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

doi:10.3390/genes14091805

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

Institute of Experimental Dermatology

8 Citations (Scopus)

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 language	English
Article number	1805
Journal	Genes
Volume	14
Issue number	9
ISSN	2073-4425
DOIs	https://doi.org/10.3390/genes14091805
Publication status	Published - 09.2023

Funding

We deeply thank all Mennonite participants for volunteering for this study, and the staff of the Human Molecular Genetics Laboratory (UFPR), for assistance in blood collection, interviews, and DNA/RNA extraction. We are also grateful to Monique de Souza Almeida Lopes, from INCA, for technical assistance in pyrosequencing. We extend our thanks to Danielle Malheiros Ferreira, for donating the material used for one experiment. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. eQTL and sQTL effects of genetic variants associated in this study were obtained from https://gtexportal.org/home/snp/ (accessed on 7 June 2023). This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Empresa Brasileira de Serviços Hospitalares (Ebserh) grant numbers 423317/2021-0 and 313741/2021-2 (8520137521584230), Research for the United Health SUS System (PPSUS-MS), CNPq, Fundação Araucária and SESA-PR, Protocol Nº: SUS2020131000106, and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PROAP – Finance Code 001). A.B.W.B. receives CNPq research productivity scholarships (protocols 314288/2018-0 and 313741/2021).

Research Areas and Centers

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

DFG Research Classification Scheme

2.22-17 Endocrinology, Diabetology, Metabolism
2.11-05 General Genetics and Functional Genome Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kolb, K. L., Mira, A. L. S., Auer, E. D., Bucco, I. DO., de Lima e Silva, C. E., dos Santos, P. I., Hoch, V. B. B., Oliveira, L. C., Hauser, A. B., Hundt, J. E., Shuldiner, A. R., Lopes, F. L., Boysen, T. J., Franke, A., Pinto, L. F. R., Soares-Lima, S. C., Kretzschmar, G. C., & Boldt, A. B. W. (2023). Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population. Genes, 14(9), Article 1805. https://doi.org/10.3390/genes14091805

@article{252e7849f22f4d9198472f055387735a,

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

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.",

author = "Kolb, \{Kathleen Liedtke\} and Mira, \{Ana Luiza Sprotte\} and Auer, \{Eduardo Delabio\} and Bucco, \{Isabela Dall{\textquoteright}Oglio\} and \{de Lima e Silva\}, \{Carla Eduarda\} and \{dos Santos\}, \{Priscila Ianzen\} and Hoch, \{Val{\'e}ria Bumiller Bini\} and Oliveira, \{Luana Caroline\} and Hauser, \{Aline Borsato\} and Hundt, \{Jennifer Elisabeth\} and Shuldiner, \{Alan R.\} and Lopes, \{Fabiana Le{\~a}o\} and Boysen, \{Teide Jens\} and Andre Franke and Pinto, \{Luis Felipe Ribeiro\} and Soares-Lima, \{Sheila Coelho\} and Kretzschmar, \{Gabriela Canalli\} and Boldt, \{Angelica Beate Winter\}",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = sep,

doi = "10.3390/genes14091805",

language = "English",

volume = "14",

journal = "Genes",

issn = "2073-4425",

number = "9",

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Kolb, KL, Mira, ALS, Auer, ED, Bucco, IDO, de Lima e Silva, CE, dos Santos, PI, Hoch, VBB, Oliveira, LC, Hauser, AB, Hundt, JE, Shuldiner, AR, Lopes, FL, Boysen, TJ, Franke, A, Pinto, LFR, Soares-Lima, SC, Kretzschmar, GC & Boldt, ABW 2023, 'Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population', Genes, vol. 14, no. 9, 1805. https://doi.org/10.3390/genes14091805

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

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 - https://www.scopus.com/pages/publications/85172805353

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 -

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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