TY - JOUR
T1 - Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome
T2 - Insights from the Mennonite Population
AU - Kolb, Kathleen Liedtke
AU - Mira, Ana Luiza Sprotte
AU - Auer, Eduardo Delabio
AU - Bucco, Isabela Dall’Oglio
AU - de Lima e Silva, Carla Eduarda
AU - dos Santos, Priscila Ianzen
AU - Hoch, Valéria Bumiller Bini
AU - Oliveira, Luana Caroline
AU - Hauser, Aline Borsato
AU - Hundt, Jennifer Elisabeth
AU - Shuldiner, Alan R.
AU - Lopes, Fabiana Leão
AU - Boysen, Teide Jens
AU - Franke, Andre
AU - Pinto, Luis Felipe Ribeiro
AU - Soares-Lima, Sheila Coelho
AU - Kretzschmar, Gabriela Canalli
AU - Boldt, Angelica Beate Winter
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85172805353&partnerID=8YFLogxK
U2 - 10.3390/genes14091805
DO - 10.3390/genes14091805
M3 - Journal articles
AN - SCOPUS:85172805353
SN - 2073-4425
VL - 14
JO - Genes
JF - Genes
IS - 9
M1 - 1805
ER -