rs6557160 — CCDC170/ESR1

CCDC170/ESR1 rs6557160 — A Second Independent Signal at the Estrogen Receptor Locus

The 6q25.1 region on chromosome 6 is one of the most genetically complex and biologically important loci in estrogen-sensitive tissue biology. It encodes estrogen receptor alpha (ERα)¹¹ estrogen receptor alpha (ERα)
ESR1 protein — the principal nuclear receptor mediating estrogen's effects on breast, uterine, bone, and cardiovascular tissue and the adjacent coiled-coil domain containing protein 170 (CCDC170), whose precise function is still being characterized but whose expression is tightly linked to the estrogenic milieu of target tissues.

rs6557160 sits in the intergenic region approximately 7 kilobases upstream of CCDC170 and roughly 23–28 kilobases from ESR1 itself. It is a distinct genetic signal from the better-studied rs2046210 at this same locus — fine-mapping of 6q25 in over 118,000 participants²² fine-mapping of 6q25 in over 118,000 participants
Dunning et al. Nature Genetics, 2016 identified at least five independent causal variants in this region, each associating with different phenotype sets. rs6557160 tags a separate causal variant that specifically regulates CCDC170 expression and shows the strongest phenotypic associations with breast cancer risk and estrogen-sensitive tissue growth.

The Mechanism

rs6557160 functions as an expression quantitative trait locus (eQTL)³³ expression quantitative trait locus (eQTL)
An eQTL is a genomic position where genetic variation statistically predicts how much of a nearby gene is expressed across people for CCDC170. The C risk allele is associated with increased CCDC170 transcript levels in multiple tissues. CCDC170 is expressed in breast and reproductive epithelial cells, and recent evidence suggests it interacts with estrogen signaling pathways — potentially modulating ligand-activated ERα activity or cytoskeletal organization in estrogen-responsive cells.

The eQTL relationship was confirmed in a GWAS of gynecological traits in 11,348 Japanese women⁴⁴ GWAS of gynecological traits in 11,348 Japanese women
Hirata et al. Scientific Reports, 2018 where rs6557160 reached genome-wide significance for bust size (P = 1.7 × 10⁻¹⁶), a trait with known genetic architecture overlapping breast cancer susceptibility loci. Epigenomic annotation pinpointed CCDC170 as the likely functional target of this signal rather than ESR1 directly, distinguishing rs6557160 from the nearby rs2046210 variant (which primarily upregulates ESR1 transcription).

The Evidence

The strongest statistical evidence comes from breast cancer genetics. Fine-mapping by Dunning et al. (2016)⁵⁵ Dunning et al. (2016)
Nature Genetics, 48:374–386 identified rs6557160 as an independent breast cancer risk variant at 6q25 with an effect size (β ≈ 0.23, p ≈ 2 × 10⁻²⁰) that is robust across large multi-ethnic consortia. The variant is also independently associated with bone mineral density (p ≈ 3 × 10⁻¹⁰), consistent with the known role of estrogen receptor signaling in skeletal maintenance. Together, these associations point to a variant that modulates CCDC170 expression and thereby fine-tunes sensitivity across multiple estrogen-responsive tissues.

The endometriosis-specific evidence for rs6557160 is currently indirect — it derives from the well-replicated observation that the 6q25.1 ESR1/CCDC170 locus as a whole is one of the most robustly replicated endometriosis susceptibility regions in GWAS, and that modulation of estrogen signaling at this locus is mechanistically central to ectopic endometrial lesion growth. The distinction between which SNPs at 6q25.1 drive endometriosis versus breast cancer versus bone density susceptibility is an active area of research; the Dunning 2016 fine-mapping paper was the first to formally show that at least five independent signals co-exist at this locus with partially overlapping and partially distinct phenotypic consequences.

Practical Actions

For carriers of the C risk allele, the primary clinical relevance is heightened estrogen-sensitive tissue proliferation risk. The breast cancer signal is directly actionable: C allele carriers benefit from age-appropriate mammographic screening and awareness of personal risk factors. Since the same locus regulates estrogen-sensitive gynecological tissue more broadly, women with pelvic pain or subfertility should have a lower threshold for endometriosis evaluation.

Bone density is a secondary concern — estrogen signaling at 6q25 is a key determinant of bone mineral maintenance, and variants that alter CCDC170/ESR1 expression at this locus have been linked to bone density differences (p ≈ 3 × 10⁻¹⁰). C allele carriers should ensure adequate calcium and vitamin D intake and consider baseline bone density assessment.

Dietary indole-3-carbinol (I3C) from cruciferous vegetables promotes 2-hydroxylation of estradiol via CYP1A1/CYP1A2, shifting estrogen metabolism toward the less proliferative 2-OH pathway. This is relevant for any variant that increases estrogen-tissue sensitivity, including at the CCDC170/ESR1 axis.

Interactions

rs2046210 (ESR1 upstream regulatory, ~1.2 kb away): The two variants tag distinct signals at 6q25.1. rs2046210 primarily upregulates ESR1 transcription; rs6557160 is an eQTL for CCDC170. Women carrying risk alleles at both loci have additive estrogenic sensitization through two parallel mechanisms — higher estrogen receptor protein levels (rs2046210 effect) combined with altered CCDC170 expression (rs6557160 effect). The combined genotype has not been formally studied but theoretically amplifies estrogen-driven proliferative signaling in breast and endometrial tissue.

rs12700667 (7p15.2, near HOXA10/HOXA11): The HOXA locus is the strongest replicated endometriosis GWAS signal. Carrying risk alleles at both rs6557160 (CCDC170/ESR1 estrogen sensitization) and rs12700667 (altered HOX gene-regulated endometrial patterning) represents convergent mechanistic pathways for endometriosis. Combined recommendation: earlier gynecological evaluation and lower diagnostic threshold. Evidence: both loci individually well-replicated; combined effect not formally tested.