rs1111875 — HHEX HHEX/IDE locus T2D risk variant

HHEX/IDE — The Primary T2D Locus Tag SNP

Among the first genes implicated in type 2 diabetes by genome-wide association studies, the HHEX/IDE locus¹¹ HHEX/IDE locus
Hematopoietically Expressed Homeobox / Insulin- Degrading Enzyme — two neighboring genes on chromosome 10q23 with distinct roles in beta-cell biology has been replicated across dozens of populations and hundreds of thousands of participants. The SNP rs1111875 is the primary tag marker for this locus — in complete linkage disequilibrium (r²=1) with rs5015480 — and serves as the alternative genotyped position for this signal on consumer chips and whole-genome sequencing platforms that capture rs1111875 but not rs5015480.

The Mechanism

HHEX encodes a homeodomain transcription factor expressed in the liver, thyroid, and — critically — the developing pancreas. During embryogenesis, HHEX is required for proper formation of the ventral pancreatic bud; animal knockout models lacking HHEX fail to form a normal pancreas and show severe deficits in insulin-producing beta-cell mass. In adult beta cells, HHEX continues to regulate genes governing beta-cell identity and insulin gene expression programs.

The C allele at rs1111875 is associated with reduced HHEX expression in pancreatic tissue. The consequence is a diminished beta-cell secretory capacity and, specifically, a blunted first-phase insulin response²² first-phase insulin response
The rapid insulin burst in the first 10 minutes after a glucose load — this pulse is critical for suppressing post-meal blood glucose and is characteristically impaired in pre-diabetes and early T2D. The nearby IDE gene encodes insulin-degrading enzyme, which degrades secreted insulin and may further modulate circulating insulin levels, though whether HHEX or IDE is the primary causal gene at this locus remains under investigation.

The Evidence

rs1111875 has been studied as the lead marker for the HHEX/IDE locus across multiple independent GWAS and replication cohorts since 2007.

The landmark Sladek et al. 2007 Nature GWAS³³ Sladek et al. 2007 Nature GWAS
Sladek R et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature, 2007 identified the IDE-KIF11-HHEX region as one of four novel T2D risk loci in a French case-control cohort of 392,935 SNPs. The Scott et al. 2007 FUSION study⁴⁴ Scott et al. 2007 FUSION study
Scott LJ et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science, 2007 confirmed HHEX among validated T2D susceptibility loci with a per-C-allele OR of ~1.13 (p = 5.7 × 10⁻¹⁰) in combined European cohorts.

The Grarup et al. 2007 Danish cohort⁵⁵ Grarup et al. 2007 Danish cohort
Grarup N et al. Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects. Diabetes, 2007 provided direct functional evidence: the C allele was strongly associated with lower acute insulin response during an oral glucose tolerance test and with decreased insulin release after intravenous tolbutamide injection in young healthy subjects, implicating impaired beta-cell function specifically.

A meta-analysis by Wang et al. 2011⁶⁶ meta-analysis by Wang et al. 2011
Wang Y et al. Quantitative assessment of the influence of hematopoietically expressed homeobox variant (rs1111875) on type 2 diabetes risk. Mol Genet Metab, 2011 pooled 26 studies encompassing 110,875 subjects and confirmed the per-C-allele OR of 1.16 (95% CI 1.13–1.20). A larger Li et al. 2012 PLoS One meta-analysis⁷⁷ Li et al. 2012 PLoS One meta-analysis
Li X et al. Hematopoietically-expressed homeobox gene three widely-evaluated polymorphisms and risk for diabetes: a meta-analysis. PLoS One, 2012 extended this to 49 studies (57,931 cases, 74,658 controls), yielding an identical per-allele OR of 1.16. Both meta-analyses document significant ethnic heterogeneity — the C allele runs at ~58% in Europeans but only ~18% in East Asian populations, where the TT protective genotype predominates (~68% frequency).

Practical Implications

The HHEX/IDE locus impairs T2D risk through the insulin secretion axis — specifically reduced beta-cell mass and blunted first-phase insulin output — rather than the insulin resistance axis. This has direct dietary implications: beta cells with reduced secretory capacity are less able to handle large, rapid glucose loads. Spreading carbohydrate intake across meals, choosing lower-glycemic-index foods, and pairing carbohydrates with protein and fat all directly reduce the demand on first-phase insulin secretion.

Periodic metabolic monitoring (fasting glucose, HbA1c) is particularly valuable for this genotype because the first-phase secretory impairment is precisely what blunts early post-meal glucose suppression and progressively loads beta-cell reserve over decades.

Interactions

rs1111875 is in complete LD (r²=1) with rs5015480 — both tag the same functional signal at the HHEX/IDE locus. Carrying risk alleles at both this locus (impaired secretion) and at TCF7L2 rs7903146 (impaired Wnt-mediated beta-cell function) compounds T2D risk through converging but mechanistically independent pathways. Similarly, co-inheritance with SLC30A8 rs13266634 (zinc transporter affecting insulin granule crystallization) further loads the insulin secretion pathway. Individuals with risk alleles at multiple secretion-pathway loci should prioritize metabolic monitoring and glycemic-load management.