Rs7028661

The minor allele of rs7028661 has been associated with an additive risk of thyroid cancer in Southern Europeans. This SNP is located in the 9q22 region in the gene FOXE1 [PMID 25855579].

Thyroid cancer is characterized by a tumor in the thyroid, an endocrine gland located in the neck. Incidence has been increasing since the 1970s, and lifetime risk is approximately 0.8% for women and 0.3% for men as of 2005 [PMID 16236090]. Thyroid cancer has the highest known heritability (53%) among non-Mendelian cancers [PMID 11979442], but no common high-penetrance causal variants have been found [PMID 25855579].

Researchers seeking to unearth some of the hidden heritability of thyroid cancer performed a genome-wide association study of 1820 thyroid cancer cases and 2410 controls in five different Southern European populations (four in Spain, one in Italy). The study found rs7028661, located in FOXE1, to be associated with a 1.64-fold higher risk of thyroid cancer (p = 1.0E-22). The odds ratio varied somewhat among populations, and was highest in Italians (OR = 1.97) and lowest in Galicians (OR = 1.17) [PMID 25855579].

The same study also found alleles of rs10122541, rs7037324, rs2997312, rs10788123, rs1254167, rs944289 to be associated with an increased risk of thyroid cancer. Two of these, rs10122541 and rs7037324, are also located in FOXE1, but still showed a statistically significant association with thyroid cancer risk after controlling for rs7028661 genotype, suggesting that multiple variants in this region may be independently contribute to thyroid cancer. One allele, at rs4075570, was identified as protective against thyroid cancer.

Four earlier GWAS also implicated variants at the 9q22 locus (containing FOXE1) in thyroid cancer [PMID 22267200][PMID 19198613][PMID 20350937][PMID 23894154].

FOXE1 is known to be a thyroid transcription factor. Variants in FOXE1 (Forkhead Box E1) have also been implicated in other thyroid disorders [PMID 21981779] and in cleft lip and palate [PMID 19779022].