rs10766383 — NUCB2

Intronic NUCB2 variant associated with type 2 diabetes risk in females and oral cancer progression in older males — the T allele modestly reduces nesfatin-1 signaling efficiency across metabolic and oncological contexts

See your personal result for NUCB2

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

NUCB2 rs10766383 — An Intronic Nesfatin-1 Variant With Metabolic and Oncological Associations

Nucleobindin-2 (NUCB2) on chromosome 11p15.1 encodes the precursor protein for nesfatin-111 nesfatin-1
An 82-amino acid neuropeptide cleaved from NUCB2 that suppresses appetite and modulates insulin secretion via melanocortin MC3/MC4 receptors and CRF2 — functions leptin-independently, so it retains activity even in obesity where leptin resistance has developed, a neuropeptide governing appetite, glucose regulation, blood pressure, and sleep-wake cycling. The rs10766383 variant sits deep within an intron of NUCB2 (GRCh38 chr11:17308251), close to other studied NUCB2 intronic and coding variants — rs1330 and rs214101 — that have been linked to overlapping metabolic and oncological phenotypes. Like its neighbours, rs10766383 does not alter the nesfatin-1 amino acid sequence; its effects are thought to be regulatory, influencing NUCB2 transcript levels, splicing efficiency, or local chromatin accessibility.

The T allele is the minor allele globally (~25%) but reaches ~50% frequency in East Asian populations, explaining why its T2DM association was first detected in a Chinese Han cohort. The G allele is the GRCh38 reference and represents the common, wild-type NUCB2 expression state. This is a straightforward CLEAN pattern: GG carries the lowest genetic risk at this locus.

The Mechanism

As a deep intron variant, rs10766383 does not produce a protein-level change. Its regulatory mechanism is inferred from population-level associations and from what is known about how NUCB2 intronic variants affect gene expression. Possibilities include altered binding of transcription factors or RNA-binding proteins within an intronic regulatory element, changes in alternative splicing efficiency across NUCB2's multiple transcript isoforms, or effects on local histone modification patterns that alter promoter accessibility. Any of these would reduce the amount of NUCB2 protein available for proteolytic processing into nesfatin-1.

Reduced circulating nesfatin-1 is a consistent finding in obesity, insulin-resistant states, and several cancers — suggesting that an intronic variant that lowers NUCB2 expression could compound both metabolic and oncological vulnerability through a single mechanism of nesfatin-1 insufficiency. The sex-specific pattern of T2DM association (significant only in females in the Li 2020 cohort) mirrors the pattern seen at rs1330 in the same study and likely reflects estrogen-dependent modulation of NUCB2 transcription in hypothalamic and pancreatic circuits.

The Evidence

Type 2 diabetes. Li et al. (2020)22 Li et al. (2020)
Li XS et al. NUCB2 polymorphisms are associated with an increased risk for type 2 diabetes in the Chinese population. Endocr Connect, 2020 genotyped 578 T2DM patients against 1,609 healthy controls in a Chinese Han population. rs10766383 was one of four NUCB2 SNPs significantly associated with T2DM overall (T allele OR 1.29, 95% CI 1.12–1.47, P=0.0003). In sex-stratified analysis, the association was statistically significant only in females (OR 1.32, 95% CI 1.03–1.68, P=0.027) and did not reach significance in males (P=0.096). The T allele frequency in cases was 47.8% vs 41.6% in controls. No significant BMI association was detected at this specific locus, unlike rs1330 which did show BMI effects.

Oral cancer progression. Yu et al. (2026)33 Yu et al. (2026)
Yu CC et al. Association of NUCB2 genetic variants with the clinicopathological features of oral cancer. 2026 examined four NUCB2 SNPs in 1,161 Taiwanese male oral cancer patients and 1,186 healthy controls. rs10766383 TG/GG genotypes (T as the analyzed allele here) were not associated with overall oral cancer susceptibility after lifestyle-factor adjustment. However, in patients aged ≥60 years, carrying TG or GG genotypes (at least one T allele) was associated with significantly higher risk of advanced-stage (III/IV) disease (OR 1.748, 95% CI 1.160–2.632) and lymph node metastasis (OR 1.963, 95% CI 1.207–3.194). The pattern was consistent with the other three NUCB2 SNPs studied, all showing associations with progression rather than susceptibility — supporting the hypothesis that reduced nesfatin-1 activity impairs anti-tumor immune surveillance or directly promotes tumor invasiveness in older patients.

Nesfatin-1 and cancer biology. A 2021 review by Kmiecik et al.44 Kmiecik et al.
Kmiecik AM et al. Nucleobindin-2/Nesfatin-1-A New Cancer Related Molecule? Int J Mol Sci, 2021 synthesized evidence that nesfatin-1 exhibits anti-proliferative and pro-apoptotic effects in colorectal, hepatocellular, and other cancer cell lines. Reduced serum nesfatin-1 has been documented in multiple cancer contexts, suggesting a tumor-suppressive function that nesfatin-1 deficiency (from either obesity or genetic factors reducing NUCB2 expression) may undermine.

Sleep biology. rs10766383 has not been studied directly in sleep research, but NUCB2/nesfatin-1 has an established role in sleep-wake regulation. Vas et al. (2013, PLoS One)55 Vas et al. (2013, PLoS One)
Vas S et al. Nesfatin-1/NUCB2 as a potential new element of sleep regulation in rats. PLoS One, 2013 showed that central nesfatin-1 reduces REM sleep and increases wakefulness in rats, and that hypothalamic NUCB2 expression rebounds during sleep recovery after deprivation. Intronic variants reducing NUCB2 output may therefore affect sleep architecture at the population level, though direct human data at rs10766383 are lacking.

Practical Implications

The T2DM association is female-specific and of moderate effect size (OR ~1.3). The most actionable implication is metabolic monitoring in female T carriers — fasting glucose and insulin resistance markers are the appropriate early warning signals. For the oral cancer finding, the association applies to older patients already diagnosed (progression risk), not susceptibility, so oncological surveillance context is the practical frame for GT/TT carriers, particularly males over 60.

Interactions

rs10766383 was studied alongside rs1330, rs214101, and rs757081 in both the Li 2020 T2DM and Yu 2026 oral cancer papers. All four NUCB2 variants showed broadly consistent directions of effect — T2DM risk (Li 2020) and oral cancer progression risk (Yu 2026) — suggesting they may act as a haplotype or collectively reduce NUCB2/nesfatin-1 output through complementary regulatory and protein-level mechanisms. Individuals carrying risk alleles at multiple NUCB2 loci may experience compounded nesfatin-1 insufficiency beyond what any single variant predicts.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal

Two copies of the reference G allele — standard NUCB2 expression, no added metabolic or oncological risk from this intronic locus

You carry two copies of the GRCh38 reference G allele at rs10766383. This is the most common genotype globally, found in approximately 56% of people based on 1000 Genomes data. The GG genotype is the comparison group in published T2DM and oral cancer studies, and does not carry the T allele associations with diabetes risk or oral cancer progression.

Your NUCB2 nesfatin-1 system is not under additional genetic pressure from this intronic locus. In East Asian populations the T allele is more common (~50% frequency), so the GG genotype is less common there (~25%) — population context matters when interpreting this result.

GT Intermediate

One T allele — intermediate nesfatin-1 expression state with modest T2DM risk in females and intermediate oral cancer progression association

The sex-specific T2DM pattern at rs10766383 mirrors the rs1330 finding from the same paper (Li 2020): both NUCB2 intronic variants showed diabetes risk predominantly in females. Estrogen modulates hypothalamic NUCB2 expression, potentially redirecting the T allele's regulatory impact toward insulin sensitivity in women while sparing males at the metabolic level.

In the Yu 2026 oral cancer cohort (Taiwanese males), carriers of at least one T allele showed elevated risk of late-stage disease and lymph node metastasis in patients ≥60 years (OR ~1.75 and ~1.96 respectively). These are progression associations, not susceptibility — they apply to cancer patients rather than predicting cancer development. For general-population interpretation, the key implication is metabolic monitoring in female GT carriers and cancer staging awareness in older male patients.

TT High Risk

Two copies of the T allele — strongest association with T2DM risk in females and oral cancer progression in older males; reflects the greatest potential impairment of NUCB2/nesfatin-1 output at this intronic locus

The TT genotype at rs10766383 has been studied in two independent cohorts. In Li 2020 (578 T2DM cases, 1,609 controls, Chinese Han), TT homozygotes represented 23.4% of T2DM cases versus 16.7% of controls — a distribution consistent with the overall T allele OR of 1.29. The sex-stratified signal was significant only in females, suggesting that the same hormonal modulation that shapes rs1330's sex-specific pattern also applies here.

In Yu 2026 (1,161 oral cancer patients, Taiwanese males), TG/GG genotypes (at least one T allele) were grouped together for the progression analysis. TT homozygotes fall within the highest-risk group for oral cancer stage and metastasis in older patients, though the study did not separately report TT-only odds ratios for this locus.

Multiple NUCB2 variants (rs1330, rs214101, rs757081, rs10766383) have shown concordant directions of effect in both published cohorts — metabolic and oncological risk consistently increases with T allele burden. Carrying TT at rs10766383 alongside risk alleles at other NUCB2 loci may compound nesfatin-1 insufficiency through additive regulatory and protein-level mechanisms.