rs1971256 — CCDC170 CCDC170/ESR1 Endometriosis Estrogen Signaling Variant

Intronic variant in CCDC170 at the 6q25.1 estrogen-signaling locus, co-regulated with ESR1; the C allele increases endometriosis risk (OR 1.09) and has been independently replicated across European, East Asian, and Taiwanese-Han populations

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CCDC170 — An Independent Estrogen-Signaling Variant at the Endometriosis Locus

The chromosome 6q25.1 region is one of the most replicated genetic risk zones for endometriosis. It harbors the estrogen receptor alpha gene (ESR1) and, just upstream, CCDC170 (Coiled-Coil Domain Containing 170) — a gene that encodes a Golgi-microtubule organizing protein. Variants across this region have been identified in multiple large GWAS studies spanning European, East Asian, and Taiwanese-Han populations. The rs1971256 C allele is one such signal: an intronic variant that sits within CCDC170 and contributes independently to endometriosis susceptibility beyond the well-studied ESR1 polymorphisms rs9340799 and rs2234693 already characterized on this platform.

The Mechanism

rs1971256 lies in intron 1 of CCDC170, at GRCh38 position chr6:151,494,876. The T allele is the GRCh38 reference; the C allele is the endometriosis risk allele identified in the GWAS Catalog (OR 1.09, p = 4×10⁻⁸). Because the variant is intronic, it does not change the CCDC170 protein sequence directly — instead, it likely acts as a regulatory or tagging variant influencing expression of CCDC170, neighboring ESR1, or both.

CCDC170 protein localizes to the Golgi apparatus, where it organizes Golgi-associated microtubule networks11 Golgi-associated microtubule networks
the Golgi is a cellular sorting hub; its microtubule connections enable polarized protein trafficking and cell migration. Cancer-associated truncations of CCDC170 abolish Golgi localization and disrupt directional cell migration — a mechanism relevant to how ectopic endometrial cells survive outside the uterus and evade immune clearance. Co-regulation with ESR1 is central: fine-mapping studies of the 6q25.1 region in over 118,000 individuals found that risk variants here regulate both CCDC170 and ESR1 through distinct enhancer elements22 distinct enhancer elements
enhancers are non-coding DNA switches that control when and where genes are active, meaning a single variant can alter estrogen receptor expression, CCDC170 protein levels, or both simultaneously.

The net biological picture is of a locus where estrogen signaling efficiency and cellular polarity/migration are regulated in concert — two processes that together determine whether ectopic endometrial tissue can implant and proliferate outside the uterus.

The Evidence

The CCDC170 locus at 6q25.1 was first established as an endometriosis risk locus by a meta-analysis of 11 GWAS datasets totalling 17,045 cases and 191,596 controls33 meta-analysis of 11 GWAS datasets totalling 17,045 cases and 191,596 controls
Sapkota et al. Nature Communications, 2017, which identified five novel endometriosis loci implicating sex steroid hormone pathways, including FN1, CCDC170, ESR1, SYNE1, and FSHB.

The most comprehensive evidence comes from a landmark meta-GWAS of 60,674 endometriosis cases and 701,926 controls across European and East Asian ancestry cohorts44 meta-GWAS of 60,674 endometriosis cases and 701,926 controls across European and East Asian ancestry cohorts
Rahmioglu et al. Nature Genetics, 2023, which identified 42 genome-wide significant loci — the largest endometriosis genetic study to date. The 6q25.1 region (encompassing rs1971256) was among the replicated signals, with the C allele conferring OR ≈ 1.09 (p = 4×10⁻⁸). This is a modest per-allele effect typical of complex-trait GWAS: the C allele does not cause endometriosis, but each copy meaningfully shifts the population risk distribution.

Cross-ethnic replication strengthens confidence: a Taiwanese-Han GWAS of 2,794 cases and 27,940 controls55 Taiwanese-Han GWAS of 2,794 cases and 27,940 controls
Sheu et al. Journal of Human Genetics, 2024 independently confirmed CCDC170 at 6q25.1 as a cross-population susceptibility locus alongside WNT4 and RMND1, suggesting the biological mechanism operates across ancestral backgrounds.

The risk allele C is notably more common in African populations (~69%) than in Europeans (~21%), which is informative for interpreting population-level risk distributions but does not change the per-allele effect estimate.

Practical Implications

This variant sits in the estrogen-signaling axis and provides additional evidence that a woman's risk for endometriosis is partially encoded in how her CCDC170 and ESR1 regulatory landscape is tuned. Clinically, the most important consequence is heightened vigilance: C allele carriers — especially CC homozygotes — benefit from earlier evaluation of pelvic pain symptoms rather than attributing them to normal dysmenorrhea.

For women with confirmed endometriosis who carry the C allele at this locus (and particularly those who also carry risk alleles at rs9340799 or rs2234693 in ESR1), the estrogen-pathway context informs medical management. Aromatase inhibitors such as letrozole and anastrozole66 Aromatase inhibitors such as letrozole and anastrozole
aromatase converts androgens to estrogen in peripheral tissues including endometriotic implants; inhibiting it reduces local estrogen production are undergoing late-phase clinical trials for endometriosis pain, with promising results. Women with documented estrogen-pathway genetic risk may be better candidates for this class of therapy when first-line progestins fail.

Combined oral contraceptive (COC) selection also matters: progestin-dominant formulations (e.g., dienogest-containing pills, the levonorgestrel IUD) suppress ectopic implant growth more directly than estrogen-dominant formulations, which can in some cases stimulate lesion activity.

Interactions

rs9340799 (ESR1 XbaI) and rs2234693 (ESR1 PvuII): Both variants sit within the same 6q25.1 estrogen-signaling block as rs1971256. Fine-mapping studies indicate that rs1971256 is an independent signal — conditional analysis in GWAS data shows it retains significance after accounting for the classical ESR1 PvuII and XbaI variants. Women carrying risk alleles at multiple loci in this block (rs1971256-C + rs9340799-G + rs2234693-C) may face compounded estrogen-signaling dysregulation in endometrial tissue. A compound action is proposed below for women carrying risk alleles at both rs1971256 and rs9340799.

rs12700667 (near HOXA10): The WNT4-HOXA endometrial development axis represents a separate pathway; carrying risk alleles at both the estrogen-signaling (rs1971256) and developmental patterning (rs12700667) loci may additively increase endometriosis susceptibility, though formal interaction testing has not been published.

Genotype Interpretations

What each possible genotype means for this variant.

TT Common Genotype Normal

No copies of the CCDC170 risk allele — baseline endometriosis risk at this locus

You carry two copies of the T reference allele at rs1971256. The TT genotype is not associated with elevated endometriosis risk from this specific locus. About 40% of the global population shares this genotype; it is more common in Europeans (~62%) and less common in African populations (~10% by Hardy-Weinberg equilibrium at the C allele frequency of 0.69).

This result does not eliminate endometriosis risk — many other genetic and environmental factors contribute, and endometriosis affects approximately 10% of reproductive-age women regardless of this genotype. Regular awareness of symptoms remains important.

CT Heterozygous Carrier Intermediate

One copy of the endometriosis risk allele at the CCDC170/ESR1 locus

The rs1971256 C allele operates in an additive (dose-dependent) pattern: each copy adds roughly the same increment of risk. At one copy, the additional risk over baseline is modest (~9% per copy). This genotype is not a high-penetrance finding but is meaningful in combination with clinical symptoms or other estrogen-pathway variants.

Heterozygosity at this locus is especially relevant for women who have already been diagnosed with endometriosis: the CCDC170/ESR1 locus context supports the biological rationale for estrogen-pathway medical management (progestins, GnRH agonists, or aromatase inhibitors) when symptoms are inadequately controlled by standard first-line therapy.

CC Homozygous Risk High Risk

Two copies of the endometriosis risk allele — highest genetic contribution at this locus

The additive architecture of rs1971256 means CC carries approximately twice the incremental risk of CT. While the absolute risk increment per allele is modest (OR ≈ 1.09), two copies together shift individual risk by roughly 18-19% relative to TT. In a condition where average population prevalence is 10%, this translates to an estimated background-adjusted individual risk of approximately 12-13% — not deterministic, but clinically meaningful for clinical decision-making when symptoms are present.

The CCDC170 locus has been replicated independently in European, East Asian, and Taiwanese-Han GWAS cohorts, making CC homozygosity at this SNP one of the more robustly supported individual genetic signals for endometriosis among currently catalogued variants.

For CC carriers with confirmed endometriosis, the estrogen-pathway biology informs both medical and surgical planning. Ectopic implants in estrogen- pathway variant carriers may be especially responsive to treatments that reduce local estrogen bioavailability — including aromatase inhibitors, GnRH agonists, and progestin-dominant hormonal suppression.