Role of IL-10 −1082, IFN-γ +874, and TNF-α −308 Genes Polymorphisms in Suicidal Behavior

Role of IL-10 �1082, IFN-cþ874, and TNF-a �308Genes Polymorphismsin Suicidal Behavior

Mir Davood Omrani, Behzad Bushehri, Morteza Bagheri,Shaker Salari-Lak, Azize Alipour, Mohamad-Reza Anoshae,and Reza Massomi

In this study, it was determined whether the IL-10 �1082, IFN-c þ874, andTNF-a �308 polymorphisms were associated with suicidal behavior. One hundredforty five patients with suicidal behavior and 160 normal individuals were genotypedfor IL-10 �1082, IFN-c þ874, and TNF-a �308 polymorphisms usingASO-PCR method. TNF-a �308 G=G genotype has been increased in maleswith completed suicide behavior versus control group (p value¼ 0.017). IL-10�1082 A=A genotype is higher in both male and female suicide completed groups(p value¼ 0.017). IFN-c (þ874) A=A genotype was significantly higher in maleswith completed suicide behavior versus normal male control (p value¼ 0.027).It can be concluded that IL-10, IFN-c, and TNF-a polymorphisms may play arole in suicidal behavior.

Keywords IFN-c þ874, IL-10 �1082, suicide behavior, TNF-a �308

INTRODUCTION

Cytokines as low molecular mass proteinsare produced from wide range of cellsincluding T cells, glial cells, and macro-phages; and contribute in normal functionsof central nervous system (CNS)(Pollmacher, Haack, Schuld et al., 2000;Woodroofe, 1995). Production and secretionof cytokines is transient and local and reg-ulate the inflammatory responses of theimmune system (Kronfol & Remick,2000; Muller & Ackenheil, 1998; Ozaki &Leonard, 2002). Cytokines play a centralrole in CNS diseases’ predisposition,and mainly impact the monoaminergic

neurotransmitter systems (Gogos, Morgan,Luine et al., 1998; Muller & Ackenheil,1998). It has been suggested that cytokinesor other immune response modulatorsmay play a role in psychiatric disorders(Dantzer, Wollman, Vitkovic et al., 1999;Licinio & Wong, 1999). Psychiatric historycould increase the risk of suicidal behavior(Rujescu, Giegling, Gietl et al., 2003). Therole of inheritance in suicide was foundto be about 55% (Statham, Heath, Maddenet al., 1998). The results of twin andfamilial-based investigations showed thatthe rate of suicidal behaviors in probandfamily depends on familial history of sui-cide behavior. In this regard, status of

Archives of Suicide Research, 13:330–339, 2009Copyright # International Academy for Suicide ResearchISSN: 1381-1118 print=1543-6136 onlineDOI: 10.1080/13811110903266418

330

family history determines the suicidalattempts or completed suicide behavior inthe family members which is transmittedvertically in the family (Roy, 1986; Roy,Segal, Centerwall et al., 1991; Schulsinger,Kety, Rosenthal et al., 1979). Several inves-tigations within different countries showthat the rate of suicide among youngpeople has increased, and has been identi-fied as great problem for people’s health(Beautrais, 2000; Graham & Burvill,1992). Since the majority of the Iranianpopulation consists of young people andthe rate of suicide is increasing in thiscountry like all other countries, it isimportant to find all the predisposingfactors for suicidal behavior. One of theinteresting fields for this purpose is tracingthe individual cytokines and cytokinegene polymorphisms of affected people.Cytokine production is individual-specificand dependent on single nucleotide poly-morphisms of cytokine gene’s promoteror other regulatory sequences (Hollegaard& Bidwell, 2006). An earlier study (Alkelai,Baum, Carless et al., 2007) has identifiedassociation between IL28 R polymorph-isms and suicidal thinking during treatmentprotocols. Therefore, the goal of the cur-rent study was to evaluate a potential asso-ciation between IL-10 �1082, IFN-cþ874, and TNF-a �308 genes polymorph-isms with suicidal behavior in the Iranianpopulation.

METHODS

According to C-CASA classification byPosner, Osquendo, Gould et al. (2007),145 persons with completed suicide beha-vior (age: 25.82 (mean)� 12.57 (S.D.)),who subdivided to two fatal and non-fatalsubgroups (fatal group: 28 males; age:33.46 (mean)� 18.15 (S.D.) and 17 females;age: 27.35 (mean)� 14.58 (S.D.)) and 100non fatal but hospitalized patients (46males; age: 24.10 (mean)� 9.90 (S.D.) and

54 females; age: 22.85 (mean)� 8.42(S.D.)), as well as 160 normal male andfemales (age: 70.6 (mean)� 10 (S.D.)) par-ticipated in the study. The entire controlgroup and all patients were examined tosee if they had any history of psychiatricdisorders according to DSM-IV criteria(including axis-I and -II diagnosis protocol;American Psychiatric Association, 1994).Normal individuals were selected fromthe same race and geographical area asthe patient’s sample. Only Azari ethnicityof West Azarbijan province in North Westof Iran took part in the study. Five ml ofblood was collected from them inthe EDTA-contained tubes. Salting outmethod was used for DNA isolation(Miller, Dykes, & Polesky, 1988). IFN-cþ874 (A=T), IL-10 �1082 (A=G), andTNF-a �308 (A=G) typing was performedusing allele-specific oligonucleotide poly-merase chain reaction method (ASO-PCR)as shown in Table 1 (Huang, Zhou, Xia,et al., 1999; Pravica, Perrey, Stevens et al.,2000; Verjans, Brinkman, VanDoorniket al., 1994). Each PCR reaction was per-formed in a 20-ul volume containing50–100 ng of genomic DNA, 1� reactionbuffer 10 pmol of each primer, 200 umoleach of dNTPs, 1 unit of Taq DNA poly-merase, 1.5mmol MgCl2. The amplifiedASO-PCR products were monitored byelectrophoresis on 1.5% agarose gel con-taining ethidium bromide stain. Allelic andgenotypic frequencies were found by directcounting and division by the number ofsubjects in each group. Fit to Hardy-Weinberg equilibrium, allelic, and genotypicfrequencies of IFN-c þ874, IL-10 �1082,and TNF-a �308 were compared by v2

test. The level of significance was set atp¼ 0.05. The minimum sample size wascalculated as 43 subjects for studied groups(two-sided test, power (1� b): 90% level ofsignificance a: 5%). The SPSS VER. 16.0for windows and Microsoft Excel 2007were used to calculate the Pearson v2 test,the odds ratio, and 95% confidence interval.

M. D. Omrani et al.

ARCHIVES OF SUICIDE RESEARCH 331

RESULTS

The genotypic and allelic frequencies ofIFN-c þ874 (A=T), IL-10 �1082 (A=G)and TNF-a �308 (A=G) gene polymorph-isms among healthy control (males or

females) and patients with completedsuicide behavior (non-fatal or fatal groups)are summarized in Table 2a, b, and c. Themost common form of suicide method inthis study was chemical drugs or otherhousehold poisons (75.17%; 67.57% males

TABLE 2. The Genotypic and Allelic Frequencies of TNF-a�308, IL-10�1082, and IFN-cþ874 GenePolymorphism among Compared Healthy Individuals, and Completed Suicide Behavior

a. GroupsNumberof subjects

TNF-a �308 allele and genotypes frequency

A G A/A A/G G/G

Normal individuals 155 153 157 8 137 10

Completed suicide behavior 145 133 157 7 119 19

b. GroupsNumberof subjects

IL-10 �1082 allele and genotype frequency

A G A/A A/G G/G



c. GroupsNumberof subjects

IFN-c þ874 allele and genotype frequency

A G A/A A/T T/T



TABLE 1. Cytokines, Primers, PCR Condition used for Their Amplification and Product Size

Polymorphism Sequence of primers and PCR conditionsPCR

products Reference

IFN-c þ874 Common primer: 50-tca aca aag ctg ata ctc ca-30,

T allele primer: 50-ttc tta caa cac aaa atc aaa tct-30,

A allele primer: 50-ttc tta caa cac aaa atc aaa

tca-30, 10 cycles: 94�C 30 s, 62�C 50 s, 72�C 40 s,

and 20 cycles: 94�C 20 s, 56�C 50 s, 72�C 40 s

261 bp Pravica, Perrey,

Stevens et al.

(2000)

IL-10 �1082 Common primer: 50-cag ccc ttc cat ttt act ttc-30,

G allele primer: 50-tac taa ggc ttc ttt ggg ag-30,

A allele primer: 50-cta cta agg ctt ctt tgg gaa-30, 30

cycles: 94�C 30 s, 56�C 30 s, 72�C 30 s

550 bp Huang, Zhou,

Xia, et al. (1999)

TNF-a �308 Common primer: 50-tct cgg ttt ctt ctc cat cg-30,

G allele primer: 50-ata ggt ttt gag ggg cat gg-30,

A allele primer: 50-ata ggt ttt gag ggg cat ga-30, 30

cycles: 94�C 30 s, 61�C 2.5min, 72�C 1min

184 bp Verjans, Brinkman,

VanDoornik et al.

(1994)

IL-10 �1082, IFN-c þ874, & TNF-a �308 Polymorphisms and Suicidal Behavior

332 VOLUME 13 � NUMBER 4 � 2009

TABLE 3. Demographic Features of Patients with Completed Suicide Behavior(Non-fatal and Fatal Groups)

Male Female TotalN¼ 74 N¼ 71 N¼ 145F(%F) F(%F) F(%F)

Marriage status

Married 28(37.84) 33(46.48) 61(42.07)

Single 46(62.16) 34(47.89) 80(55.17)

Separated 0(0) 4(5.634) 4(2.759)

Education

Without school qualification 11(14.86) 10(14.08) 21(14.48)

Elementary 10(13.51) 16(22.54) 26(17.93)

Intermediate 30(40.54) 18(25.35) 48(33.1)

Diploma 21(28.38) 21(29.58) 42(28.97)

University qualification 2(2.703) 6(8.451) 8(5.517)

Living place

City 51(68.92) 46(64.79) 97(66.9)

Village 23(31.08) 25(35.21) 48(33.1)

Place of suicide attempts

Private house 58(78.38) 55(77.46) 113(77.93)

Rental house 10(13.51) 12(16.9) 22(15.17)

Office 2(2.703) 1(1.408) 3(2.069)

Student accommodation 3(4.054) 2(2.817) 5(3.448)

Unknown 1(1.351) 1(1.408) 2(1.379)

History of suicide behaviors 61(82.43) 58(81.69) 119(82.07)

No 4(5.405) 2(2.817) 6(4.138)

Yes 7(9.459) 7(9.859) 14(9.655)

Two times 2(2.703) 4(5.634) 6(4.138)

More than two times

History of suicide in first degree relatives 71(95.95) 67(94.37) 138(95.17)

No 3(4.054) 3(4.225) 6(4.138)

Yes 0(0) 1(1.408) 1(0.69)

Unknown

Suicidal methods

Hanging 14(18.92) 3(4.225) 17(11.72)

Firearms 4(5.405) 7(9.859) 11(7.586)

Poisoning 50(67.57) 59(83.1) 109(75.17)

Falling 0(0) 1(1.408) 1(0.69)

Drowning 4(5.405) 0(0) 4(2.759)

Violent means (guns, knives . . .) 1(1.351) 0(0) 1(0.69)

Non-violent means 1(1.351) 1(1.408) 2(1.379)

M. D. Omrani et al.


TABLE4.OR

(95%

CI,Pvalue)CalculatedforComparisonsamongStudiedGroupswithSuicideBehaviorandControl

TNF-a

�308genotype

comparisonbetw

eengroups

AAOR

(95%

CI,Pvalue)

AG

OR

(95%

CI,Pvalue)

GG

OR

(95%

CI,Pvalue)

AGþGG

OR

(95%

CI,Pvalue)

Completedvs.control

0.93(0.5,1.36,0.79)

0.92(0.36,1.48,0.76)

2.03(1.14,2.92,0.023)

1(0.43,1.57,0.77)

Fem

alecompletedvs.femalecontrol

0.84(0.19,1.49,0.89)

0.98(0.51,1.45,0.78)

1.2(0.53,1.87,0.69)

1.01(0.41,1.61,0.75)

Malecompletedvs.malecontrol

0.45(0.08,0.82,0.92)

0.94(0.3,1.58,0.59)

3.2(1.25,5.15,0.017)

1.01(0.64,1.38,0.77)

IL-10�1082genotype

comparison

betw

eengroups

AAOR

(95%

CI,Pvalue)

AG

OR

(95%

CI,Pvalue)

GG

OR

(95%

CI,Pvalue)

AGþGG

OR

(95%

CI,Pvalue)

Completedvs.control

1.78(1.11,2.63,0.017)

0.97(0.48,1.46,0.57)

0.76(0.39,1.13,0.79)

0.96(0.42,1.5,0.81)

Fem


1.76(1.25,2.27,0.032)

0.96(0.29,1.63,0.87)

1.05(0.5,1.52,0,68)

0.96(0.31,1.61,0.69)


1.8(1.31,2.29,0.019)

0.99(0.45,1.53,0.75)

00.97(0.33,1.61,0.67)

IFN-c

þ874genotype

comparisonbetw

eengroups

AAOR

(95%

CI,Pvalue)

AT

OR

(95%

CI,Pvalue)

TT

OR

(95%

CI,Pvalue)

ATþTT

OR

(95%

CI,Pvalue)

Completedvs.control

1.35(0.67,2.03,0.089)

1.18(0.62,1.74,0.08)

0.56(0.27,0.85,0.067)

0.96(045,1.47,071)

Fem


1.02(0.43,1.61,0.65)

1.2(0.73,1.67,0.092)

0.7(0.31,1.09,0.87)

1.01(0.56,1.46,0.68)


1.57(1.16,1.98,0.027)

1.2(0.68,1.72,0.68)

0.47(0.24,0.7,0.079)

0.88(0.39,1.37,0.65)

334 VOLUME 13 � NUMBER 4 � 2009

and 83.1% females). Demographic findingsof patients with completed suicide behaviorare summarized in Table 3. Odds ratio andconfidence interval in compared groupswere also summarized in Table 4. Asshown in Table 4, there is no significantdifference in TNF-a �308 polymorphismsbetween females with completed suicidebehavior versus female controls (p value>0.05). TNF-a �308 G=G genotype hasbeen increased in males with completedsuicide behavior versus control (p value¼0.017) group. When a comparison was car-ried out among all patients with completedsuicide behavior against normal controls,significant difference was observed inTNF-a �308 G=G genotype (p value¼0.023). Adversely, IL-10 �1082 A=A geno-type is higher in both male and femalesuicide completed groups (p value¼ 0.017).IFN-c (þ874) A=A genotype was signifi-cantly increased in males with completedsuicide behavior versus normal malecontrols (p value¼ 0.027).

DISCUSSION

The suicide rate in Iran is 0.3 per 100,000among males and 0.1 per 100,000 amongfemales. In 2006, the total rate of suicidein West Azerbaijan (a province of Iran) was1.72 per 100,000 (Salari-Lak, Entezarmahdi,Afshani et al., 2006). The mean age ofthe suicide completers was 27.64� 14.25for males and 23.92� 10.29 for females.Females continue to show complete suicidebehavior at a younger age than males. Ourresults indicate that the suicide rate in thisstudy is higher than the suicide rate in Iran(1.72 vs. 0.2 per 100,000 people). In ourstudy, the rate of suicide in males wassignificantly higher than females. In thisstudy, the most common form of suicidalbehavior is using chemical drugs and otherhousehold poisons (75.17%; 67.57% malesand 83.1% females). Methods such ashanging (18.92% for males, 4.22% for

females) and firearms (5.40% for males,9.85% for females) occupied second andthird place, respectively. Hanging was thesecond most frequent among males withcompleted suicide behavior. Also in thecase of females, poisoning (83.1%), fire-arms (9.8%), and hanging (4.22%) havethe highest frequencies. When the geno-type of the suicide completer group wasexamined (fatal and non-fatal), it was foundthat there is no significant difference inTNF-a �308 polymorphisms betweenfemales with completed suicide behaviorversus female controls (p value> 0.05).TNF-a �308 G=G genotype has beenincreased in male with completed suicidebehavior versus control (p value¼ 0.017)group. When a comparison was carriedout among all patients with completedsuicide behavior against normal controls,significant difference was observed inTNF-a �308 G=G genotype (p value¼0.023). Lanquillon, Krieg, Bening-Abu-Shach et al. (2000) and Mikova,Yakimova, Bosmans et al. (2001) in theirfindings showed that the level of TNF-ahas been increased in major depression(Lanquillon, Krieg, Bening-Abu-Shach et al.,2000; Mikova, Yakimova, Bosmans et al.,2001); also Brek, Wadee, Kuschke et al.(1997), Maes, Bosmans, Suy et al. (1991),and Weizman, Laor, Podliszewski et al.(1994) found that the production ofIL-1b and IL-6 as pro-inflammatory cyto-kines has been increased in major depres-sion (Berk, Wadee, Kuschke et al., 1997;Maes, Bosmans, Suy et al., 1991; Weizman,Laor, Podliszewski et al., 1994). Interest-ingly, the biological effect of IL-1b is simi-lar to TNF-a. These findings emphasizethat pro-inflammatory cytokines such asTNF-a play a critical role in psychiatric dis-orders. Our results showed that the lowproducing form of TNF-a �308 poly-morphism (G=G) is significantly higher inmale completers in comparison to malesin the normal control group. A strongintent to die mainly influences the suicide

M. D. Omrani et al.


behavior and individuals with a strongintent to complete suicide (Beautrais, 2003;Brent, Perper, Goldstein et al., 1988). Indi-viduals who continue suicide attempts withlow intent, but with access to a violentmethod may die. However, lack of knowl-edge on suicide pattern may increase mor-tality (Brent, Perper, Moritz et al., 1993).Some reports are not in line with our find-ings. For example, Pilar, Paz, Begona et al.(2008) showed no association between IL-1or TNF-a gene polymorphisms and suici-dal behavior. Jun, Pae, Chae et al. (2003)indicated that Tumor necrosis factor-bmay not be associated with major depres-sive disorders in the Korean population.The results of Tonelli, Stiller, Rujescuet al. (2008) showed that TNF-a produc-tion did not significantly increase infemales who completed suicide and theexpression of IL-4 significantly increasedin female suicide completers, and IL-13 inmale suicide completers. Huang and Lee(2007) indicated that the level of TNF-abetween patients with and without suicidalbehavior was not significantly different.The TNF-a gene is located on shortarm of Chromosome 6 within the MHCcomplex region (class III). It has beendemonstrated that this region is associatedwith high production and secretion ofTNF-a; and have shown ethnic differences(Abraham, French & Dawkins, 1993; Keso,Perola, Laippala et al., 2001). Therefore alarge-scale case-control study of ethnicpopulations is suggested. In contrast, IL-10�1082 A=A genotype is higher in bothmale and female suicide completed groups(p value¼ 0.017). This cytokine has animmunosuppressive effect. Capuron,Ravaud, Gualde et al. (2001) reportedthat IL-10 production was significantlyincreased in patients with major depressivedisorder. IL-10 as major regulator of othercytokines has immunomodulating and hasimmunoregulatory effects on the immuneresponses (Turner, Williams, Sankaranet al., 1997). Huang and Lee (2007)

indicated that the level of IL-10 betweenpatients with and without suicidal behaviorwas not significantly different. IL-10 as themain inhibitor of TNF-a may implicate itsrole due to suppression of T helper 1 subsets (Huang, Ullrich, & Ber Eli, 1999). Inour study, low production of IL-10 wasobserved. IFN-c (þ874) A=A genotypewas significantly increased in males withcompleted suicide behavior versus normalmale controls (p value¼ 0.027). The find-ings of Connor and Leonard (1998)showed that cytokine storm of IL-1b,IL-6, and IFN-c has been associated withdepressive disorders. Mann, Waternaux,Haas et al. (1999) reported that aggressivepersonality of patients triggers the suicideattempts. Cytokine abnormalities in patientswith psychiatric disorders show several con-troversial reports. Some differences werefound among female versus male groupsin allele or genotype frequencies which arisefrom the different levels of estrogen hor-mone in males and females (Balthazart,Foidart, Absil, et al., 1996). Several studiesindicated that there is an association betweenneuropsychiatry diseases and gender(Dauvilliers, Neidhart, Lecendreux et al.,2001; Qian, Wang, Zhou et al., 2003). Also,environmental or other unknown factorscould impact the distribution of cytokinepolymorphisms in male and female patientswith psychiatric disorders, which is notexcluded from this study. Limitations ofpresent study include: (1) poor quality ofmedical records’ documentations by regis-tration systems; (2) the samples are notbalanced in the groups that were studiedwith regard to the subjects’ number, gender,and status of clinical diagnosis; (3) our malescontrol group’s age was higher than theiractual male with suicide behavior; and (4)lack of medical history of attempters withfatal suicidal behavior. It is suggested tocontinue the investigation in larger groups,taking into consideration the psychiatricbackground of the patients, body massindex, gender, race, human leukocyte


336 VOLUME 13 � NUMBER 4 � 2009

antigens, and the ratio calculation ofT helper 1 to T helper 2 cytokines.

CONCLUSION

Presently it can be emphasized that thesuicide incidence within West Azerbaijanis higher than the suicide incidence in otherparts of Iran. Our results suggest thatIL-10, IFN-c, and TNF-a polymorphismsmay play a role in suicidal behavior in theWest Azerbaijani population. Other epide-miologic studies could be useful for defin-ing the details of suicidal risk factors in theregion of current study.

AUTHOR NOTE

This study was supported by a researchgrant from the Legal Justice and ForensicMedicine Department.

Mir Davood Omrani, Department ofGenetics, Urmia University of MedicalSciences, Motahari Hospital, Urmia, Iran.

Behzad Bushehri, Department ofToxicology, Urmia University of MedicalSciences, Urmia, Iran.

Morteza Bagheri, Department ofGenetics, Urmia University of MedicalSciences, Motahari Hospital, Urmia, Iran.

Shaker Salari-Lak, Department ofEpidemiology, Urmia University of MedicalSciences, Urmia, Iran.

Azize Alipour, Department of Genetics,Urmia University of Medical Sciences,Motahari Hospital, Urmia, Iran.

Mohamad-Reza Anoshae, Departmentof Psychiatry, Urmia University of MedicalSciences, Urmia, Iran.

Reza Massomi, Department of LegalJustice and Forensic Medicine, Urmia, Iran.

Correspondence concerning this articleshould be addressed to Dr. Mir DavoodOmrani, Associate Prof. of Genetics,Motahari Hospital, Kashani Ave., Urmia,West Azerbaijan, Iran. E-mail: [email protected]

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Role of IL-10 −1082, IFN-γ +874, and TNF-α −308 Genes Polymorphisms in Suicidal Behavior

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