Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population

Kathleen Liedtke Kolb, Ana Luiza Sprotte Mira, Eduardo Delabio Auer, Isabela Dall’Oglio Bucco, Carla Eduarda de Lima e Silva, Priscila Ianzen dos Santos, Valéria Bumiller Bini Hoch, Luana Caroline Oliveira, Aline Borsato Hauser, Jennifer Elisabeth Hundt, Alan R. Shuldiner, Fabiana Leão Lopes, Teide Jens Boysen, Andre Franke, Luis Felipe Ribeiro Pinto, Sheila Coelho Soares-Lima, Gabriela Canalli Kretzschmar, Angelica Beate Winter Boldt*

*Corresponding author for this work

Abstract

The regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with polymorphisms and the methylation degree of the glucocorticoid receptor gene (NR3C1) and is potentially involved in the development of metabolic syndrome (MetS). In order to evaluate the association between MetS with the polymorphisms, methylation, and gene expression of the NR3C1 in the genetically isolated Brazilian Mennonite population, we genotyped 20 NR3C1 polymorphisms in 74 affected (MetS) and 138 unaffected individuals without affected first-degree relatives (Co), using exome sequencing, as well as five variants from non-exonic regions, in 70 MetS and 166 Co, using mass spectrometry. The methylation levels of 11 1F CpG sites were quantified using pyrosequencing (66 MetS and 141 Co), and the NR3C1 expression was evaluated via RT-qPCR (14 MetS and 25 Co). Age, physical activity, and family environment during childhood were associated with MetS. Susceptibility to MetS, independent of these factors, was associated with homozygosity for rs10482605*C (OR = 4.74, pcorr = 0.024) and the haplotype containing TTCGTTGATT (rs3806855*T_ rs3806854*T_rs10482605*C_rs10482614*G_rs6188*T_rs258813*T_rs33944801*G_rs34176759*A_rs17209258*T_rs6196*T, OR = 4.74, pcorr = 0.048), as well as for the CCT haplotype (rs41423247*C_ rs6877893*C_rs258763*T), OR = 6.02, pcorr = 0.030), but not to the differences in methylation or gene expression. Thus, NR3C1 polymorphisms seem to modulate the susceptibility to MetS in Mennonites, independently of lifestyle and early childhood events, and their role seems to be unrelated to DNA methylation and gene expression.

Original languageEnglish
Article number1805
JournalGenes
Volume14
Issue number9
ISSN2073-4425
DOIs
Publication statusPublished - 09.2023

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
  • Research Area: Medical Genetics

DFG Research Classification Scheme

  • 205-17 Endocrinology, Diabetology, Metabolism
  • 201-05 General Genetics and Functional Genomics

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