Identification and Characterization of Genetic Variants Conveying Risk to Develop Uterine Leiomyomata

• Main Author: Eggert, Stacey Lynn
• Other Authors: Morton, Cynthia Casson
• Language: en_US
• Published: Harvard University 2013
• Subjects: genetics
• Online Access: http://dissertations.umi.com/gsas.harvard:10005; http://nrs.harvard.edu/urn-3:HUL.InstRepos:10121981

Uterine leiomyomata (UL), commonly known as fibroids, are a major public health problem given their extreme prevalence (>70%), severity of associated symptoms, and indication for hysterectomies in women of reproductive age. Familial aggregation and twin studies have provided evidence for a genetic component to predisposition to develop UL. To date, a small number of genes involved in UL biology, including HMGA2, have been discovered through cytogenetic studies of the tumors. HMGA2 is involved in recurrent translocations in UL and a TC repeat polymorphism in the gene is associated with UL diagnosis. In this thesis, I investigate the possible role of the TC repeat in HMGA2 expression. In 293T cells, the TC repeat number did not affect promoter activation, however, in the more relevant UL and myometrial cells, HMGA2 promoter activation was severely impaired and a definitive conclusion could not be made. Genome-wide linkage and association studies provide a promising, unbiased approach for revealing additional regions of the genome associated with UL. In this thesis, I describe results from the first genome-wide linkage and association studies performed in white women affected with UL. A genome-wide linkage study of affected white sister pairs revealed two significant linkage peaks in 10p11 (LOD=4.15) and 3p21 (LOD=3.73) with five suggestive peaks (LOD>2.00) in 2q37, 5p13, 11p15, 12q14, and 17q25. A meta-analysis of genome-wide association results in two independent cohorts of white women revealed a single nucleotide polymorphism (SNP) with genome-wide significance that is associated with UL diagnosis (rs4247357, P=3.05E-08, odds ratio (OR) =1.299). The candidate SNP is located under the UL linkage peak at 17q25 and is in a large block of linkage disequilibrium (LD) which spans three genes: fatty acid synthase (FASN), coiled-coil domain containing 57 (CCDC57) and solute carrier family 16, member 3 (SLC16A3). FAS transcripts and/or protein levels are up-regulated in various neoplasms and have been implicated in tumor cell survival. By tissue microarray immunohistochemistry, we found FAS protein expression elevated three-fold in UL when compared to matched myometrial tissue implicating FASN as the first UL risk allele identified in white women by a genome-wide, unbiased approach.