Genetic Variants in <i>HTR3B</i> Locus Influence Glycemic Control and Type 2 Diabetes Susceptibility in Koreans

Objectives: HTR3B encodes the serotonin 5-HT 3 receptor subunit and regulates pancreatic -cell function.This regulation directly impacts type 2 diabetes mellitus (T2DM) development.This study examined how genetic polymorphisms within the HTR3B locus associate with T2DM susceptibility and correlate with metabolic parameters among Korean participants from the Korean Association REsource (KARE) cohort.Methods: This study investigated the association between five single nucleotide polymorphisms (rs4938058, rs4938056, rs4936285, rs1185027, and rs10789970) located within the HTR3B genomic region and the risk of T2DM.The analysis utilized data from 6,475 Korean individuals participating in KARE study, which included 5,721 metabolically healthy controls and 754 T2DM cases.Results: A significantly enhanced susceptibility to T2DM was observed for the rs4938058 variant (odds ratio [OR] = 1.21, 95% confidence interval [CI]: 1.07-1.36,P = 0.0027), while rs4936285 demonstrated an even stronger association (OR = 1.24, 95% CI: 1.10-1.39,P = 0.0006).The evaluation of metabolic phenotypes revealed that the risk alleles had consistent directional effects on glycemic control parameters.Significant associations were found with fasting glucose concentrations for rs4938058 ( = 0.83 0.40 mg/dL, P = 0.0356) and with HbA1c values for both rs4938058 ( = 0.05% 0.02%, P = 0.0047) and rs4936285 ( = 0.05% 0.02%, P = 0.0011).Notably, rs4936285 showed the strongest signal in the HTR3B region.Conclusion: These findings identify rs4936285 as a genetic risk variant for T2DM and support the involvement of the serotonin pathway in T2DM pathogenesis in Koreans.