A role for coding functional variants in HNF4A in type 2 diabetes susceptibility

Area of Science:

• Genetics
• Endocrinology
• Metabolic Diseases

Background:

• Rare mutations in HNF4A cause MODY, and common variants may contribute to multifactorial diabetes.
• Two HNF4A variants, V255M and T130I, influence gene expression and are investigated for type 2 diabetes association.

Purpose of the Study:

• To evaluate the contribution of HNF4A variants V255M and T130I to type 2 diabetes susceptibility.
• To conduct a large-scale association analysis of these variants in diverse populations.

Main Methods:

• Genotyping of V255M and T130I in over 5,745 cases and 14,756 controls from the UK and Denmark.
• Expanded association analysis including additional European and Canadian cohorts.
• Meta-analysis of T130I association studies with up to 14,279 cases and 26,835 controls.

Main Results:

• No significant association was found between the V255M variant and type 2 diabetes.
• The T130I variant showed a modest association with type 2 diabetes in UK and Danish samples (OR 1.17, p=1.5×10⁻⁴).
• Meta-analysis strengthened the association for T130I (OR 1.20, p=2.1×10⁻⁵), though not reaching genome-wide significance.

Conclusions:

• The low-frequency T130I variant in HNF4A may influence type 2 diabetes risk.
• The association for T130I requires further validation against stringent significance thresholds.
• This study highlights challenges in the genetic association testing of low-frequency variants in complex diseases.