Expressive

rs10886471 (GRK5): Type 2 Diabetes Risk in East Asians

Key takeaways

  • rs10886471 in the GRK5 gene is linked to type 2 diabetes risk in Chinese Han and other East Asian populations at genome-wide significance (P = 7.1 x 10^-9).
  • The association appears specific to East Asians - the provided research does not document replication in European or other ancestry groups.
  • The risk allele is linked to higher fasting insulin in people without diabetes, but not to fasting glucose.
  • Evidence is drawn from over 43,000 participants across three study stages, including de novo and in silico replication.
  • GTEx data show the alternate allele reduces GRK5 expression specifically in thyroid tissue.

Key takeaways

  • rs10886471 in the GRK5 gene is linked to type 2 diabetes risk in Chinese Han and other East Asian populations at genome-wide significance (P = 7.1 x 10^-9).
  • The association appears specific to East Asians - the provided research does not document replication in European or other ancestry groups.
  • The risk allele is linked to higher fasting insulin in people without diabetes, but not to fasting glucose.
  • Evidence is drawn from over 43,000 participants across three study stages, including de novo and in silico replication.
  • GTEx data show the alternate allele reduces GRK5 expression specifically in thyroid tissue.

What the research says A three-stage genome-wide association study (GWAS) in Chinese Hans identified rs10886471, located in GRK5 (G-protein-coupled receptor kinase 5 - an enzyme that regulates signaling receptors on cell surfaces), as a novel type 2 diabetes (T2D) susceptibility locus at genome-wide significance (P = 7.1 x 10^-9). In participants without T2D, the risk allele was associated with higher fasting insulin (a measure of insulin levels after an overnight fast, P = 0.0169) but not with fasting glucose. The authors note the association at this locus appears specific to East Asian populations.

Reported associations

  • Type 2 diabetes: genome-wide significant association in Chinese Han populations (P = 7.1 x 10^-9); the signal appears specific to East Asian ancestry based on the available evidence.
  • Fasting insulin (nondiabetic individuals): the risk allele was associated with higher fasting insulin levels (P = 0.0169) among 3,614 participants from two population-based studies.
  • Fasting glucose (nondiabetic individuals): no significant association was found between the risk allele and fasting glucose levels.

Evidence quality The GWAS used a three-stage design totaling approximately 43,000 participants: a discovery scan (1,999 T2D cases, 1,976 controls), a stage 2 replication (6,570 cases, 6,947 controls), a de novo stage 3 replication (3,410 cases, 3,412 controls), and an in silico replication in the AGEN-T2D dataset (6,952 cases, 11,865 controls). The combined P-value of 7.1 x 10^-9 meets criteria for genome-wide significance as described by the authors. The authors explicitly note that the GRK5 signal appears specific to East Asian populations, and no cross-ethnic replication data are included in the provided study. Fasting insulin associations were drawn from a sub-sample of 3,614 participants, a more modest scale that warrants cautious interpretation.

Tissue-specific expression effects

  • GRK5: the alternate allele is associated with reduced expression in thyroid tissue, based on GTEx v11 data across 953 donors. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs10886471?

rs10886471 is a single nucleotide polymorphism (a one-letter DNA change) located in the GRK5 gene, which encodes G-protein-coupled receptor kinase 5. It was identified as a type 2 diabetes risk locus in Chinese Han and East Asian populations.

Is rs10886471 linked to type 2 diabetes?

Yes, a three-stage genome-wide association study in Chinese Han populations found this variant to be significantly associated with type 2 diabetes (P = 7.1 x 10^-9), meeting genome-wide significance criteria. The association appears specific to East Asian ancestry and has not been documented in European populations in the available research.

What does the GRK5 gene do?

GRK5 (G-protein-coupled receptor kinase 5) encodes an enzyme that regulates the activity of G-protein-coupled receptors on cell surfaces - proteins that relay signals from outside the cell to the inside. The provided research does not detail the specific biological mechanism by which GRK5 variants may influence diabetes risk.

Does rs10886471 affect insulin levels?

In people without diabetes, carrying the risk allele was associated with higher fasting insulin but not with fasting glucose, based on a sub-sample of 3,614 participants. This finding should be interpreted cautiously given the smaller sample size.

Is this GRK5 variant found across all ethnic groups?

The genome-wide significant association was found in Chinese Han populations, and the researchers reported it appears specific to East Asian ancestry. The available evidence does not include replication in European or other non-East-Asian populations.