Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study.
ABSTRACT: We evaluated the association of 56 candidate SNPs identified in two published genome-wide association studies (GWAS) of uterine leiomyoma (UL), or fibroids, with the risk and tumor size in the multi-ethnic uterine fibroid study (NIEHS-UFS). The selected SNPs were genotyped in 916 premenopausal women of African American (AA) and European American (EA) descents and their association with the outcomes was evaluated in race-stratified models and in meta-analysis of risk in NIEHS-UFS and discovery and replication GWAS in the Japanese population. We report moderate associations of variant rs4954368 in THSD7B (thrombospondin, type I, domain containing 7B) with tumor size in pooled analysis of AA and EA samples (P = 0.004), and at TNRC6B (trinucleotide repeat containing 6B) variants rs138039 and rs139909 in EA (P = 0.001 and 0.008, respectively). The most significant associations with risk in meta-analysis were observed at TNRC6B variants rs739182 (P = 3.7 × 10(-10)) and rs2072858 (P = 1.1 × 10(-9)) and were stronger than those reported in the discovery GWAS (P = 2.01 × 10(-8) and 2.58 × 10(-8), respectively). The present study failed to replicate the associations reported for CCDC57 and FASN in a discovery GWAS in populations of European descent. Consistent with previous replication studies in the Right From the Start Study (RFTS) and the BioVU DNA repository, we provide independent evidence for association of TNRC6B with both risk and size of UL. The present study is the first to report a replicated association of THSD7B with UL, albeit with tumor size and not with risk.
Project description:Uterine fibroid (UFs) affect 77 % of women by menopause and account for $9.4 billion in healthcare costs each year. Although UFs are heritable, genetic risk is poorly understood. The first genome-wide association study (GWAS) of UFs was recently performed in a Japanese population, with reported genome-wide significance for single nucleotide polymorphisms (SNPs) across three chromosomal regions. We tested these SNPs for association with UFs in US cohorts. Women were enrolled in the Right from the Start (RFTS) cohort and the BioVU DNA repository. UF status in both cohorts was determined by pelvic imaging. We tested 65 candidate and haplotype-tagging SNPs for association with UFs presence using logistic regression in RFTS and the top three GWAS-associated SNPs in BioVU. We also combined association results from both cohorts using meta-analysis. 1,086 European American (EA) cases and 1,549 controls were examined. Two SNP associations replicated [blocked early in transport 1 homolog (BET1L) rs2280543, RFTS-BioVU meta-odds ratio (OR) = 0.67 95 % confidence interval (CI) 0.38-0.96, Q = 0.70, I = 0, p = 6.9 × 10?³; trinucleotide repeat containing 6B (TNRC6B) rs12484776, RFTS-BioVU meta-OR = 1.21, 95 % CI 1.07-1.35, Q = 0.24, I = 28.37, p = 8.7 × 10?³). Meta-analyses combining evidence from RFTS, BioVU, and prior GWAS showed little heterogeneity in effect sizes across studies, with meta-p values between 7.45 × 10?? and 3.89 × 10??, which were stronger than prior GWAS and supported associations observed for all previously identified loci. These data suggest common variants increase risk for UF in both EA and Japanese populations. However, further research is needed to assess the role of these genes across other racial groups.
Project description:Uterine leiomyoma (UL) are benign neoplasms arising from the smooth muscle cells of the uterus. One of the established risk factors for UL is African American ethnicity. Studies have consistently shown that African Americans have two to three times higher risk compared with that of non-Hispanic Whites. However, there is still no adequate explanation for the higher risk among African Americans. To investigate the genetic contribution to the observed difference between the African American and European American populations, we conducted an admixture scan in 525 eligible African American women participants to the NIEHS uterine fibroid study (NIEHS-UFS). In models with no stratification, we found multiple genomic regions showing significant and suggestive evidence of association, with chromosomal band 2q32.2 at rs256552 showing the highest score (Z-score=7.86, Bonferroni adjusted P-value=5.5 × 10(-12)) consistent with the suggestive evidence reported for this genomic region in the Black Women's Health Study. However, in models stratified by the body mass index (BMI) covariate, chromosome 1q42.2 was the sole genomic region that consistently showed suggestive associations across the BMI categories tested (Z-scores ?-3.96, Bonferroni adjusted P-values ?0.107). In age-stratified models, a significant association was observed in the older category (age >40) reaching a Z-score of 6.44 (Bonferroni-adjusted P-value=1.64 × 10(-7)) at rs256552. The mean percentage of European ancestry among cases was lower than that among controls in the NIEHS-UFS study. However, our study did not show a significant association between mean percentage of European ancestry and UL.
Project description:We conducted a follow-up association study across extended candidate chromosomal regions for uterine leiomyoma (UL), or fibroids, to search for loci influencing the size of UL in 916 premenopausal North American women participants to the NIEHS uterine fibroid study. Proportional odds models with adjustments for confounders were fitted to evaluate the association of a final set of 2,484 single nucleotide polymorphisms (SNPs) with the size of uterine fibroids measured by transabdominal and transvaginal ultrasounds. SNP association with UL size was tested in a case-only design comparing three categories of tumor size (small, medium and large tumors) and in a design that included UL-free controls as the lowest category of a four-level ordinal outcome to account for misclassifications due to small, undetected tumors. In the case-only design, rs2285789 in SORCS2 (sortilin-related VPS10 domain containing receptor 2) was the sole variant that remained significant after correction for multiple testing (Bonferroni-adjusted P=0.037). Several other SNPs, namely those located in MYT1L, TMCC1 and BRCA1, reached promising associations. In the design that included the controls, several genes of potential relevance to UL pathogenesis were associated (Bonferroni-unadjusted P < 0.01) with tumor size, particularly LIFR-AS1 (leukemia inhibitory factor receptor alpha-antisense RNA 1), which showed the strongest association (Bonferroni-unadjusted P=0.0006) among the genes with regulated expression in UL. In conclusion, SORCS2, a known GWAS candidate for circulating IGF-I and IGFBP-3, may act through IGF-I signaling to affect the size of fibroids. Through down-regulation of LIFR, LIFR-AS1 may mediate the inhibitory action of LIF (leukemia inhibitory factor), a cytokine invol