Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

Huiling He, Wei Li, Sandya Liyanarachchi, Mukund Srinivas, Yanqiang Wang, Keiko Akagi, Yao Wang, Dayong Wu, Qianben Wang, Victor Jin, David E. Symer, Rulong Shen, John Phay, Rebecca Nagy, Albert De La Chapelle

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2(PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we fine-mapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.

Original languageEnglish (US)
Pages (from-to)6128-6133
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - May 12 2015


  • Functional variants
  • Genetic susceptibility
  • Long-range enhancer
  • SNP rs965513
  • Thyroid cancer

ASJC Scopus subject areas

  • General


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