<i>DNMT3B</i> (rs2424913) polymorphism is associated with systemic lupus erythematosus alone and with co-existing periodontitis in a Brazilian population

Dias, Larissa Nadine da Silva; Coêlho, Marina de Castro; Persuhn, Darlene Camati; Ribeiro, Isabella Lima Arrais; Freire, Eutilia Andrade Medeiros; Oliveira, Naila Francis Paulo de; Aquino, Sabrina Garcia de

doi:10.1590/1678-7757-2021-0567

Larissa Nadine da Silva Dias

Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós Graduação em Odontologia, João Pessoa, PB, Brasil.

http://orcid.org/0000-0002-1951-9852

Marina de Castro Coêlho

Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós Graduação em Odontologia, João Pessoa, PB, Brasil.

http://orcid.org/0000-0002-2007-8863

Darlene Camati Persuhn

Universidade Federal da Paraíba - UFPB, Centro de Ciências Exatas e da Natureza, Departamento de Biologia Molecular, João Pessoa, PB, Brasil.

http://orcid.org/0000-0001-5291-5454

Isabella Lima Arrais Ribeiro

Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós Graduação em Odontologia, João Pessoa, PB, Brasil.

http://orcid.org/0000-0001-6538-6811

Eutilia Andrade Medeiros Freire

Universidade Federal da Paraíba - UFPB, Centro de Ciências Médicas, Departamento de Medicina Interna, João Pessoa, PB-Brasil.

http://orcid.org/0000-0003-1989-4764

Naila Francis Paulo de Oliveira

Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós Graduação em Odontologia, João Pessoa, PB, Brasil.

Universidade Federal da Paraíba - UFPB, Centro de Ciências Exatas e da Natureza, Departamento de Biologia Molecular, João Pessoa, PB, Brasil.

http://orcid.org/0000-0002-0855-2518

Sabrina Garcia de Aquino Corresponding address: Dra. Sabrina Garcia de Aquino, Universidade Federal da Paraíba - UFPB - Centro de Ciências da Saúde - Departamento de Odontologia Clínica e Social - Cidade Universitária - Campus I - 58051-900 - João Pessoa-PB - Brasil. Phone: +55 83 3216-7243 , e-mail: sabrina.aquino@academico.ufpb.br

Universidade Federal da Paraíba- UFPB, Centro de Ciências da Saúde, Departamento de Odontologia Clínica e Social, João Pessoa, PB, Brasil.

http://orcid.org/0000-0002-3988-1939

Corresponding address: Dra. Sabrina Garcia de Aquino, Universidade Federal da Paraíba - UFPB - Centro de Ciências da Saúde - Departamento de Odontologia Clínica e Social - Cidade Universitária - Campus I - 58051-900 - João Pessoa-PB - Brasil. Phone: +55 83 3216-7243 , e-mail: sabrina.aquino@academico.ufpb.br

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Authors’ contributions

Dias, Larissa NS: Data curation (Equal); Formal analysis (Lead); Investigation (Lead); Methodology (Equal); Writing – original draft (Equal). Aquino, Sabrina Garcia: Conceptualization (Equal); Data curation (Equal); Methodology (Equal); Project administration (Equal); Supervision (Lead); Writing – original draft (Equal); Writing – review & editing (Equal). Oliveira, Naila FP: Conceptualization (Equal); Data curation (Equal); Methodology (Equal); Project administration (Equal); Writing – original draft (Equal); Writing – review & editing (Equal). Coêlho, Marina Castro: Data curation (Equal); Formal analysis (Equal); Investigation (Equal); Writing – review & editing (Equal). Persuhn, Darlene Camati: Data curation (Equal); Methodology (Lead); Writing – review & editing (Equal). Freire, Eutília AM: Data curation (Equal); Investigation (Equal); Methodology (Equal); Writing – review & editing (Equal). Ribeiro, Isabella Lima Arrais: Data curation (Supporting)

Variable	Control	Periodontitis	SLE	SLE + Periodontitis	p value
	(n = 60)	(n = 51)	(n = 47)	(n = 38)
Age (mean SD)	38.48 (±8.16)	48.96 (±11.30)	33.17 (±8.95)	38.87 (±10.03)	0.110 ^I I One-way ANOVA (Tukey post-hoc test);
Gender n (%)
Female	47 (78.30%)	29 (56.90%)	43 (91.50%)	36 (94.70%)	<0.001 ^II II Chi-Square test with Yates Correction;
Male	13 (21.70%)	22 (43.10%)	4 (8.50%)	2 (5.30%)
SLE duration (years)	-	-	5.21	10.34	0.001 ^III III Student T-test;
(mean SD)			(5.17)	(7.81)
SLE activity
Inactive SLE n (%)	-	-	20 (42.60%)	24 (63.20%)	<0.001 ^IV IV Chi-Square test;
Active SLE n (%)	-		27 (57.40%)	14 (36.80%)
Medication use
Use of corticosteroid n (%)	-	-	18 (38.30%)	16 (42.10%)	0.086 ^IV IV Chi-Square test;
Use of immunosuppressive n (%)	-	-	30 (63.80%)	17 (44.70%)	0.825 ^IV IV Chi-Square test;
Use of hydroxychloroquine n (%)	-	-	42 (89.40%)	34 (89.50%)	0.987 ^IV IV Chi-Square test;
Periodontal status
Stage II n (%)	-	25 (49.00%)	-	18 (47.40%)	0.877 ^IV IV Chi-Square test;
Stage III or IV n (%)	-	26 (51.00%)	-	20 (52.60%)
Number of missing teeth (mean SD)	-	7.84 (5.84)	8.04 (5.15)	9.16 (4.54)	0.332 ^I I One-way ANOVA (Tukey post-hoc test);
Bleeding sites (median (p25; p75))	-	41.00 a (24.00; 56.00)	3.00 b (1.00; 8.00)	19.50 c (7.00; 40.00)	<0.001 ^V V Kruskal-Wallis test;
Sites with periodontal pockets (median (p25; p75))	-	25.00 (16.00; 46.00)	-	12.00 (6.00; 23.75)	0.002 ^VI VI Mann-Whitney U test. Significance level=5%.
Probing depth (median (p25; p75))	-	7.00 (6.00; 8.00)	-	5.50 (5.00; 7.00)	0.032 ^VI VI Mann-Whitney U test. Significance level=5%.
CAL (mean SD)	-	4.77 (+1.57)	-	5.14 (+1.42)	0.253 ^III III Student T-test;

Gene SNP	MTHFR C677T(rs1801133)		DNMT3B C46359T (rs2424913)
Allelic frequency	C	T	C	T
Control ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... n=60	85 (70.80%)	35 (29.20%)	82 (68.30%)	38 (31.70%)
Perio ²2 Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Clin Periodontol. 2018;45(Suppl 20):149-61. doi: 10.1002/JPER.18-0006 https://doi.org/10.1002/JPER.18-0006... n=51	69(67.60%)	33(32.40%)	48(47.06%)	54(52.94%)
p value^1.2	0.181		0.011
SLE ³3 Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110-21. doi: 10.1111/jcpe.12945 https://doi.org/10.1111/jcpe.12945... n=47	70(74.50%)	24(25.50%)	37(39.36%)	57(60.64%)
p value^1.3	0.565		<0.001
Inactive SLE ⁴4 Rutter-Locher Z, Smith TO, Giles I, Sofat N. Association between systemic lupus erythematosus and periodontitis: a systematic review and meta-analysis. Front Immunol. 2017;17;8:1295. doi: 10.3389/fimmu.2017.01295 https://doi.org/10.3389/fimmu.2017.01295... n=20	28(70.00%)	12(30.00%)	13(32.50%)	27(67.50%)
p value^1.4	0.897		0.002
Active SLE ⁵5 Graves DT, Corrêa JD, Silva TA. The oral microbiota is modified by systemic diseases. J Dent Res. 2018;98(2):148-56. doi: 10.1177/0022034518805739 https://doi.org/10.1177/0022034518805739... n=27	42(77.78%)	12(22.22%)	24(44.44%)	30(55.56%)
p value^1.5	0.360		0.002
SLE + Perio ⁶6 Mutlu S, Richards A, Maddison P, Scully C. Gingival and periodontal health in systemic lupus erythematosus. Community Dent Oral Epidemiol. 1993;21(3):158-61. doi: 10.1111/j.1600-0528.1993.tb00742.x https://doi.org/10.1111/j.1600-0528.1993... n=38	51(67.10%)	25(32.90%)	41(53.95%)	35(46.05%)
p value^1.6	0.529		0.138
Inactive SLE + Perio ⁷7 Calderaro DC, Ferreira GA, Corrêa JD, Mendonça SM, Silva TA, Costa FO, et al. Is chronic periodontitis premature in systemic lupus erythematosus patients? Clin Rheumatol. 2017;36(3):713-8. doi: 10.1007/s10067-016-3385-8 https://doi.org/10.1007/s10067-016-3385-... n = 24	32(66.67%)	16(33.33%)	24(50.00%)	24(50.00%)
p value^1.7	0.810		0.020
Active SLE + Perio ⁸8 Mendonça SM, Corrêa JD, Souza AF, Travassos DV, Calderaro DC, Rocha NP, et al. Immunological signatures in saliva of systemic lupus erythematosus patients: influence of periodontal condition. Clin Exp Rheumatol. 2019;37(2):208-14. n= 14	19(67.86%)	09(32.14%)	17(60.71%)	11(39.29%)
p value^1.8	0.773		0.370

Gene SNP	MTHFR C677T (rs1801133)			DNMT3B C46359T (rs2424913)
Genotype frequencies	CC	CT	TT	CC	CT	TT
Control ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0...	31	23	6	27	28	5
n=60	(51.70%)	(38.30%)	(10.00%)	(45.00%)	(46.70%)	(8.30%)
Perio ²2 Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Clin Periodontol. 2018;45(Suppl 20):149-61. doi: 10.1002/JPER.18-0006 https://doi.org/10.1002/JPER.18-0006...	21	27	3	11	26	14
n=51	(41.20%)	(52.90%)	(5.90%)	(21.60%)	(51.00%)	(27.50%)
p-value ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... , ²2 Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Clin Periodontol. 2018;45(Suppl 20):149-61. doi: 10.1002/JPER.18-0006 https://doi.org/10.1002/JPER.18-0006...		0.275			0.005
SLE ³3 Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110-21. doi: 10.1111/jcpe.12945 https://doi.org/10.1111/jcpe.12945...	27	16	4	8	21	18
n=47	(57.40%)	(34.00%)	(8.50%)	(17.00%)	(44.70%)	(38.30%)
p-value ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... , ³3 Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110-21. doi: 10.1111/jcpe.12945 https://doi.org/10.1111/jcpe.12945...		0.842			<0.001
Inactive SLE ⁴4 Rutter-Locher Z, Smith TO, Giles I, Sofat N. Association between systemic lupus erythematosus and periodontitis: a systematic review and meta-analysis. Front Immunol. 2017;17;8:1295. doi: 10.3389/fimmu.2017.01295 https://doi.org/10.3389/fimmu.2017.01295...	10	8	2	1	11	8
n=20	(50.00%)	(40.00%)	(10.00%)	(5.00%)	(55.00%)	(40.00%)
p-value ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... , ⁴4 Rutter-Locher Z, Smith TO, Giles I, Sofat N. Association between systemic lupus erythematosus and periodontitis: a systematic review and meta-analysis. Front Immunol. 2017;17;8:1295. doi: 10.3389/fimmu.2017.01295 https://doi.org/10.3389/fimmu.2017.01295...		0.991			<0.001
Active SLE ⁵5 Graves DT, Corrêa JD, Silva TA. The oral microbiota is modified by systemic diseases. J Dent Res. 2018;98(2):148-56. doi: 10.1177/0022034518805739 https://doi.org/10.1177/0022034518805739...	17	8	2	7	10	10
n=27	(63.00%)	(29.60%)	(7.40%)	(26.00%)	(37.00%)	(37.00%)
p-value ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... , ⁵5 Graves DT, Corrêa JD, Silva TA. The oral microbiota is modified by systemic diseases. J Dent Res. 2018;98(2):148-56. doi: 10.1177/0022034518805739 https://doi.org/10.1177/0022034518805739...		0.618			0.003
SLE + Perio ⁶6 Mutlu S, Richards A, Maddison P, Scully C. Gingival and periodontal health in systemic lupus erythematosus. Community Dent Oral Epidemiol. 1993;21(3):158-61. doi: 10.1111/j.1600-0528.1993.tb00742.x https://doi.org/10.1111/j.1600-0528.1993...	19	13	6	11	19	8
n=38	(50.00%)	(34.20%)	(15.80%)	(28.90%)	(50.00%)	(21.10%)
p-value ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... , ⁶6 Mutlu S, Richards A, Maddison P, Scully C. Gingival and periodontal health in systemic lupus erythematosus. Community Dent Oral Epidemiol. 1993;21(3):158-61. doi: 10.1111/j.1600-0528.1993.tb00742.x https://doi.org/10.1111/j.1600-0528.1993...		0.735			0.105
Inactive SLE⁺Perio⁷7 Calderaro DC, Ferreira GA, Corrêa JD, Mendonça SM, Silva TA, Costa FO, et al. Is chronic periodontitis premature in systemic lupus erythematosus patients? Clin Rheumatol. 2017;36(3):713-8. doi: 10.1007/s10067-016-3385-8 https://doi.org/10.1007/s10067-016-3385-...	11	10	3	7	10	7
n=24	(45.80%)	(41.70%)	(12.50%)	(29.20%)	(41.70%)	(29.20%)
p-value ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... , ⁷7 Calderaro DC, Ferreira GA, Corrêa JD, Mendonça SM, Silva TA, Costa FO, et al. Is chronic periodontitis premature in systemic lupus erythematosus patients? Clin Rheumatol. 2017;36(3):713-8. doi: 10.1007/s10067-016-3385-8 https://doi.org/10.1007/s10067-016-3385-...		0.876			0.042
Active SLE⁺Perio⁸8 Mendonça SM, Corrêa JD, Souza AF, Travassos DV, Calderaro DC, Rocha NP, et al. Immunological signatures in saliva of systemic lupus erythematosus patients: influence of periodontal condition. Clin Exp Rheumatol. 2019;37(2):208-14.	8	3	3	4	9	1
n=14	(57.20%)	(21.40%)	(21.40%)	(28.60%)	(64.30%)	(7.10%)
p-value ¹1 Sete MR, Figueredo CM, Sztajnbok F. Periodontitis and systemic lupus erythematosus. Rev Bras Reumatol. 2016;56(2):165-70. doi: 10.1016/j.rbre.2015.09.001 https://doi.org/10.1016/j.rbre.2015.09.0... , ⁸8 Mendonça SM, Corrêa JD, Souza AF, Travassos DV, Calderaro DC, Rocha NP, et al. Immunological signatures in saliva of systemic lupus erythematosus patients: influence of periodontal condition. Clin Exp Rheumatol. 2019;37(2):208-14.		0.378			0.620

Outcomes	Variable	Categories	Non–adjusted			Adjusted
			p value	OR	IC 95%	p value	OR	IC 95%
Periodontitis x Control	Gender	Female	-	1.00	-	-	-	-
		Male	0.017	2.74	1.20-6.27	-	-	-
	Age		<0.001	1.11	1.06-1.16	<0.001	1.11	1.05-1.16
	DNMT3B	CC	-	1.00	-	-	1.00	-
		CT	0.067	2.27	0.94-5.50	0.363	1.60	0.58-4.43
		TT	0.002	6.87	1.20-23.71	0.032	4.53	1.13-18.05
SLE x Control	Gender	Female	-	1.00	-	-	-	-
		Male	0.074	0.33	0.10-1.11	-	-	-
	Age		0.003	0.92	0.88-0.97	0.008	0.92	0.87-0.98
	DNMT3B	CC	-	1.00	-	-	1.00	-
		CT	0.061	2.53	0.95-6.68	0.094	2.37	0.86-6.53
		TT	<0.001	12.15	3.42-43.11	<0.001	11.57	3.12-42.84
SLE x Periodontitis	Gender	Female	-	1.00	-	-	1.00	-
		Male	<0.001	0.12	0.03-0.39	0.023	0.11	0.01-0.73
	Age		<0.001	0.85	0.79-0.91	0.003	0.82	0.72-0.93
	Bleeding sites		<0.001	0.92	0.89-0.95	<0.001	0.91	0.87-0.95
SLE with periodontitis x Control	Gender	Female		1.00	-	-	-	-
		Male	0.042	0.20	0.04-0.94	0.026	0.15	0.03-0.79
	Age		0.834	1.00	0.96-1.05
	DNMT3B	CC		1.00	-	-	1.00	-
		CT	0.273	1.66	0.66-4.14	0.240	1.75	0.68-4.45
		TT	0.042	3.92	1.05-14.68	0.023	5.27	1.25-22.11
SLE with Periodontitis x Periodontitis	Gender	Female	-	1.00	-	-	-	-
		Male	0.001	0.07	0.01-0.33	-	-	-
	Age		<0.001	0.91	0.87-0.96	0.004	0.90	0.83-0.96
	Sites with periodontal pocket		0.047	0.96	0.93-0.98	0.024	0.95	0.92-0.99
SLE x SLE with Periodontitis	Bleeding sites		0.002	0.95	0.92-0.98	0.002	0.95	0.92-0.98

[1] Corresponding address: Dra. Sabrina Garcia de Aquino, Universidade Federal da Paraíba - UFPB - Centro de Ciências da Saúde - Departamento de Odontologia Clínica e Social - Cidade Universitária - Campus I - 58051-900 - João Pessoa-PB - Brasil. Phone: +55 83 3216-7243 , e-mail: sabrina.aquino@academico.ufpb.br

Brasil

Brasil

DNMT3B (rs2424913) polymorphism is associated with systemic lupus erythematosus alone and with co-existing periodontitis in a Brazilian population

Abstract