An association study of <i>FOXO3</i> variant and longevity

Silva-Sena, Geralda Gillian; Camporez, Daniela; Santos, Lígia Ramos dos; Silva, Aline Sesana da; Sagrillo Pimassoni, Lúcia Helena; Tieppo, Alessandra; Pimentel Batitucci, Maria do Carmo; Morelato, Renato Lírio; Paula, Flavia de

doi:10.1590/1678-4685-GMB-2017-0169

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Human and Medical Genetics • Genet. Mol. Biol. 41 (2) • Apr./June 2018 • https://doi.org/10.1590/1678-4685-GMB-2017-0169 copy

An association study of FOXO3 variant and longevity

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Human longevity is a polygenic and multifactorial trait. Pathways related to lifespan are complex and involve molecular, cellular, and environmental processes. In this analytical observational study, we evaluated the relationship between environment factors, oxidative stress status, DNA integrity level, and the association of FOXO3 (rs2802292), SOD2 (rs4880), APOE (rs429358 and rs7412), and SIRT1 (rs2273773) polymorphisms with longevity in oldest-old individuals from southeastern Brazil. We found an association between the FOXO3 GG genotype and gender. While lifestyle, anthropometric, and biochemical characteristics showed significant results, DNA damage and oxidative stress were not related to lifespan. We found that long-lived individuals with FOXO3 GT genotype had low levels of triglycerides. This study is the first to demonstrate that FOXO3 could be a candidate gene for longevity in the Brazilian population. These results are important in terms of provisions of health care for age-related diseases and lifespan, and provide insight for further research on epigenetic, gene regulation, and expression in oldest-old individuals.

Keywords:
Lifespan; SNPs; environmental factors; oxidative stress; genomic damage

Characteristics (n)	LLI			Controls			p ^** * Comparison between gender;
Gender (452)	Men (64)	Women (156)	p^* b (standard deviation or standard error of the mean) or number of subjects with percentage in parentheses. Abbreviations: n - number of individuals; LLI - Long-Lived Individuals; a.u. - arbitrary units;	Men (75)	Women (157)	p^* b (standard deviation or standard error of the mean) or number of subjects with percentage in parentheses. Abbreviations: n - number of individuals; LLI - Long-Lived Individuals; a.u. - arbitrary units;
Age (452)	88.8 ± 4.1	89.3 ± 4.6	0.467	72.3 ± 1.8	72.4 ± 1.7	0.457	0.000
Ethnicity (449)
Caucasian	38 (17.4%)	93 (42.5%)		48 (20.9%)	100 (43.5%)
Black	9 (4.1%)	26 (11.9%)	0.898	12 (5.2%)	21 (9.1%)	0.755	0.612
Brown	16 (7.3%)	37 (16.9%)		14 (6.1%)	35 (15.2%)
Descent Family - Italy (87)	37 (42.5%)		50 (57.5%)				0.099
Marital status (330)							0.000
Married	42 (25.8%)		85 (50.9%)
Widower	94 (57.6%)		53 (31.7%)
Separated/divorced/never married	27 (16.6%)		29 (17.4%)
Monthly Income ($200.00) (297)	150 (50.5%)		147 (49.5%)
Years of Education (325)							0.015
0 years	15 (9.9%)	51 (31.7%)	0.255	9 (5.5%)	34 (20.7%)
1-4 years	29 (18.0%)	48 (29.8%)		34 (20.7%)	61 (37.2%)	0.325
5-8 years	4 (2.5%)	11 (6.8%)		8 (4.9%)	14 (8.5%)
> 8 years	1 (0.6%)	1 (0.6%)		1 (0.6%)	3 (1.8%)
Home (290)							0.108
Own home	119 (88.1%)			145 (93.5%)
Rented/ Live with other	16 (11.9%)			10 (6.5%)
Biochemical physical and anthropometric data
Diastolic Blood Pressure (mmHg) (299)	77.4 ± 10.4			79.5 ± 11.3			0.675
Systolic Blood Pressure (mmHg) (299)	133.9 ± 20.1			134.9 ± 20.7			0.093
Cholesterol (mg/dl) (257)	181.9 ± 39.9			187.9 ± 43.6			0.256
High-Density Lipoprotein Cholesterol (mg/dl) (246)	48.8 ± 10.6			46.7 ± 12.8			0.177
Low-Density Lipoprotein Cholesterol (mg/dl) (242)	110.1 ± 33.6			111.9 ± 38.7			0.701
Triglycerides (mg/dl) (249)	120.9 ± 73.6			152.0 ± 111.3			0.009
Glucose (mg/dl) (279)	106.9 ± 28.3			118.1 ± 47.4			0.017
Waist:hip ratio (265)	0.9 ± 0.1			0.9 ± 0.1			0.984
BMI (251)							0.003
< 23 kg/m² (Underweight)	36 (31.3%)			22 (16.2%)
23 \|- 28 kg/m² (Normal weight)	58 (50.4%)			64 (47.1%)
28 \|-30 kg/m²(Overweight)	7 (6.1%)			18 (13.2%)
> = 30 kg/m² (Obesity)	14 (12.2%)			32 (23.5%)
Eat Vegetables (5 times/day) (309)							0.174
Yes	122 (39.5%)			128 (41.4%)
No	23 (7.4%)			36 (11.7%)
Eat Fruits (5 times/day) (309)							0.052
Yes	124 (40.1%)			126 (40.8%)
No	21 (6.8%)			38 (12.3%)
Alcohol consumption (326)							0.019
Use	6 (3.8%)	4 (2.5%)	0.071	18 (10.7%)	6 (3.6%)	0.000
No use	43 (27.2%)	105 (66.5%)		36 (21.4%)	108 (64.3%)
Smoker Status (328)							0.229
Never smoked	21 (13.3%)	73 (46.2%)	0.008	21 (12.4%)	95 (55.9%)
Former smoked	25 (15.8%)	30 (19.0%)		30 (17.6%)	18 (10.6%)	0.000
Current smoked	4 (2.5%)	5 (3.2%)		5 (2.9%)	1 (0.6%)
Physical activity (283)							0.004
Yes	11 (24.4%)	10 (11.2%)	0.047	17 (38.6%)	28 (26.7%)	0.147
No	34 (75.6%)	79 (88.8%)		27 (61.4%)	77 (73.3%)
Family history (68)							0.006
Cardiovascular Disease	13 (44.8%)		4 (10.5%)
Diabetes	5 (17.2%)		11(28.9%)
Cancer	11 (38.0%)		23 (60.5%)
Malondialdehyde (μmol/L plasma) (100)	1.99 ± 0.66	2.03 ± 0.73	0.879	1.91 ± 0.62	1.77 ± 0.63	0.447	0.137
Genomic damage (a.u.) (30)^b b (standard deviation or standard error of the mean) or number of subjects with percentage in parentheses. Abbreviations: n - number of individuals; LLI - Long-Lived Individuals; a.u. - arbitrary units;	0.044 ± 0.011		0.031 ± 0.007				0.567

	Groups (n)	LLI (218)					Controls (231)					OR(95% CI)^ Comparison between CT and LLI;	p ^ Comparison between CT and LLI;	p ^* ***** p-values are uncorrected; For APOE, n= 213 (LLI) and n= 213 (Controls). FOXO3 (rs2802292:G>T. RefSeqNM_001455.3), SOD2 (rs4880:T>C. RefSeqNG_008729.1), SIRT1 (rs2273773:T>C. RefSeqNM_001142498.1) and APOE (rs429358:T>C. RefSeqNG_007084.2 and rs7412:C>T. RefSeqNG_007084.2).
Genes	Genotypes	Men	Women	Total	OR (95% CI)^* * Comparison between gender;	p ^* * Comparison between gender;	Men	Women	Total	OR (95% CI)^* * Comparison between gender;	p ^* * Comparison between gender;
		n (%)	n (%)	n (%)			n (%)	n (%)	n (%)
					0.348					0.955		0.910
FOXO3	GG	6 (2.8)	36 (16.5)	42 (19.3)	(0.139-0.873)	0.020	15 (6.5)	33 (14.3)	48 (20.8)	(0.482-1.894)	0.896	(0.573-1.445)	0.689	0.907
					1.425					0.869		1.073
	GT	38(17.4)	80 (36.7)	118(54.1)	(0.786-2.583)	0.242	37 (16.0)	84 (36.4)	121(52.4)	(0.500-1.511)	0.619	(0.740-1.555)	0.711
					1.284					1.238		0.988
	TT	19 (8.7)	39 (17.9)	58 (26.6)	(0.671-2.458)	0.449	22 (9.5)	40 (17.3)	62 (26.8)	(0.670 - 2.287)	0.496	(0.650-1.501)	0.955
SOD2
					0.841					1.412		0.987
	CC	15 (6.9)	42 (19.3)	57 (26.1)	(0.426-1.659)	0.617	23 (10.0)	38 (16.5)	61 (26.4)	(0.765-2.607)	0.269	(0.648-1.502)	0.950	0.369
					1.070					0.821		1.238
	CT	36(16.5)	86 (39.4)	122(56.0)	(0.592-1.932)	0.823	35 (15.1)	82 (35.5)	117(50.6)	(0.472-1.428)	0.484	(0.854-1.795)	0.259
					1.115					0.895		0.732
	TT	12 (5.5)	27 (12.4)	39 (17.9)	(0.525-2.370)	0.776	16(6.9)	37 (16.0)	53 (22.9)	(0.460-1.740)	0.743	(0.461-1.162)	0.185
APOE
					1.291					0.996		1.088
	∊2∊3	10 (4.7)	16 (7.5)	26 (12.2)	(0.553-3.012)	0.658	8 (3.8)	20 (9.4)	28 (13.2)	(0.412-2.401)	1.000	(0.615-1.927)	0.884	0.973
					1.493					0.904		1.079
	∊3∊3	43(20.1)	72 (33.8)	115(53.9)	(0.837-2.662)	0.191	33 (15.5)	86 (40.4)	119(55.9)	(0.498-1.643)	0.762	(0.736-1.580)	0.770
					0.492					2.542		0.796
	∊2∊4	1 (0.5)	4 (1.9)	5 (2.4)	(0.054-1.889)	0.667	2 (0.9)	2 (0.9)	4 (1.8)	(0.350-18.468)	0.324	(0.211-3.006)	1.000
					0.547					1.105		0.885
	∊3∊4	14 (6.6)	44 (20.7)	58 (27.3)	(0.276-1.084)	0.102	16 (7.5)	37 (17.4)	53 (24.9)	(0.560-2.182)	0.861	(0.574-1.365)	0.659
					1.000					0.702		1.000
	∊4∊4	3(1.4)	6 (2.8)	9 (4.2)	(0.243-4.121)	1.000	2 (0.9)	7 (3.3)	9 (4.2)	(0.142-3.479)	1.000	(0.389-2.570)	1.000
SIRT1
					2.508					2.137		2.140
	CC	2 (0.9)	2 (0.9)	4 (1.8)	(0.346-18.208)	0.347	1 (0.4)	1 (0.4)	2 (0.8)	(0.132-34.643)	0.584	(0.388-11.804)	0.438	0.660
					0.936					0.661		0.945
	CT	10 (4.6)	26 (11.9)	36 (16.5)	(0.422-2.076)	0.871	10 (4.3)	30 (13.0)	40 (17.3)	(0.304-1.437)	0.294	(0.576-1.548)	0.821
					0.937					1.409		0.989
	TT	51(23.4)	127(58.3)	178(81.7)	(0.442-1.984)	0.865	63 (27.3)	126(54.5)	189(81.8)	(0.665-2.987)	0.370	(0.613-1.596)	0.964
		LLI	Controls
	Allele	n	%	n	%	p ^ Comparison between CT and LLI;	OR (95%CI)
							0.975
FOXO3	G	202	46.3	217	47.0	0.848	(0.750-1.267)
							1.026
	T	234	53.7	245	53.0	0.472	(0.789-1.334)
SOD2	C	236	54.1	239	51.7		1.101
							(0.847-1.431)
	T	200	45.9	223	48.3		0.908
							(0.699-1.181)
APOE	∊2	31	7.3	32	7.5	0.867	0.904
							(0.542-1.509)
	∊3	314	73.7	319	74.9		0.768
							(0.576-1.024)
	∊4	81	19.0	75	17.6		1.018
							(0.721-1.438)
SIRT1	C	44	10.1	44	9.5	0.775	1.066
							(0.687-1.656)
							0.938
	T	392	89.9	418	90.5		(0.604-1.456)

	FOXO3 SNP Genotypes (rs2802292)
Variables (n)/Groups	GG	GT	TT	p ^* * Comparison between mean values of parameters for genotypes within LLI and controls;
Triglycerides (mg/dl) (249)
LLI	108.2 ± 34.0	109.8 ± 63.6^a a p < 0.05 (Tukey test); For heart disease and diabetes, values refer to that morbidity carrier.FOXO3 (rs2802292:G > T. RefSeqNM_001455.3).	147.6 ± 96.9^a a p < 0.05 (Tukey test); For heart disease and diabetes, values refer to that morbidity carrier.FOXO3 (rs2802292:G > T. RefSeqNM_001455.3).	0.036
Controls	150.1 ± 131.6	148.6 ± 83.7	163.1 ± 140.2	0.818
Glucose (mg/dl) (279)
LLI	109.2 ± 37.5	106.1 ± 26.4	107.1 ± 25.1	0.896
Controls	122.8 ± 50.6	119.6 ± 48.9	106.8 ± 25.7	0.226
Body Mass Index (251)
LLI	25.1 ± 3.7	24.3 ± 4.7	26.7 ± 4.7	0.070
Controls	26.7 ± 4.4	26.8 ± 4.6	27.4 ± 4.8	0.760
Heart disease (236)
LLI	19 (45.2%)	65 (55.1%)	30 (51.7%)	0.545^ Odds Ratio was not calculated because p > 0.05;
Controls	26 (54.2%)	61 (50.4%)	35 (56.5%)	0.725^ Odds Ratio was not calculated because p > 0.05;
Diabetes (108)
LLI	6 (14.3%)	24 (20.3%)	10 (17.2%)	0.663^ Odds Ratio was not calculated because p > 0.05;
Controls	14 (29.2%)	36 (29.8%)	18 (29.0%)	0.994^ Odds Ratio was not calculated because p > 0.05;
Malondialdehyde (μmol/L plasma) (100)
LLI	1.68 ± 0.23	1.91 ± 0.66	2.28 ± 0.74	0.116
Controls	1.88 ± 0.75	1.81 ± 0.55	1.58 ± 0.24	0.393
Genomic damage (a.u.) (30)^b b (standard deviation or standard error of the mean) or number of subjects with percentage in parentheses. Abbreviations: n - number of individuals; LLI - Long-Lived Individuals; a.u. - arbitrary units;
LLI	0.015 ± 0.009	0.065 ± 0.017	0.027 ± 0.012	0.108
Controls	0.045 ± 0.025	0.027 ± 0.008	0.032 ± 0.014	0.731

Gene	Genotypes/Groups (n)	Healthy LLI (83)	Frail LLI (135)	p ^* * Comparison between genotypes of frailty and healthy status;	OR (95% CI)^ p-value for Odds Ratio; For APOE, n= 81 (Healthy LLI) and n= 132 (Frailty LLI). FOXO3 (rs2802292:G > T. RefSeqNM_001455.3), SOD2 (rs4880:T > C. RefSeqNG_008729.1), SIRT1 (rs2273773:T > C. RefSeqNM_001142498.1) APOE (rs429358:T > C. RefSeqNG_007084.2 and rs7412:C > T. RefSeqNG_007084.2).	p ^ p-value for Odds Ratio; For APOE, n= 81 (Healthy LLI) and n= 132 (Frailty LLI). FOXO3 (rs2802292:G > T. RefSeqNM_001455.3), SOD2 (rs4880:T > C. RefSeqNG_008729.1), SIRT1 (rs2273773:T > C. RefSeqNM_001142498.1) APOE (rs429358:T > C. RefSeqNG_007084.2 and rs7412:C > T. RefSeqNG_007084.2).
		n (%)	n (%)
FOXO3	GG	19 (22.9)	23 (17)		1.446 (0.732 - 2.856)	0.287
	GT	43 (51.8)	75 (55.6)	0.567	0.860 (0.497 - 1.488)	0.590
	TT	21(25.3)	37 (27.4)		0.897 (0.482 - 1.673)	0.733
SOD2	CC	25 (30.1)	32 (23.7)		1.387 (0.751-2.565)	0.295
	CT	41(49.4)	81 (60.0)	0.342	0.651 (0.375-1.129)	0.125
	TT	17 (20.5)	22 (16.3)		1.323 (0.656-2.670)	0.433
APOE	∊2∊3	11 (13.6)	17 (12.9)		1.063 (0.471-2.400)	0.883
	∊3∊3	39 (48.1)	80 (60.6)		0.640 (0.345-1.055)	0.075
	∊2∊4	1 (1.2)	3 (2.3)	0.313	0.538 (0.055-5.257)	1.000
	∊3∊4	25 (30.9)	28 (21.2)		1.658 (0.883-3.112)	0.114
	∊4∊4	5 (6.2)	4 (3.0)		2.105 (0.548-8.080)	0.306
SIRT1	CC	3 (3.6)	1 (0.7)		5.025 (0.514-49.160)	0.156
	CT	12 (14.5)	24 (17.8)	0.292	0.782 (0.367-1.662)	0.577
	TT	68 (81.9)	110 (81.5)		1.030 (0.507-2.092)	1.000

Sociedade Brasileira de Genética Rua Cap. Adelmio Norberto da Silva, 736, 14025-670 Ribeirão Preto SP Brazil, Tel.: (55 16) 3911-4130 / Fax.: (55 16) 3621-3552 - Ribeirão Preto - SP - Brazil
E-mail: editor@gmb.org.br

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[1] Send correspondence to Flavia de Paula. Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas – Centro de Ciências Humanas e Naturais, Universidade Federal do Espírito Santo, Av. Fernando Ferrari, 514, Goiabeiras, 29075-910, Vitória, ES, Brazil. E-mail: flapvit@yahoo.com.br