rs2241423 — MAP2K5

MAP2K5 — The Adipogenesis Brake That Controls Fat Cell Formation

MAP2K5 (Mitogen-Activated Protein Kinase Kinase 5, also known as MEK5) encodes a critical signaling kinase in the MAPK signaling cascade¹¹ MAPK signaling cascade
A chain of proteins that relays signals from cell surface receptors to the nucleus, controlling cell growth, differentiation, and survival. MEK5 is the sole known activator of ERK5²² ERK5
Extracellular signal-regulated kinase 5, the terminal kinase in this pathway that directly controls gene expression programs for adipocyte differentiation, making this pathway a key gatekeeper of fat cell formation.

The rs2241423 variant sits within the last intron of MAP2K5 on chromosome 15 and was identified in one of the largest BMI GWAS meta-analyses ever conducted.

The Mechanism

The MEK5-ERK5 pathway acts as a brake on adipogenesis³³ adipogenesis
The process by which precursor cells differentiate into mature fat-storing adipocytes. When MEK5 is active, it phosphorylates ERK5, which in turn suppresses the adipogenic transcription program via the PKA signaling axis⁴⁴ PKA signaling axis
Protein kinase A pathway, which interacts with ERK5 to modulate the balance between fat cell formation and maintenance of the precursor state.

Fine-mapping studies have identified rs7175517 (in near-perfect linkage disequilibrium with rs2241423, r² = 0.99) as the likely causal variant⁵⁵ causal variant
Lu et al. showed through dual-luciferase assays and electrophoretic mobility shift assays that the G allele at rs7175517 binds more RNA splicing regulators, reducing MAP2K5 mRNA expression. The G allele binds more spliceosomes, reducing MAP2K5 expression. Less MEK5 protein means less ERK5 activation, which releases the brake on adipogenesis — resulting in more fat cell formation.

Additionally, miR-143⁶⁶ miR-143
A microRNA that independently suppresses MAP2K5 expression targets MAP2K5 mRNA to promote adipocyte differentiation, establishing the MEK5-ERK5 axis as a convergent regulatory node for fat cell biology.

The Evidence

The Speliotes et al. 2010 GWAS⁷⁷ Speliotes et al. 2010 GWAS
Speliotes et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet, 2010 identified the MAP2K5-LBXCOR1 locus among 18 new BMI-associated regions in a meta-analysis of 249,796 individuals — the largest BMI GWAS at the time. The signal confirmed 14 previously known obesity loci and newly implicated MAP2K5 in body weight regulation.

A replication study in children⁸⁸ replication study in children
Rask-Andersen et al. The MAP2K5-linked SNP rs2241423 is associated with BMI and obesity in two cohorts of Swedish and Greek children. BMC Med Genet, 2012 confirmed the association in two independent European pediatric cohorts. The A (minor) allele showed a protective effect against obesity in Swedish children (OR 0.79, P = 0.029) and was associated with lower BMI z-scores in Greek children (P = 0.028). Notably, the effect appears stronger in children than adults, suggesting MAP2K5 may be particularly important during developmental adipogenesis.

A fine-mapping study⁹⁹ fine-mapping study
Lu et al. Fine mapping of the MAP2K5 region identified rs7175517 as a causal variant related to BMI in China and the United Kingdom populations. Front Genet, 2022 using UK Biobank and Chinese cohort data identified the molecular mechanism: the G allele at the causal SNP reduces MAP2K5 expression by altering spliceosome binding, leading to reduced MEK5 protein and enhanced adipogenesis. The effect was consistent across European and East Asian populations.

Practical Actions

Since MAP2K5 affects adipogenesis — the formation of new fat cells — rather than the size of existing ones, interventions that modulate fat cell formation pathways are more relevant than simple calorie restriction. Once formed, fat cells persist for years and are difficult to eliminate. This makes prevention of excessive adipogenesis during critical periods (childhood, puberty, periods of weight gain) particularly important.

Interactions

MAP2K5 sits in the adipogenesis pathway that was highlighted by the Shungin et al. 2015 GWAS as a key process in fat distribution. The MEK5-ERK5 axis intersects with PPARG signaling (rs1801282), since PPARG is the master transcription factor driving terminal adipocyte differentiation. Carriers of risk alleles at both MAP2K5 (enhanced adipogenesis) and PPARG (altered adipocyte maturation) may have compounded effects on fat cell biology.