Hepatocyte Nuclear Factor 4 Alpha Polymorphisms and the Metabolic Syndrome in French-Canadian Youth

<div><p>Objectives</p><p>Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor involved in the regulation of serum glucose and lipid levels. Several <i>HNF4A</i> gene variants have been associated with the risk of developing type 2 diabetes mellitus. However, no study has yet explored its association with insulin resistance and the cardiometabolic risk in children. We aimed to investigate the relationship between <i>HNF4A</i> genetic variants and the presence of metabolic syndrome (MetS) and metabolic parameters in a pediatric population.</p><p>Design and Methods</p><p>Our study included 1,749 French-Canadians aged 9, 13 and 16 years and evaluated 24 <i>HNF4A</i> polymorphisms that were previously identified by sequencing.</p><p>Results</p><p>Analyses revealed that, after correction for multiple testing, one SNP (rs736824; <i>P</i><0.022) and two haplotypes (P1 promoter haplotype rs6130608-rs2425637; <i>P</i><0.032 and intronic haplotype rs736824-rs745975-rs3212183; <i>P</i><0.025) were associated with the risk of MetS. Additionally, a significant association was found between rs3212172 and apolipoprotein B levels (coefficient: -0.14 ± 0.05; <i>P</i><0.022). These polymorphisms are located in <i>HNF4A</i> P1 promoter or in intronic regions.</p><p>Conclusions</p><p>Our study demonstrates that HNF4α genetic variants are associated with the MetS and metabolic parameters in French Canadian children and adolescents. This study, the first exploring the relation between <i>HNF4A</i> genetic variants and MetS and metabolic variables in a pediatric cohort, suggests that HNF4α could represent an early marker for the risk of developing type 2 diabetes mellitus.</p>