rs1054564 — GDF15 GDF15 3'UTR rs1054564

3'UTR variant that controls GDF15 expression via microRNA regulation — C allele raises baseline GDF15 (metabolic and atherosclerosis risk); G allele lowers it (increased pregnancy nausea sensitivity)

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GDF15 rs1054564 — The MicroRNA Switch That Sets Your Pregnancy Nausea Threshold

Growth Differentiation Factor 15 (GDF15) is perhaps the most dramatic hormone you've never heard of. Outside pregnancy its circulating levels sit quietly in the low hundreds of picograms per millilitre. During the first trimester, largely driven by the feto-placental unit, they surge 10- to 100-fold11 10- to 100-fold
Plasma GDF15 rises from roughly 200–600 pg/mL outside pregnancy to 10,000–100,000 pg/mL in the first trimester; the highest levels are reached around 7–12 weeks. This hormone acts on GFRAL receptors22 GFRAL receptors
Glial cell-derived neurotrophic factor family receptor alpha-like — expressed almost exclusively in the area postrema and nucleus tractus solitarius of the hindbrain; the brain's primary nausea and vomiting control centre in the brainstem, triggering nausea, food aversion, and vomiting. Your rs1054564 genotype determines how much GDF15 you make outside pregnancy — and that baseline sets your sensitivity when the first-trimester surge arrives.

The Mechanism

The rs1054564 variant sits in the 3' untranslated region (3'UTR) of GDF15, a stretch of mRNA that does not encode protein but governs how much of the mRNA is translated. The G allele (carried by ~89% of people globally) maintains the canonical stem-loop secondary structure at this position, allowing hsa-miR-1233-3p33 hsa-miR-1233-3p
A microRNA that binds the GDF15 3'UTR and suppresses translation; miR-1233-3p is expressed in a range of tissues including adipose, liver, and cardiovascular tissue to bind efficiently and suppress GDF15 translation.

The C allele disrupts the stem-loop structure, reducing miR-1233-3p binding affinity and partially abolishing translational suppression44 partially abolishing translational suppression
Reporter assay in HEK293T cells showed significantly higher luciferase activity for the C-allele construct vs G-allele (P=0.034); western blot confirmed reduced endogenous GDF15 protein when miR-1233-3p mimics were transfected into G-allele-bearing cells. The result: C-allele carriers have measurably higher circulating GDF15 at baseline, across all physiological states, throughout their lives.

The Evidence

Metabolic and cardiovascular effects: In a cohort of metabolic disease patients, Guardiola et al. 202455 Guardiola et al. 2024
Guardiola M et al., "The GDF15 3' UTR Polymorphism rs1054564 Is Associated with Diabetes and Subclinical Atherosclerosis." Int J Mol Sci, 2024 found that rs1054564 variant carriers (C-allele) had significantly higher serum GDF15 levels, higher prevalence of diabetes, and higher frequency of subclinical carotid atherosclerosis compared to GG homozygotes, independently of standard confounders. The direction is consistent with the molecular mechanism: more GDF15 → more of the hormone's downstream cardiometabolic stress signalling.

Ho et al. 201266 Ho et al. 2012
Ho JE et al., "Clinical and Genetic Correlates of GDF15 in the Community." Clinical Chemistry, 2012 analysed 2,991 participants in the Framingham Offspring Study and identified rs1054564 as one of two independent cis-expression quantitative trait loci (eQTL) at the GDF15 locus — meaning the variant directly influences how much GDF15 mRNA is made or translated in blood cells, with genome-wide-significant associations (P = 2.74 × 10⁻³²) at the combined locus signal.

Pregnancy nausea and hyperemesis gravidarum: The connection runs in the opposite direction for GG homozygotes. The landmark Fejzo et al. 2024 Nature paper77 Fejzo et al. 2024 Nature paper
Fejzo M et al., "GDF15 linked to maternal risk of nausea and vomiting during pregnancy." Nature, 2024; 625(7996):760-767 established that women with lower pre-pregnancy GDF15 levels face higher risk of hyperemesis gravidarum (HG). The proposed mechanism is a desensitisation model: women chronically exposed to higher baseline GDF15 (C-allele carriers, and notably patients with β-thalassemia, who have constitutively elevated GDF15) build tolerance to the hormone's emetic effects, such that the first-trimester surge causes less nausea. Women with lower baseline GDF15 (G-allele homozygotes) have not pre-sensitised their brainstem GFRAL receptors and react more severely to the same fetal GDF15 surge.

Consistent with this model, genetic variants that lower circulating GDF15 were specifically enriched in women with recurrent HG in family studies Fejzo et al. 2018 Nat Commun88 Fejzo et al. 2018 Nat Commun
Fejzo MS et al., "Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum." Nature Communications, 2018, and a Mendelian randomisation analysis in the 2024 Nature paper further supported that lower baseline GDF15 is causally linked to HG, not merely correlated with it.

Practical Actions

The rs1054564 genotype informs two distinct clinical contexts depending on biological sex and reproductive status:

For women planning pregnancy, the GG genotype identifies a group with lower baseline GDF15 and therefore higher susceptibility to severe pregnancy nausea. This is actionable before conception: pre-pregnancy interventions that raise GDF15 levels (metformin has been shown to increase GDF15, and a 2025 study found pre-pregnancy metformin use was associated with 70–82% reduced HG risk) may be relevant for women with GG and prior HG history, though this remains to be confirmed in prospective trials specifically targeting rs1054564.

For C-allele carriers, the higher baseline GDF15 reduces pregnancy nausea susceptibility but introduces a different consideration: chronically elevated GDF15 is a biomarker of metabolic stress, and the variant independently increases diabetes and subclinical atherosclerosis risk. Fasting glucose and carotid ultrasound are the specific screening tools that correspond to this genotype's risk profile.

Interactions

rs45543339 and rs1054221 (GDF15, same gene): These are the two common GDF15 haplotype-tagging variants identified in the Fejzo 2024 GWAS of hyperemesis gravidarum. They likely tag partially overlapping haplotypes with rs1054564. The combined effect of carrying low-expression variants at multiple GDF15 regulatory positions has not been formally analysed but would be expected to compound the reduction in baseline GDF15.

rs888663 (GDF15 promoter): rs888663 is the primary cis-eQTL signal at the GDF15 locus identified in the Ho 2012 Framingham study — a stronger signal than rs1054564, which is a secondary independent signal at the same locus. The two variants likely have independent but additive effects on GDF15 expression through different regulatory mechanisms (promoter activity vs 3'UTR translation).

Genotype Interpretations

What each possible genotype means for this variant.

GG Low GDF15 Expression Normal

Common genotype — lower baseline GDF15, standard pre-pregnancy nausea susceptibility

The G allele at rs1054564 maintains the canonical stem-loop secondary structure in the GDF15 3'UTR, enabling efficient miR-1233-3p binding and translational suppression. GG homozygotes have the lowest baseline GDF15 among the three genotypes at this locus.

The clinical relevance for pregnancy is supported by the desensitisation model established in Fejzo et al. (Nature, 2024): patients with constitutively elevated GDF15 (β-thalassemia) rarely experience pregnancy nausea; women with lower pre-pregnancy GDF15 are over-represented among hyperemesis gravidarum (HG) cases. This is a dose-response relationship — the lower the baseline GDF15, the larger the relative fold-change during early pregnancy, and the less prior GFRAL receptor desensitisation the brainstem has developed.

GG homozygotes are not guaranteed to develop HG (the overall HG prevalence is 0.3–2%), but this genotype does represent the higher-susceptibility end of the genetic spectrum at this locus. For women with a personal or family history of severe pregnancy nausea, the GG genotype reinforces the biological plausibility of that experience.

Outside pregnancy, the GG genotype does not carry the elevated metabolic risk associated with C-allele carriers, which is the one distinct advantage of lower-expression GDF15 variants from a cardiometabolic perspective.

CG Intermediate GDF15 Expression Intermediate

One C allele — intermediate GDF15 levels, modestly reduced pregnancy nausea susceptibility

Heterozygotes sit at an intermediate position between the lower-GDF15 (GG) and higher-GDF15 (CC) extremes. The cis-eQTL data from Ho et al. (2012) and the clinical data from Guardiola et al. (2024) show additive effects across genotypes at this locus, consistent with codominant inheritance.

The dual phenotype at this locus — lower GDF15 = more HG risk, higher GDF15 = more metabolic risk — means CG heterozygotes occupy a middle ground with neither the most favourable nor least favourable outcome at either end. Population-level data do not show a clinically significant risk elevation specifically for CG heterozygotes at either the metabolic or pregnancy-nausea endpoint; the most robust associations are with CC homozygotes for metabolic outcomes and GG homozygotes for HG susceptibility.

CC High GDF15 Expression High

Two C alleles — highest baseline GDF15, lowest pregnancy nausea susceptibility, elevated metabolic risk

CC homozygosity at rs1054564 produces the highest constitutive GDF15 expression through complete loss of miR-1233-3p-mediated translational repression on both chromosomes. In Guardiola et al. (2024), CC and CG carriers combined showed significantly higher serum GDF15 levels and higher rates of diabetes and carotid plaque compared to GG homozygotes.

Chronically elevated GDF15 reflects — and may contribute to — metabolic stress. GDF15 is upregulated by mitochondrial dysfunction, ER stress, inflammation, and oxidative damage. Whether constitutively elevated GDF15 from a genetic baseline variant represents the same biological state as GDF15 elevation driven by active disease is an open question; the Guardiola 2024 data suggest it does carry independent metabolic risk even in a patient cohort adjusted for known confounders.

The cardiovascular finding (higher carotid plaque frequency) is consistent with GDF15's known associations with cardiovascular stress markers in the community (Framingham Offspring Study, Ho 2012), where GDF15 was positively correlated with age, diabetes, and reduced kidney function.

For women: the pregnancy-protective effect (high baseline GDF15 → GFRAL desensitisation → reduced first-trimester nausea) is a genuine biological advantage for this genotype in the reproductive context. This mirrors the observation in clinical GDF15 biology that β-thalassemia patients, who have among the highest circulating GDF15 values, very rarely experience pregnancy nausea.