Abstracto
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Objective
The incidence of uterine leiomyomata (UL) is 2-3 times higher among African Americans than European Americans. In a recent genome-wide association study (GWAS) among women of European descent, a single nucleotide polymorphism (SNP), rs4247357, reached genome-wide significance in association with UL. This SNP is located on chromosome 17 in a large linkage disequilibrium (LD) block that contains three genes, fatty-acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute carrier family 16, member 3 (SLC16A3). Levels of FAS, the enzyme responsible for de novo fatty-acid synthesis, were shown to be higher in UL tissue than in matched myometrium. We sought to replicate the association between rs4247357 and UL risk in the Black Women’s Health Study.
DesignProspective cohort study of African American women.
Materials and Methods
We genotyped 2,014 incident UL cases and 1,939 controls for rs4247357 and a panel of validated ancestry informative markers (AIMs). All women were premenopausal, had intact uteri, and were aged 23-50 years in 1997. Associations were assessed using logistic regression with control for age, geographic region of residence, and percent European ancestry.Results
Overall, rs4247357 was not associated with risk of UL. Relative to the CC genotype (28.7%), the odds ratio was 0.96 (95% confidence interval (CI): 0.83, 1.11) for the AC genotype (52.2%) and 1.01 (CI: 0.84, 1.22) for the AA genotype (19.1%) (P-trend=0.9572). No appreciable associations were found between rs4247357 and UL risk when we stratified the data by age at baseline, surgical treatment, family history of UL, and recency of pelvic ultrasound. In contrast, we found evidence of an association among the women with the highest levels of %European ancestry (≥40%), but numbers were small: relative to the CC genotype (24.0%), the odds ratio was 1.94 (CI: 0.83, 1.11) for the AC genotype (54.0%) and 2.29 (CI: 1.00, 5.23) for the AA genotype (22.0%) (P-trend=0.0506; P-interaction=0.1248).Conclusion
Our data indicate that rs4247357 is not associated with UL incidence in African American women. This observation is further Supported by suggestive evidence of a positive association only among women with ≥40% European ancestry. Fine-mapping may be warranted to determine whether this genomic region is causally related to UL in African American populations and, if so, whether there are other SNPs that are more closely correlated with the causal variant.