NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

Souza, Manoel Carlos L. A.; Martins, Clarissa S.; Silva Junior, Ivan M.; Chriguer, Rosangela S.; Bueno, Ana C.; Antonini, Sonir R.; Silva Jr., Wilson Araújo; Zago, Marco A.; Moreira, Ayrton C.; Castro, Margaret de

doi:10.1590/0004-2730000002868

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Artigos Originais • Arq Bras Endocrinol Metab 58 (1) • Feb 2014 • https://doi.org/10.1590/0004-2730000002868 copy

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

Polimorfismos NR3C1 em brasileiros de ascendência caucasiana, africana e asiática: sensibilidade aos glicocorticoides e associação de genótipos

About the authors

Objective

: The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population.

Materials and methods

: We assessed NR3C1 polymorphisms in Brazilians of Caucasian, African and Asian ancestry (n = 380). In a subgroup (n = 40), we compared the genotypes to glucocorticoid (GC) sensitivity, which was previously evaluated by plasma (PF) and salivary (SF) cortisol after dexamethasone (DEX) suppression tests, GC receptor binding affinity (K _d ), and DEX-50% inhibition (IC ₅₀ ) of concanavalin-A-stimulated mononuclear cell proliferation. p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) allelic discrimination was performed by Real-Time PCR (Polymerase Chain Reaction). Exons 3 to 9 and exon/intron boundaries were amplified by PCR and sequenced.

Results

: Genotypic frequencies (%) were: rs6195 (n = 380; AA:96.6/AG:3.14/GG:0.26), rs6189-6190 (n = 264; GG:99.6/GA:0.4), rs41423247 (n = 264; CC:57.9/CG:34.1/GG:8.0), rs6188 (n = 155; GG:69.6/GT:25.7/TT:4.7), rs258751 (n = 150; CC:88.0/CT:10.7/TT:1.3), rs6196 (n = 176; TT:77.2/TC:20.4/CC:2.4), rs67300719 (n = 137; CC:99.3/CT:0.7), and rs72542757 (n = 137; CC:99.3/CG:0.7). The rs67300719 and rs72542757 were found only in Asian descendants, in whom p.N363S and p.ER22/23EK were absent. The p.ER22/23EK was observed exclusively in Caucasian descendants. Hardy-Weinberg equilibrium was observed, except in the Asian for rs6188 and rs258751, and in the African for p.N363S. The K _d , IC ₅₀ , baseline and after DEX PF or SF did not differ between genotype groups. However, the mean DEX dose that suppressed PF or SF differed among the BclI genotypes (P = 0.03). DEX dose was higher in GG- (0.7 ± 0.2 mg) compared to GC- (0.47 ± 0.2 mg) and CC-carriers (0.47 ± 0.1 mg).

Conclusion

: The genotypic frequencies of NR3C1 polymorphisms in Brazilians are similar to worldwide populations. Additionally, the BclI polymorphism was associated with altered pituitary-adrenal axis GC sensitivity.

NR3C1 genotypes; allelic frequencies; glucocorticoid sensitivity

Primers			Probes
BclI	FWD	5'-CAGGGTTCTTGCCATAAAGTAGACA-3'	WT	5'-CTCTTAAAGAGATT G ATCAGC-3'
	REW	5'-GCACCATGTTGACACCAATTCC-3'	VT	5'-CTCTTAAAGAGATT C ATCAGC-3'
N363S	FWD	5'-GTCATTCCACCAATTCCCGTTG-3'	WT	5'-ACCTATTCCAA T TTTCGG-3'
	REW	5'-GTCAAGTTGTCATCTCCAGATCCTT-3'	VT	5'-CCTATTCCAA C TTTCGG-3'
ER22/23EK	FWD	5'-AGAAGAAAACCCCAGCAGTGT-3'	WT	5'-CACATCTCCC C T C TCCTGA-3'
	REW	5'-CAGTAGCTCCTCCTCTTAGGGTTTTA-3'	VT	5'-CACATCTCCC T T T TCCTGA-3'

Location				Caucasian	African	Asian	Total
	db SNP	Minor	Rare	n	n	n	n
	Accession	change	allele	(Genotypic frequency)	(Genotypic frequency)	(Genotypic frequency)	(Genotypic frequency)
				(allelic frequency)	(allelic frequency)	(allelic frequency)	(allelic frequency)
Exon 2	rs 6195	A/G	G	276	70	34	380
	(p.N363S)			(AA:96/AG:4)	(AA:97.2/AG:1.4/GG:1.4)	(AA:100)	(AA:96.6/AG:3.14/GG:0.26)
				(A:98.0/G:2.0)	(A:97.8/G:2.2)	(A:100)	(A:98.15/G:1.85)
Exon 2	rs 6189/6190	G/A	A	230 (GG:99.5/GA:0.5)	31	3 (GG:100)	264 (GG:99.6/GA:0.4)
	(p.ER22/23EK)			(G:97.8/A:2.2)	(GG:100)	(G:100)	(G:99.8/A:0.2)
					(G:100)
Intron 2	rs41423247	C/G	G	230	31	3	264
	BcII			(CC:59.5/CG:32.6/GG:7.8)	(CC:48.3/CG:45.1/GG:6.4)	(CC:33/CG:33/GG:33)	(CC:57.9/CG:34.1/GG:8.0)
				(C:75.8/G:24.2)	(C:71.0/G:29.0)	(C:50.0/G:50.0)	(C:75.0/G:25.0)
Intron D	rs 6188	G/T	T	91	31	33	155
	(IVS4 -16)			(GG:68.1/GT:29.6/TT:2.3)	(GG:54.8/GT:32.2/TT:13)	(GG:87.8/GT:9/TT:3.2)	(GG:69.6/GT:25.7/TT:4.7)
				(G:83.0/T:17.0)	(G 71.0/T 29.0)	(G:92.5/T:7.5)	(G:82.6/T:17.4)
Exon 8	rs 258751	C/T	T	50	50	50	150
	(p.D678D)			(CC:98/CT:2)	(CC:82/CT:18)	(CC:84/CT:12/TT:4)	(CC:88/CT:10.7/TT:1.3)
				(C:99.0/T:1.0)	(C:91.0/CT:9.0)	(C:90.0/T:10.0)	(C:93.3/T:6.7)
Intron H	rs72542757	C/G	G	48	40	49	137
	(IVS8 -9)			(CC:100)	(CC:100)	(CC:98/CG:2)	(CC:99.3/CG:0.7)
				(C:100)	(C:100)	(C:99.0/G:1.0)	(C:99.7/G:0.3)
Exon 9	rs67300719	C/T	T	48	40	49	137
	p.(P750P)			(CC:100)	(CC:100)	(CC:98/CT:2)	(CC:99.3/CT:0.7)
				(C:100)	(C:100)	(C:99.0/T:1.0)	(C:99.7/T:0.3)
Exon 9	rs 6196	T/C	C	86	40	50	176
	p.(N766N)			(TT:80.2/TC:17.4/CC:2.4)	(TT:62.5/TC:32.5/CC:5)	(TT:84/TC:16)	(TT:77.2/TC:20.4/CC:2.4)
				(T:89.0/C:11.0)	(T :78.75/C:21.25)	(T:92.0/C :8.0)	(T:87.5/C:12.5)

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[1] Correspondence to
Margaret de Castro. School of Medicine of Ribeirao Preto, Universidade de Sao Paulo. Av. dos Bandeirantes, 3900. 14049-900 – Ribeirao Preto, SP, Brazil. castrom@fmrp.usp.br