research, we leveraged 2959 AML cases and 3450 controls in a candidate gene study framework. We tested the association between SNPs located in the FTO gene using multivariable logistic regression assuming an additive model adjusting for age and sex. Further stratified was performed by genomic ancestry (European American, African American, and Hispanic), and body mass index (BMI). SNP and BMI interaction analysis was performed. Results After performing standard candidate gene quality control measures, we found 130 SNPs in the FTO gene available for testing. We found 14 significantly associated FTO SNPs associated with increased risk of AML in obese European American cases compared to controls and a significant interaction between SNPs and BMI was detected.

Methods Using the DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after Blood and Marrow Transplantation), a well-powered genome-wide association study consisting of 2 cohorts of BMT recipients with acute leukemias and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research, we leveraged 2959 AML cases and 3450 controls in a candidate gene study framework. We tested the association between SNPs located in the FTO gene using multivariable logistic regression assuming an additive model adjusting for age and sex. Further stratified was performed by genomic ancestry (European American, African American, and Hispanic), and body mass index (BMI). SNP and BMI interaction analysis was performed.

Results After performing standard candidate gene quality control measures, we found 130 SNPs in the FTO gene available for testing. We found 14 significantly associated FTO SNPs associated with increased risk of AML in obese European American cases compared to controls and a significant interaction between SNPs and BMI was detected. While our power was limited, we did not find any significant associations between FTO SNPs and AML risk in other races/ethnicities.

Conclusion Our study provides evidence that FTO variants may contribute to AML, and not only solid tumors, while highlighting the importance of FTO variants in obesity and cancer. Identification of risk variants in AML by BMI is important for clinical risk stratification, as well as underlying functional molecular mechanisms of FTO in AML etiology.

Rights

© 2022, Avery Ulrich

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