rs1238574 — SULT1E1 SULT1E1 intronic variant

Intronic variant in SULT1E1 (estrogen sulfotransferase) associated with altered SULT1E1-related outcomes; the C allele, enriched in East Asian populations, has been linked to worse colorectal cancer survival and may influence local estrogen bioavailability through effects on SULT1E1 expression regulation

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SULT1E1 rs1238574 — Estrogen Clearance, Local Hormone Balance, and Cancer Susceptibility

Estrogens do not simply circulate and act — they are continuously inactivated and reactivated in tissues through a biochemical toggle controlled by sulfotransferases and sulfatases. SULT1E111 SULT1E1
Estrogen sulfotransferase; a phase II metabolizing enzyme that adds a sulfate group to estradiol and estrone, converting them to biologically inactive sulfate conjugates that cannot bind the estrogen receptor is the primary enzyme responsible for this inactivation step, with particularly high activity in endometrial, hepatic, and placental tissue. When SULT1E1 activity falls — whether through genetic variation, epigenetic silencing, or tissue-specific dysregulation — local estrogen concentrations rise in ways that circulating hormone assays may not capture.

rs1238574 is an intronic variant located deep within SULT1E1 (c.772+856 on the transcript, chr4:69843305 GRCh38). It does not change the SULT1E1 protein sequence, but its position within an intron raises the possibility of effects on pre-mRNA processing, intronic regulatory elements, or splicing efficiency. The C allele — the minor allele globally at roughly 5–6% in European populations but substantially more common in East Asians (~36%) — has been associated with worse cancer outcomes and is the focus of emerging research interest.

The Mechanism

SULT1E1 sulfates estradiol (E2) and estrone (E1) at the 3-hydroxyl position, producing estrogen sulfates that are hydrophilic, receptor-inactive, and destined for excretion. This sulfation reaction is the counterpart to steroid sulfatase (STS), which cleaves the sulfate back off — the balance between SULT1E1 and STS sets local estrogen tone in tissues independently of the ovarian cycle.

Studies of endometriosis tissue directly document this imbalance: SULT1E1 mRNA and protein expression are significantly reduced in ovarian endometriotic lesions22 SULT1E1 mRNA and protein expression are significantly reduced in ovarian endometriotic lesions
Hevir et al. Mol Cell Endocrinol, 2013, creating a state of local estrogen excess driven not by increased synthesis but by impaired inactivation. A 2024 study using Mendelian randomization33 2024 study using Mendelian randomization
Zou et al. Biology (Basel), 2024 identified SULT1E1 as a likely causal susceptibility gene for ovarian endometriosis through cross-tissue regulatory network analysis, suggesting genetically determined variation in SULT1E1 expression can propagate into disease risk.

The Evidence

The most direct evidence linking rs1238574 to clinical outcomes comes from a Chinese case-control study of estrogen metabolic pathway genes and colorectal cancer44 Chinese case-control study of estrogen metabolic pathway genes and colorectal cancer
Li et al. Archives of Toxicology, 2018. Among SULT1E1 variants studied, rs1238574 was associated with significantly worse progression-free survival (HR = 1.24, 95% CI 1.02–1.50, P = 0.028) and overall survival (HR = 1.51, 95% CI 1.16–1.97, P = 0.002) in colorectal cancer patients. The companion variant rs3822172 showed similar associations (HR = 1.30–1.53). These findings are biologically coherent: estrogens have been proposed to reduce colorectal cancer risk partly through anti-inflammatory and cell-cycle effects, and impaired estrogen inactivation in colonic tissue could paradoxically alter local estrogenic signaling quality.

At the gene level, SULT1E1 variants have been connected to endometrial cancer risk in a population-based case-control study of 502 cases and 1,326 controls55 population-based case-control study of 502 cases and 1,326 controls
Rebbeck et al. J Natl Cancer Inst, 2006: the SULT1E1 promoter G→A variant carried an odds ratio of 1.45 (95% CI 1.06–1.99) for endometrial cancer, particularly when combined with hormone replacement therapy use. A separate Korean study66 Korean study
Choi et al. Cancer Epidemiol Biomarkers Prev, 2005 found SULT1E1 haplotypes were associated with both breast cancer risk and recurrence (hazard ratio >3 for certain haplotype combinations).

The evidence for rs1238574 specifically is limited to a single study in a Chinese cohort and is classified as emerging. Replication in independent cohorts and functional characterization of this intronic variant's effect on SULT1E1 expression are needed.

Practical Actions

For individuals carrying the C allele, particularly in the context of estrogen-sensitive conditions or cancer risk assessment, the relevant clinical consideration is whether SULT1E1-mediated estrogen inactivation is functioning optimally. Phytoestrogens from soy — specifically isoflavones — have been shown to elevate SULT1E1 enzyme levels in endometriotic stromal cells77 elevate SULT1E1 enzyme levels in endometriotic stromal cells
Tarumi et al. Gynecol Endocrinol, 2025, suggesting dietary phytoestrogen intake may partially compensate for reduced SULT1E1 activity. Cruciferous vegetables support phase II metabolism broadly.

Monitoring for estrogen-driven conditions — endometriosis, uterine fibroids, and estrogen-sensitive cancers — is a reasonable precaution for C allele carriers given the biological plausibility of the SULT1E1 pathway and the emerging cancer survival data.

Interactions

rs3822172 (SULT1E1): This second SULT1E1 intronic variant was studied in the same Chinese colorectal cancer cohort as rs1238574 and showed nearly identical survival associations (HR = 1.30 for PFS, HR = 1.53 for OS). Whether these two variants are in linkage disequilibrium or tag independent functional effects within SULT1E1 is not yet established. Both should be considered together when assessing SULT1E1 function.

Estrogen metabolism pathway: SULT1E1 operates in concert with CYP1B1 (which activates catechol estrogens), CYP1A1 (estrogen hydroxylation), STS (sulfatase reactivation), and UGT enzymes (glucuronidation). Combined variation across these enzymes, particularly CYP1A1 and SULT1A1, has been associated with amplified endometrial cancer risk in case-control studies. Compound action proposals for supervisor: consider a SULT1E1/CYP1A1 interaction action if rs1238574 and a CYP1A1 risk allele co-occur in the same user, given the documented combined OR of 4.58 (Hirata et al. 2008, PMID 18318428).

Nutrient Interactions

estradiol altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

TT Typical SULT1E1 Activity Normal

Common genotype — no C allele copies at this SULT1E1 locus

You carry two copies of the T allele at rs1238574, the most common genotype worldwide. Approximately 88% of people globally share this TT genotype, rising to about 94% in people of European ancestry. This variant does not appear to confer elevated risk at this SULT1E1 locus.

SULT1E1 regulates estrogen inactivation in tissues; this result suggests no genetically-driven disruption at this particular intronic position. Other factors influencing SULT1E1 activity — including diet, body composition, and other SULT1E1 variants — still apply.

CT One C Allele Intermediate

One copy of the rare SULT1E1 C allele — modest emerging signal

The SULT1E1 gene encodes the estrogen sulfotransferase enzyme, which inactivates estradiol and estrone by sulfation. Intronic variants can influence gene expression through effects on splicing regulatory elements, intronic transcription factor binding sites, or RNA secondary structure. rs1238574 sits at c.772+856 — 856 bp into the intron following coding exon position 772 — placing it in a region that may contain intronic regulatory elements.

Research on SULT1E1 expression in endometriosis shows that the enzyme is consistently downregulated in ectopic lesion tissue, contributing to local estrogen excess and lesion persistence. Whether rs1238574 genotype influences this tissue- specific expression pattern has not been directly studied, but the Mendelian randomization data identifying SULT1E1 as a causal gene for endometriosis supports investigating genetic modifiers of its expression.

CC Two C Alleles High Risk

Two copies of the rare SULT1E1 C allele — highest emerging signal at this locus

SULT1E1 homozygous CC individuals are rare in European populations but constitute about 14% of East Asians at this locus. The CC genotype represents the maximum potential disruption of intronic regulation at this position. In the context of estrogen metabolism, if the C allele reduces SULT1E1 expression, CC homozygotes would be expected to have the lowest SULT1E1 activity at this locus, leading to the greatest relative increase in local tissue estrogen concentrations.

SULT1E1 expression is already known to be reduced in endometriosis lesions independent of genotype; additional genetically determined reduction in CC carriers could exacerbate this imbalance. The connection to colorectal cancer survival may reflect a role for estrogen inactivation quality in colonic mucosa biology. Prospective studies in CC-enriched East Asian populations are needed to formally quantify this risk.