rs519664 — TTC39B TTC39B rs519664

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.

How does this connect to endometriosis? LXR is a known anti-inflammatory transcription factor that suppresses NF-κB signalling and reduces prostaglandin production in macrophages and stromal cells. The peritoneal fluid of women with endometriosis is a highly pro-inflammatory environment rich in activated macrophages, elevated prostaglandin E2 (PGE2), and altered lipid mediator profiles. A TTC39B variant that modulates LXR protein stability would alter the balance between pro-inflammatory and pro-resolution lipid signalling in precisely those peritoneal macrophages that are thought to facilitate endometriotic lesion survival, vascularisation, and immune evasion. The intronic rs519664 variant does not itself change the TTC39B protein, but a nearby region has been identified as a putative regulatory element with physical interactions with the TTC39B promoter — suggesting the T allele alters TTC39B expression rather than function.

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 TTC39B locus was subsequently replicated in the large-scale meta-analysis by Sapkota et al. 2017⁴⁴ Sapkota et al. 2017
Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun. 2017 (17,045 cases, 191,596 controls), which confirmed 19 independent endometriosis SNPs together explaining ~5% of disease variance. The biological mechanism underpinning the TTC39B locus was established by Tarling et al. 2016⁵⁵ Tarling et al. 2016
TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis. Nature. 2016, which showed that TTC39B is an obligate co-factor for LXR ubiquitination: mice deficient in TTC39B had markedly elevated HDL-C and reduced atherosclerosis, all attributable to LXR protein stabilisation. The most recent large-scale endometriosis GWAS by Rahmioglu et al. 2023⁶⁶ 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.

The LXR-lipid connection also has a practical implication: peritoneal macrophage inflammatory tone and prostaglandin-driven pain are known targets of omega-3 fatty acid supplementation (EPA/DHA), which promotes pro-resolution lipid mediator production. While no endometriosis trial has stratified results by TTC39B genotype, omega-3 supplementation has a plausible mechanistic rationale for T carriers through the same LXR-mediated inflammatory pathway.

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 — the same pathway TTC39B-LXR axis may modulate.