rs11172113 — LRP1

Intronic enhancer variant in LRP1 that regulates receptor expression in brain and vasculature, linking migraine susceptibility to central leptin signaling and metabolic regulation

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The Migraine-Metabolism Gateway: How LRP1 Connects Your Brain to Your Waistline

LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) is a giant scavenger receptor expressed throughout the body but especially important in the brain and blood vessels. While it was originally studied for its role in clearing lipoproteins from the bloodstream, research over the past decade has revealed that LRP1 serves as a critical hub connecting leptin signaling11 leptin signaling
Leptin is the "satiety hormone" produced by fat cells that tells the brain to stop eating, glutamate neurotransmission, and vascular integrity. The variant rs11172113 sits in an intronic enhancer region that controls how much LRP1 protein your cells produce.

The Mechanism

The rs11172113 variant lies within intron 1 of LRP1 at an enhancer element that regulates gene expression. The C allele creates a binding site for the transcriptional repressor SNAIL22 transcriptional repressor SNAIL
SNAIL (encoded by SNAI1) is a zinc-finger transcription factor that silences gene expression by binding to E-box-like sequences, which reduces LRP1 expression. The T allele does not bind SNAIL and allows higher LRP1 expression. This allele-specific repression has been confirmed experimentally: SNAIL knockdown in C/C cells significantly increases LRP1 levels, while having no effect in T/T cells.

In the brain, LRP1 directly binds both leptin and the leptin receptor complex33 leptin and the leptin receptor complex
Liu et al. showed LRP1 is required for leptin receptor phosphorylation and downstream STAT3 activation in hypothalamic neurons. When neuronal LRP1 is deleted in mice, the result is obesity driven by increased food intake and decreased energy expenditure — essentially a state of leptin resistance. Even targeted deletion of LRP1 specifically in the hypothalamus is sufficient to trigger accelerated weight gain. This means reduced LRP1 expression (as occurs with the C allele) could weaken the brain's ability to respond to leptin's satiety signals.

LRP1 also modulates NMDA receptor trafficking44 NMDA receptor trafficking
LRP1 controls the surface distribution and internalization of the NR2B subunit of NMDA receptors, which are glutamate-gated ion channels involved in pain and migraine pathophysiology at neuronal synapses. Altered NMDA receptor dynamics may contribute to the cortical hyperexcitability that underlies migraine with aura.

The Evidence

The original GWAS discovery55 original GWAS discovery
Chasman et al. Genome-wide Association Study Reveals Three Susceptibility Loci for Common Migraine in the General Population. Nat Genet, 2011 identified rs11172113 in a study of 5,122 migraineurs and 18,108 controls, with the T allele conferring protection (OR 0.90, 95% CI 0.87-0.93, p = 4.3 x 10-9). This has been replicated in European populations66 replicated in European populations
Esserlind et al. Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine. Eur J Neurol, 2013 and confirmed as the likely causal variant with posterior probability of 1.0 in fine-mapping studies.

A landmark mouse study77 mouse study
Liu et al. Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system. PLoS Biol, 2011 demonstrated that brain-specific LRP1 knockout mice develop obesity with impaired hypothalamic STAT3 phosphorylation — the key downstream step in leptin signaling. LRP1 overexpression rescued the phenotype, confirming a causal role.

The most mechanistically detailed work came from Liu et al. 202488 Liu et al. 2024
LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases. Circ Res, 2024, which used iPSC-derived smooth muscle cells to show that rs11172113 lies in an enhancer region and that the C allele permits SNAIL-mediated repression of LRP1. This variant was identified as the causal SNP for multiple traits: migraine, fibromuscular dysplasia (OR 1.34, p = 2 x 10-10), pulse pressure, and spontaneous coronary artery dissection.

The effect size for migraine is modest (OR ~1.11 per C allele), consistent with a common regulatory variant contributing to a complex trait. However, the convergence of GWAS evidence across multiple vascular and neurological phenotypes, combined with robust functional characterization, places this variant on solid mechanistic ground.

Practical Actions

Carriers of the C allele have reduced LRP1 expression, which may impair central leptin signaling and increase migraine susceptibility. Magnesium supplementation is well-established for migraine prevention and also modulates NMDA receptor activity — the same pathway influenced by LRP1. Riboflavin (vitamin B2) at 400 mg/day has strong evidence for migraine prophylaxis and supports mitochondrial function in neurons. Omega-3 fatty acids reduce neuroinflammation and support vascular health, both relevant to the LRP1 pathway.

Monitoring leptin and metabolic markers is relevant because reduced LRP1 function in the brain may contribute to leptin resistance even in the absence of frank obesity.

Interactions

LRP1's role in leptin signaling creates a potential interaction with variants in the leptin pathway. Carriers of rs11172113 CC who also carry the LEPR rs1137101 GG (reduced leptin receptor sensitivity) may experience compounded leptin resistance — both the receptor itself and the LRP1 co-receptor that facilitates its signaling are impaired. Similarly, LEP rs7799039 AA carriers (elevated leptin production) with reduced LRP1 expression may develop more pronounced leptin resistance, as the brain's capacity to transduce the leptin signal is diminished despite high circulating levels.

The FTO rs9939609 AA genotype (increased appetite drive) may compound with reduced LRP1 signaling to further weaken central satiety regulation, though this interaction has not been directly studied in humans.

Nutrient Interactions

magnesium increased_need
riboflavin increased_need
omega-3 fatty acids increased_need

Genotype Interpretations

What each possible genotype means for this variant.

TT Full LRP1 Expression Normal

Protective genotype with full LRP1 expression — no increased migraine or metabolic risk from this variant

You carry two copies of the T allele, which allows full LRP1 expression without SNAIL-mediated repression. About 36% of people globally share this genotype (higher in East Asian populations at ~62%, lower in African populations at ~32%).

Your LRP1 receptor functions at full capacity in the brain and vasculature. This means normal leptin signaling through the LRP1 co-receptor pathway, normal NMDA receptor trafficking at synapses, and no increased risk of migraine or vascular conditions from this particular locus.

CT Intermediate LRP1 Expression Intermediate

One C allele partially reduces LRP1 expression, modestly increasing migraine susceptibility

The CT genotype produces an intermediate level of LRP1 expression. The T allele drives normal expression from one chromosome, while the C allele on the other chromosome is subject to SNAIL-mediated repression. The net effect is a modest reduction in total LRP1 protein levels.

In the Chasman et al. 2011 GWAS, the per-allele OR was 0.90 for the protective T allele, translating to approximately 11% increased migraine risk per C allele. For heterozygotes, this represents a single-allele effect — present but modest. The vascular associations (fibromuscular dysplasia, pulse pressure) follow the same additive pattern, with intermediate risk for CT carriers.

CC Reduced LRP1 Expression Reduced

Two C alleles reduce LRP1 expression, increasing migraine susceptibility and potentially impairing central leptin signaling

The CC genotype at rs11172113 permits maximal SNAIL-mediated repression of LRP1 expression. In iPSC-derived smooth muscle cells, the C allele creates a SNAIL binding site in the intronic enhancer that reduces LRP1 transcription. This was demonstrated experimentally by Liu et al. (2024): SNAIL knockdown in C/C cells significantly increased LRP1 levels, while having no effect in T/T cells.

Mouse studies have shown that brain-specific LRP1 deletion causes obesity through impaired leptin receptor phosphorylation and reduced hypothalamic STAT3 activation. LRP1 directly binds both leptin and its receptor, serving as an essential component of the signaling complex. While the human variant produces reduced (not absent) expression, the direction of effect is consistent with weakened central leptin responsiveness.

The migraine association has been replicated across multiple GWAS with a combined OR of approximately 1.11 per C allele (1.23 for CC vs TT). Fine-mapping and colocalization analyses identify rs11172113 as the causal variant with near-certainty (posterior probability 1.0).