rs6981587 — ANK1 ANK1 small-ankyrin T2D locus variant

ANK1 rs6981587: Skeletal Muscle Ankyrin, Adipose Expression, and Impaired Insulin Processing

The ANK1 gene encodes ankyrin-1, a cytoskeletal scaffold protein best known for its structural role in red blood cells, where it links membrane proteins to the spectrin cytoskeleton. A second, muscle-specific transcript produces a short isoform called small ankyrin-1 (sAnk1)¹¹ small ankyrin-1 (sAnk1)
sAnk1.5 is a 17-kDa isoform expressed in skeletal muscle sarcoplasmic reticulum; it stabilises the titin filament network and organises the longitudinal sarcoplasmic reticulum. rs6981587 lies within an intronic region of ANK1 on chromosome 8, within a cluster of variants — including rs516946 and rs508419 — that together constitute one of the replicated type 2 diabetes and impaired insulin secretion loci in genome-wide association studies.

The Mechanism

The mechanism at this locus operates through at least two distinct routes. First, a nearby promoter variant (rs508419) increases sAnk1 transcriptional activity in skeletal muscle C2C12 cells²² a nearby promoter variant (rs508419) increases sAnk1 transcriptional activity in skeletal muscle C2C12 cells
Yan et al. 2016: the C allele of rs508419 showed increased luciferase reporter activity and altered DNA-protein binding; human muscle tissue carrying the CCC haplotype showed elevated sAnk1 mRNA. In cells with excess sAnk1 expression, insulin-stimulated glucose uptake is measurably reduced, suggesting that elevated sAnk1 disrupts normal GLUT4³³ GLUT4
Glucose transporter type 4 — the primary insulin-responsive glucose transporter in skeletal muscle; its translocation to the plasma membrane is the key step in insulin-stimulated glucose disposal trafficking or signalling downstream of the insulin receptor.

Second, and perhaps more mechanistically central, genome-wide colocalization analysis identified an adipose ANK1 eQTL at this locus that colocalizes with both the proinsulin GWAS signal and a type 2 diabetes signal (HyPrColoc PPFC = 0.92)⁴⁴ genome-wide colocalization analysis identified an adipose ANK1 eQTL at this locus that colocalizes with both the proinsulin GWAS signal and a type 2 diabetes signal (HyPrColoc PPFC = 0.92)
Broadaway et al. 2023: this near-certainty colocalization means the three signals are almost certainly driven by the same causal variant, pointing to adipose-expressed ANK1 as the effector gene. Notably, this adipose eQTL signal does NOT colocalize with the islet NKX6-3 eQTL, implying that the diabetes-relevant effect originates in adipose tissue rather than the pancreas — an unusual route to impaired insulin processing and T2D risk. How adipose ANK1 expression regulates circulating proinsulin remains an open question, but altered lipid storage capacity, adipokine signalling, or structural changes in the adipocyte membrane are plausible intermediaries.

The Evidence

The clearest functional evidence comes from Yan et al. 2016⁵⁵ Yan et al. 2016
Yan Y, Wang F, Xie T et al. A novel type 2 diabetes risk allele increases the promoter activity of the muscle-specific small ankyrin 1 gene. Sci Rep. 2016;6:25105. A two-stage case-control GWAS identified a CCC haplotype spanning this region with T2D odds ratio 1.447 (p < 0.001). Functional validation confirmed the rs508419-C allele increases sAnk1 promoter activity and that excess sAnk1 in human C2C12 myotubes reduces insulin-stimulated glucose uptake.

Beta-cell function effects at this locus were characterised by Harder et al. 2013⁶⁶ Harder et al. 2013
Harder MN et al. Type 2 diabetes risk alleles near BCAR1 and in ANK1 associate with decreased β-cell function. J Clin Endocrinol Metab. 2013;98(4):E801-6. In 5,739 Danish Inter99 participants, the ANK1 rs516946 C allele was associated with a decreased insulinogenic index (p = 0.005) and a decreased disposition index (p = 0.002), indicating a small but consistent impairment in beta-cell response to glucose — an effect replicated in a Chinese cohort where rs516946 conferred OR 1.39 for impaired insulin release (95% CI 1.07–1.81).

A sex-specific interaction was found by Zhu et al. 2022⁷⁷ Zhu et al. 2022
Zhu J et al. The SNP rs516946 interacted in the association of MetS with dietary iron among Chinese males but not females. Nutrients. 2022;14(10):2024. Among 1,284 Chinese men, T allele non-carriers (CC) showed a direct association between dietary iron intake and metabolic syndrome risk; this relationship was absent in T allele carriers, suggesting that the ANK1 variant modifies iron-related metabolic pathways — potentially through hepatic mechanisms, as AST elevations tracked with the variant in this cohort. Women showed no such interaction, possibly due to menstruation-mediated iron cycling.

One cautionary note: a 2026 mouse study found no difference in glucose handling in double-transgenic mice overexpressing both miR-486-5p and sAnk1.5 under standard and high-fat diets⁸⁸ found no difference in glucose handling in double-transgenic mice overexpressing both miR-486-5p and sAnk1.5 under standard and high-fat diets
Buonocore et al. 2026: PMID 41260536, suggesting that the T2D mechanism at this locus may not operate through sAnk1 overexpression alone. The adipose eQTL hypothesis remains the stronger candidate.

Practical Actions

The insulin secretion impairment at this locus is modest compared with the beta-cell effects at KCNJ11 or TCF7L2. The most relevant intervention is avoiding factors that compound the impaired insulin processing signal: specifically, high dietary iron intakes appear to interact with the T allele to increase metabolic syndrome risk in men. Monitoring fasting insulin and proinsulin-to-insulin ratio can detect early impairment in insulin processing. For TT homozygotes carrying the maximum allele dose, annual fasting metabolic screening is warranted.

Interactions

rs6981587 sits within the same intronic cluster as rs516946 (chr8:41,661,730) and rs508419 (chr8:41,665,473). These variants likely tag the same underlying causal variant — the adipose ANK1 eQTL — rather than representing independent effects. rs13412852 in the nearby LPIN1 gene (chromosome 2) shows a nominal BMI association and represents a separate fat-metabolism pathway; no interaction between the ANK1 locus and LPIN1 variants has been documented. The dietary iron × rs516946 interaction described by Zhu et al. suggests that high-iron dietary patterns may amplify risk at this locus, warranting a gene–nutrient interaction with iron intake monitoring.