rs519664 — TTC39B TTC39B rs519664

Intronic variant in TTC39B (9p22) that increases endometriosis susceptibility; the T allele carries an OR of 1.29 for endometriosis, with a stronger effect on stage III/IV disease (OR 1.35). TTC39B is a regulator of LXR protein stability that controls HDL cholesterol metabolism.

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TTC39B — A Lipid Regulator With a Surprising Role in Endometriosis

On the short arm of chromosome 9, an intronic variant in TTC39B11 TTC39B
Tetratricopeptide Repeat Domain-Containing Protein 39B — a cytoplasmic scaffold protein that controls the degradation rate of liver X receptors has emerged as one of only a handful of robustly confirmed genetic risk factors for endometriosis. The rs519664 T allele increases endometriosis risk by approximately 29% and carries an even stronger association with severe, surgically confirmed stage III/IV disease. That a gene best known for regulating HDL cholesterol metabolism is linked to a gynaecological condition characterised by chronic peritoneal inflammation points to an underappreciated role of lipid-mediated immune signalling in the development and persistence of endometriotic lesions.

The Mechanism

TTC39B acts as an E3 ubiquitin ligase adaptor that targets liver X receptors (LXRα and LXRβ)22 liver X receptors (LXRα and LXRβ)
nuclear receptors activated by oxysterols — oxidised cholesterol derivatives — that control genes for reverse cholesterol transport, fatty acid synthesis, and inflammation for proteasomal degradation. When TTC39B is functional, LXR protein is continually degraded; when TTC39B activity is reduced, LXR accumulates and drives stronger expression of its target genes — including ABCA1 (intestinal HDL biogenesis) and a suite of anti-inflammatory and cholesterol-efflux genes.

The Evidence

The endometriosis association was discovered by Steinthorsdottir et al. 201633 Steinthorsdottir et al. 2016
Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nat Commun. 2016 through a whole-genome-sequencing-based GWAS in Iceland (1,840 cases, 129,016 control women), with replication in a Danish cohort. The combined odds ratio for rs519664[T] was 1.29 (p=4.8×10⁻¹⁰). The association was stronger for histologically confirmed stage III/IV disease (OR 1.35, p=1.9×10⁻⁵) than for minimal/mild stage I/II disease (OR 1.21, p=0.013), suggesting the variant particularly predisposes to severe, deeply invasive endometriosis.

The most recent large-scale endometriosis GWAS by Rahmioglu et al. 202344 Rahmioglu et al. 2023
The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat Genet. 2023 (60,674 cases, 701,926 controls) identified 42 genome-wide significant loci, including the 9p22 region, with effect sizes largest for stage 3/4 ovarian endometriosis.

The T allele is the minor allele in most populations: approximately 22% frequency in Europeans and South Asians, 14% in East Asians, and notably 75% in Africans — a marked frequency reversal that is important context for ancestry-specific risk counselling.

Practical Actions

The T allele raises endometriosis susceptibility at a population level — it is not deterministic. Among women who develop endometriosis, however, T carriers are more likely to progress to the severe stages that cause pelvic adhesions, ovarian endometriomas, and fertility impairment. Early gynaecological evaluation and prompt investigation of cyclical pelvic pain are therefore the most actionable implications of this genotype, since stage III/IV endometriosis diagnosed early can often be managed with less invasive intervention than disease allowed to progress for years.

Interactions

rs519664 maps to a separate chromosomal region from the other robustly confirmed endometriosis loci, including rs17773813 (upstream of KDR/VEGFR2 on chromosome 4q12, discovered in the same Steinthorsdottir 2016 paper), rs2206949 (ESR1, the oestrogen receptor alpha locus), and multiple GWAS-identified loci involved in sex steroid hormone metabolism. No direct gene-gene interaction between TTC39B and other endometriosis loci has been studied in published datasets, but the combination of a TTC39B T allele (peritoneal inflammatory burden) with oestrogen-signalling loci (ESR1, FSHB) is biologically plausible given that oestrogen upregulates prostaglandin synthesis in endometriotic stroma.

Genotype Interpretations

What each possible genotype means for this variant.

CC Typical Risk Normal

Common genotype — population-average endometriosis susceptibility

You carry the C/C genotype at rs519664 in TTC39B. The C allele is the GRCh38 reference allele and the population-major allele globally (~64%). This genotype is not associated with elevated endometriosis risk at this locus — your susceptibility through the TTC39B pathway is typical for the general population.

CT Elevated Endometriosis Risk Intermediate

One copy of the endometriosis risk allele — moderately elevated susceptibility

The CT genotype places you on an intermediate risk haplotype for endometriosis through the TTC39B locus on chromosome 9p22. Cyclical pelvic pain, dysmenorrhoea, or subfertility should be investigated promptly rather than attributed to normal variation.

TT High Endometriosis Risk High Risk

Two copies of the endometriosis risk allele — substantially elevated susceptibility

The TT genotype at rs519664 confers the maximum TTC39B-pathway genetic loading for endometriosis susceptibility. For women of African descent in particular, TT is a majority genotype (~56% frequency), meaning endometriosis risk profiling with this locus is especially relevant to this group — who are also historically under-diagnosed for endometriosis in clinical practice.