Chapter - III Results and Discussion

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1 Chapter - III Results and Discussion

2 Chapter - III Results and Discussion In the present genetic epidemiological study, for evaluating association between recurrent pregnancy loss (RPL) and three pro-inflammatory cytokine gene polymorphisms viz., TNF-α (-308 G/A; rs ), TNF-β (+252 A/G; rs909253) and IFN-γ (+874 A/T; rs ), a total of 366 DNA samples were extracted from a case-control cohort comprising 139 cases of RPL and 197 age and geography matched controls from Delhi, North India. Of these, 329 samples (134 cases and 195 controls) could be genotyped for TNF-α (-308 G/A; rs ) polymorphism, 330 samples (133 cases and 197 controls) could be genotyped for TNF-β (+252 A/G; rs909253) polymorphism and 311 samples (125 cases and 186 controls) could be genotyped for IFN-γ (+874 A/T; rs ) polymorphism due to laboratory constrains. The information regarding the rs ID, chromosomal position and genotype counts of the three SNPs analyzed is listed in Table 3.1 along with the exact test for Hardy-Weinberg Equilibrium (HWE) and contingent Chi-square (cases vs. controls) test values. Both the cases and controls were found to be in HWE at each of the three polymorphic sites (p=1 in both cases and controls for rs , p = 0.46 in cases and p=0.6 in controls for rs and p = in cases and p=0.065 in controls for rs ). This demonstrates that the studied SNPs are independently distributed in the studied material and there are negligible chances of genotyping error. The contingent Chi-square test showed statistically nonsignificant differences between cases and controls (p = for rs , p = for rs and p = for rs ) indicating a similar genotype 83

3 distribution in both the study groups with respect to all the three SNP sites (Table 3.1). The allele frequencies for the three SNPs were calculated by gene counting method (Mourant et al., 1976) and the results are presented in Table 3.2. The odds ratio (OR) values calculated at 95% confidence interval (CI) along with probability values for all the four inheritance models viz., co-dominant, dominant, recessive and over-dominant with respect to the three selected SNPs viz., TNF-α (-308 G/A; rs ), TNF-β (+252 A/G; rs909253) and IFN-γ (+874 A/T; rs ) are listed in Table 3.3 along with Akaike s Information Criteria (AIC) and Bayesian Information Criteria (BIC) values TNF-α (-308 G/A; rs ) Cytokine Gene Polymorphism In case of TNF-α (-308 G/A; rs ) polymorphism, both the cases and controls were observed to have almost same frequency of GA heterozygote (8.95% in cases vs. 8.72% in controls) and normal GG homozygous (91.05% in cases vs % in controls) genotypes. Neither of the two groups showed the presence of the mutated AA homozygous condition in the samples studied (Table 3.2). In a study conducted among the Caucasian women by Pietrowski et al. (2004) on TNF-α (-308 G/A) polymorphism and RPL, GA heterozygote genotype was found in almost similar frequencies in cases (19.6%) and in controls (19.3%) and mutated AA homozygote genotype also showed the same trend (1.2% in cases and 1.9% in controls) in the genotype distribution between cases and controls (Table 3.7). A study conducted on Iranian women by Kamalli-Sarvestani et al. (2005) also observed similar genotype distribution of TNF-α (-308 G/A) between RPL cases and controls (Table 3.7) as the combined frequency of mutated homozygous AA and heterozygous GA genotypes was found to be 11% in cases vs. 15% in controls and the frequency of normal homozygous GG genotype was 89% in cases and 85% in controls. 84

4 On the other hand, Babbage et al. (2001) reported, among the RPL cases and controls in the Caucasian women of UK, comparatively higher combined frequency of GA heterozygote and mutated AA homozygote in cases (30%) compared to controls (23%) (Table 3.7). Similarly, a trend towards increased frequency of both heterozygous GA and mutated homozygous AA genotypes (25% in cases vs. 18% in controls) was reported among RPL cases in the Brazilian Caucasian women in a study conducted by Daher et al. (2003) (Table 3.7). Zammitti et al. (2008) conducted a case-control study on recurrent miscarriages and found among the cases, compared to controls, a comparatively higher frequency of mutated AA homozygote (4% in cases and 2.5% in controls), but a comparatively lower frequency of GA heterozygote (8.9% in cases and 13.5% in controls (Table 3.7). However, all the above mentioned studies found statistically non-significant differences in the genotype distribution of TNF-α (-308 G/A; rs ) polymorphism among RPL cases and controls (Table 3.10). As for the allele frequency distribution of TNF-α (-308) marker in different populations of world, mutated A allele ranged from 9% in Tunisian population (Zammitti et al., 2008) to 16% in Caucasian women of UK (Babbage et al., 2001), and the presently studied population of Delhi from North India showed a much lower frequency of the allele ( 4.36%) (Table 3.7). Like genotype distribution of TNF-α (-308 G/A; rs ), in allele frequency distribution of this SNP there was similarity in values observed in cases and controls of this study as the normal allele G frequency was 95.52% among RPL cases and 95.64% among controls and the mutated allele A frequency was 4.48% among RPL cases and 4.36% among controls (Table 3.2). Similar observations were made by Pietrowski et al. (2004) in a study conducted on Caucasian women where an almost same frequency of TNF-α (-308 G/A) mutated allele A was found among RPL cases and controls (11.1% in cases and 11.6% in controls) (Table 3.7). In yet another study conducted on the Tunisian population, an almost same frequency of mutated A allele (8% in cases and 9% in controls, p = 0.338) was seen among the early recurrent miscarriage 85

5 cases as compared to controls (Zammitti et al. (2008) which is in accord with the present finding (Table 3.7). On the other hand, the present findings are in contrast with those reported by Reid et al. (2001) who noticed an increased incidence in the carriage of TNF-α (308) A allele which was more pronounced in the women with two or more miscarriages among the Caucasian population of UK (Table 3.10). Whereas Babbage et al. (2001) observed a comparatively lower frequency of mutated A allele among the cases than the controls in the Caucasian women of UK (14% in cases vs. 16% in controls) which is also at a variance with the present study (Table 3.7). Since there was no evidence of mutated AA homozygous genotype condition in the presently studied sample from Delhi, North India for TNF-α (-308 G/A) polymorphism, the value of odds ratio was found to be same in dominant, over-dominant and one of the possible combination in the co-dominant (GA vs. GG) models of inheritance while recessive and AA vs. GG co-dominant models were not applicable in this case. Only measure of odds ratio was obtained among the cases compared to that of controls with the 95% confidence interval of and probability value of 0.941, showing no association between RPL and the studied TNF-α (-308 G/A) polymorphism in people of Delhi (Table 3.3). The present association results were similar to those reported elsewhere in the world. Babbage et al. (2001) conducted a study on the Caucasian women of UK where no association was found between TNF-α (-308 G/A) polymorphism and RPL (OR = 1.4, CI = , p = 0.4) (Table 3.10). Prigoshin et al. (2004) also did not find any evidence of association between RPL cases and controls concerning TNF-α (-308 G/A) polymorphism among the Caucasian women (Table 3.10). Pietrowski et al. (2004) also concluded that TNF-α (-308 G/A) polymorphism and resting TNF-α levels do not correlate with the propensity of RPL in the Caucasian women as they did not found a significant association between the two (OR = 0.9, CI = , p = 0.05) (Table 3.10). Studies conducted on the Argentine women by Prigoshin et al. (2004) and on Iranian women by Kamalli-Sarvestani et al. (2005) 86

6 also did not find any association concerning TNF-α (-308 G/A) polymorphism and RPL as they reported statistically non-significant differences in genotype distribution among cases and controls (Table 3.10). Zammitti et al. (2008, 2009) also reported no association of RPL with TNF-α (-308 G/A) polymorphism in Tunisian population (OR = 0.78, CI = ) (Table 3.10). However, Daher et al. (2003) demonstrated a trend for association of RPL with the high TNF-α production genotypes at -308 position (OR = 1.61) among the Brazilian Caucasian women (Table 3.10), albeit with non-significant results (p = 0.18) TNF-β (+252 G/A; rs909253) Cytokine Gene Polymorphism A comparatively lower frequency of mutated GG homozygote (3.75% in cases vs. to 8.63% in controls) and somewhat higher frequency of normal AA homozygote (57.90% in cases vs % in controls) was found among the cases as compared to the controls with respect to TNF-β (+252 A/G; rs909253) polymorphism. But like TNF-α (-308 G/A; rs ) polymorphism, in this polymorphism also a similar frequency of AG heterozygote was found in both the study groups i.e % in cases and 39.09% in controls (Table 3.2). A study conducted on the Iranian women by Kamalli-Sarvestani et al. (2005) also did not observe any significant difference in genotype distribution of TNF-β (+252 A/G) between RPL cases and controls. The combined frequency of mutated homozygous GG and heterozygous AG genotypes was found to be 47% in cases and 45% in controls while the frequency of normal homozygous AA genotype was 53% in cases and 55% in controls (p = 0.89) (Tables 3.8, 3.11). Zammitti et al. (2008) in a study conducted on early recurrent miscarriages in Tunisia found a comparatively higher frequency of TNF-β (+252) AG heterozygote (21.4% in cases vs. 17.5% in controls) and mutated GG homozygote (4.6% in cases vs. 1.5% in controls) among RPL cases as compared to controls (Table 3.8) with non-significant differences (p = and p = respectively) (Table 3.11). 87

7 As for allele frequencies of TNF-β (+252 A/G; rs909253) polymorphism, the incidence of the mutated allele G was found to be lower among the cases as compared to the controls (22.93% in cases vs % in controls) and the normal allele A was found to be at a comparatively higher frequency in the RPL cases in the present study (77.07% in cases vs % in controls) (Table 3.2). On the other hand, in a study conducted on the Tunisian population (Zammitti et al., 2008), a comparatively higher frequency of mutated G allele was found among the early miscarriage cases as compared to controls (15% in cases vs. 10% in controls) Table 3.8). The Tunisian population and population of Delhi in the present study thus show vast differences in the frequency of mutated G allele of this polymorphism (Table 3.8). In the present study from Delhi, North India, all inheritance models showed OR less than 1, with values ranging from ( ) in the codominant model to ( ) in the over- dominant model of inheritance, suggesting no association between RPL and TNF- (+252 A/G; rs909253) (Table 3.3). Similarly a study conducted on the Iranian women by Kamalli-Sarvestani et al. (2005) also did not find any association of TNF-β (+252 A/G) polymorphism with RPL as they observed non-significant difference in its genotype distribution among the two study groups (p = 0.89) (Table 3.11). On the contrary, Zammitti et al. (2008, 2009) found a positive association between TNF-β (+252 A/G) and early recurrent miscarriage among the Tunisian population with an odds ratio of 1.67 and 95% confidence interval of (Table 3.11) IFN-γ (+874 A/T; rs ) Cytokine Gene Polymorphism As for IFN-γ (+874 A/T; rs ) polymorphism, comparatively higher frequency of both AT heterozygote (40.8% in cases vs % in controls) and mutated TT homozygote (20% in cases vs % in controls) and a lower frequency of normal AA homozygote (39.2% in cases vs % in controls) was found among the RPL cases as compared to the controls in the present study in 88

8 Delhi, North Indian (Table 3.2). These findings are in accord with those of Kamalli- Sarvestani et al. (2005) who did not observe any significant difference between RPL cases and controls among the Iranian women for the distribution of IFN-γ (+874 A/T) polymorphism. In the latter study the frequency of normal homozygous AA genotype (28% in cases vs. 33% in controls), heterozygous AT genotype (48% in cases vs. 49% in controls) and mutated homozygous TT genotype (24% in cases vs. 18% in controls) was reported to be distributed with a non-significant differences between the two study groups (p = 0.35) (Table 3.9, 3.12). On the other hand, Babbage et al. (2001) found more mutated TT homozygote (27% in cases vs. 17% in controls) and a comparatively less number of AT heterozygote (46% in cases vs. 51% in controls) among the RPL cases in the Caucasian of UK but with non-significant difference with the controls (p = 0.9) (Tables 3.9, 3.12). Similar situation was seen among the Brazilian Caucasian women in a study conducted by Daher et al. (2003) where a trend towards increased frequency of mutated homozygous TT genotype was observed among the RPL cases (26% in cases vs. 14% in controls, p = 0.04) (Table 3.9, 3.12). Prigoshin et al. (2004) reported the involvement of IFN-γ (+874 A/T) polymorphism in the pathogenesis of unexplained RPL in the Caucasian Argentine population (Table 3.12), in spite of the fact that they observed more number of mutated TT homozygote among cases as compared to the controls (15% in cases vs. 22.7% in controls). They concluded their results only on the basis of genotype frequency distribution which showed statistically significant differences among the two groups studied (frequency of AT heterozygous genotype = 65% in cases vs. 35.8% in controls, p = 0.01 and frequency of normal AA homozygous genotype = 20% in cases vs. 41.5% in controls, p = 0.04) and used no appropriate statistical tool for association analysis in their study (Table 3.12). As for allele frequencies of IFN-γ (+874 A/T) polymorphism, in North Indian population a comparatively higher mutated allele T frequency (40.40%) and a lower normal allele A frequency (59.60%) was noted among the RPL cases while 89

9 in the control group a higher normal allele A frequency (67.74%) and a lower mutated allele T frequency (32.26%) was found in the present study hinting towards a positive association (Table 3.2). Like the present findings, the IFN-γ (+874 A/T) mutated allele T was found at a greater frequency among the RPL cases (45.65%) as compared to controls (38.46%) in the Brazilian Caucasian women in a study conducted by Daher et al. (2003) (Table 3.9). Babbage et al. (2001) also observed a comparatively higher frequency of mutated T allele among the cases than the controls in the Caucasian women of UK (51.19% in cases vs % in controls) (Table 3.9). In yet another study conducted by Kamalli-Sarvestani et al. (2005) among the Iranian women again a comparatively higher frequency of IFN-γ (+874 A/T) mutated allele among RPL cases was found when compared to the controls (48.11% in cases vs % in controls) (Table 3.9). Thus the frequency of mutated T allele was found to range from 38.46% in Brazilian Caucasian population to 42.86% in Caucasian population of UK and its frequency in presently studied population of Delhi is comparatively lower (32.26% ) (Table 3.9). For association findings between RPL and IFN-γ (+874 A/T) polymorphism, all inheritance models showed an odds ratio >1 in the present study hinting towards the possibility of positive association, with the values ranging from in the over-dominant model to in the TT vs. AA combination of co-dominant model. But again, none of them showed a statistically significant association with respect to 95% confidence interval and probability values (Table 3.3). Dominant model with OR = , C.I. = and p = was found to be most suitable model for IFN-γ (+874 A/T) polymorphism inheritance as it showed the minimum values of AIC and BIC out of the four inheritance models constructed. It should be noted that the model with the least AIC and BIC values show maximum significance i.e. probability value nearer to 0.05, when compared to the remaining models and this was the case in the present study also (Table 3.3). Similar results were reported by Babbage et al. (2001) who did not find any association between IFN-γ (+874 A/T) and RPL among the Caucasian women of 90

10 UK (OR = 1.1, CI = , p = 0.9 and OR = 1.8, CI = , p = 0.3 for two different models) (Table 3.12). Kamalli-Sarvestani et al. (2005) also reported no association, as they found non-significant genotype distribution (p = 0.35) of IFN-γ (+874 A/T) in RPL cases and controls among the Iranian women (Table 3.12). On the other hand, a positive association was reported by Daher et al. (2003) with the high cytokine production genotypes of IFN-γ (+874) polymorphism among the Brazilian Caucasian women and by the meta-analysis done by them on previous studies (OR = 1.92, p = 0.04) (Table 3.12) Haplotype Analysis To further understand the interplay between TNF-α (-308 G/A; rs ) and TNF-β (+252 A/G; rs909253) polymorphisms on chromosome 6, the combined effect of these two markers was evaluated using haplotype analysis (Figure 3.1). The values obtained by different measures of linkage disequilibrium (LD) are presented in Table 3.4. Although the D value (0.9987) suggests a strong LD between the two sites considered but the r 2 value (0.1305) depicts a rather different picture (p < 0.05). The reason for such a discrepancy in these two LD estimates is a small sample size as more samples are needed to maintain the optimum statistical power in different measures of association mapping. The frequency distribution of the haplotypes found in the cases and controls are listed in Table 3.5 and the association findings between the haplotypes and RPL are presented in Table 3.6. After the identification of all the possible haplotypes, it was found that there was no evidence of TNF-α (-308 G/A) mutated / TNF-β (+252 A/G) normal haplotype AA in the studied sample possibly due to very low frequency of TNF-α (-308 G/A) mutated allele and a higher frequency of TNF-β (+252 A/G) normal allele. The normal haplotype TNF-α 308G / TNF-β 252A was found to be present at the maximum frequency of 73.77% in the present study with a comparatively higher incidence among the cases than the controls (76.62% in cases vs % in controls) (Table 3.5). On the other hand, the TNF-α 308 normal 91

11 G / TNF-β 252 mutated G haplotype with a frequency of 21.87% was found to be present at a comparatively lower incidence among the cases as compared to the controls (18.99% in cases vs % in controls). The mutated haplotype TNF-α Figure 3.1: Linkage Disequilibrium plot showing D value between TNF- α and TNF-β polymorphisms 92

12 308 A / TNF-β 252 G was found at a frequency of 4.36% and was present at an almost same frequency in the two study groups (4.38% in cases and 4.35% in controls). Of the three haplotypes identified, TNF-α 308 G / TNF-β 252 A haplotype showed an odds ratio (OR) of 1 and TNF-α 308 A / TNF-β 252 G haplotype showed an OR of 1.07 (C.I. = , p = 0.86), suggesting no association between RPL and these two haplotypes. However, TNF-α 308 G / TNF-β 252 G haplotype showed an odds ratio of 1.33 (C.I. = , p = 0.14). But again, neither the 95% confidence interval nor the probability value revealed a positive association of TNF-α (-308 G/A) and TNF- β (+252 A/G) haplotypes with recurrent pregnancy loss in population of Delhi as the global haplotype association probability value in this study was found to be Baxter et al. (2001) conducted a haplotype association study among RPL cases and controls of the Caucasian population of UK by taking into account four SNP polymorphisms viz., TNF-α (-308 G/A), TNF-α (-238 G/A), TNF-β (+252 A/G) and TNF-β (codon 26). They also reported a similarity in TNF-α and TNF-β haplotype frequency between recurrent miscarriage and control couples and did not observe any association between recurrent miscarriage and variant alleles of TNF-α and TNF-β genes. On the other hand, studies conducted by Zammitti et al. (2008, 2009), wherein haplotypes were constructed with TNF-α (-308 G/A), TNF-α (-238 G/A) and TNF-β (+252 A/G) polymorphisms, reported a positive association for AGG haplotype (OR = 1.23, 95% CI = , p = 0.044) and GAG haplotype (OR = 1.27, 95%CI = , p < 0.001) with recurrent miscarriages in the Tunisian population. The results of the present study on association of recurrent pregnancy loss with three cytokine gene polymorphisms are in accord with that reported by Babbage et al. (2001), Baxter et al. (2001), Pietrowski et al. (2004) and Kamalli- Sarvestani et al. (2005) and also with Prigoshin et al. (2004) and Zammitti et al. 93

13 (2008, 2009) only for TNF-α (-308 G/A) polymorphism. But the present results are contradictory to that reported by Reid et al. (2001) and Daher et al. (2003) with respect to the three selected SNP markers and also to Prigoshin et al. (2004) for IFN-γ (+874 A/T) polymorphism and Zammitti et al. (2008, 2009) for only TNF-β (+252 A/G) polymorphism (Tables ). All the above mentioned studies were hypothesized on the basis that both pregnant and non-pregnant women with a history of recurrent pregnancy loss (RPL) showed abnormally higher levels of pro-inflammatory cytokines and thus aimed at investigating the role of cytokine gene polymorphisms in the genes regulating the expression of these cytokines with reference to unexplained recurrent pregnancy loss. It should be noted that the relation between higher pro-inflammatory cytokine levels and evidence of recurrent pregnancy loss could also be an example of the Reverse Causation of the disease, i.e. RPL, with the intermediate phenotype, i.e. elevated pro-inflammatory cytokine levels; which refers to a situation in which the outcome affects the exposure rather than the reverse. Thus, the association of the outcome, i.e. pregnancy loss, with measured exposure, i.e. high pro-inflammatory cytokine levels, could in part reflect the bias attributable to the outcome s effect on measured exposure as the outcome precedes the exposure measurement (Robins, 2001; Herna n et al., 2002). Thus, it is recommended that the concept of the reverse causation should be taken into account in the genetic epidemiological studies and the tool of the Mendelian Randomization should be applied to derive an estimate of the association that is free of the confounding and reverse causation, typical of classical epidemiology. The concept of mendelian randomization can be used as a tool for epidemiological inference on environmental risk factors by examining the genetic counterpart, such as cytokine gene polymorphisms in this study, of a suspected environmental exposure association free of confounding by conventional confounders (Davey-Smith and Ebrahim, 2003; Khoury, 2004; Davey-Smith, 2005). 94

14 Table 3.1: Genotype counts and p-values of exact test for Hardy-Weinberg equilibrium (HWE) and Chi-Square (χ 2) test with respect to three selected cytokine gene polymorphisms among RPL cases and controls SNP (rs ID) Chromosome (Position) Group No. Teste d Genotype No. Observed H.W.E. p value χ 2 p value (Cases vs. Controls) TNF-α (-308 G/A) (rs ) TNF-β (+252 A/G) (rs ) IFN-γ (+874 A/T) (rs ) No. = Number 6 ( ) 6 ( ) 12 ( ) GG GA AA Cases Control s AA AG GG Cases Control s AA AT TT Cases Control s

15 Table 3.2: Genotype and allele frequency distribution of three selected cytokine gene polymorphisms in RPL cases and controls SNP (rs ID) TNF-α (-308 G/A) (rs ) TNF-β (+252 A/G) (rs ) IFN-γ (+874 A/T) (rs ) No. = Number Group No. Tested Genotype (Frequency) Allele Frequency GG GA AA G A Cases % 4.48% (91.05) (8.95) - Control % 4.36% s (91.28) (8.72) - AA AG GG A G Cases % 22.93% (57.90) (38.35) (3.75) Control % 28.17% s (52.28) (39.09) (8.63) AA AT TT A T Cases % 40.40% (39.20) (40.80) (20.00 Control s (48.92) 70 (37.63) ) 25 (13.45 ) 67.74% 32.26% 96

16 Table 3.3: Odds ratio (OR) at 95% confidence interval (CI) calculated in four different inheritance models for three selected cytokine gene polymorphisms and RPL SNP (rs ID) TNF-α (-308 G/A) (rs ) Inheritance Model Co-dominant OR (95% CI) Dominant OR (95% CI) Recessive OR (95% CI) Over Dominant OR (95% CI) GA, AA vs GG GA+AA vs GG AA vs GG+GA GA vs GG+AA ( ( N.A. ( ) ) ) N.A. p N.A AIC BIC TNF-β (+252 A/G) (rs ) AG, GG vs AA AG+GG vs AA GG vs AA+AG AG vs AA+GG ( ) ( ) ( ( ) ( ) p AIC BIC IFN-γ (+874 A/T) (rs ) AT, TT vs AA AT+TT vs AA TT vs AA+TT AT vs AA+TT ( ) ( ) ( ) 1.61 ( ) ( ) p AIC BIC N.A. = Not Applicable, AIC = Akaike Information Criteria, BIC = Bayesian Information Criteria 97

17 Table 3.4: Linkage disequilibrium between TNF-α and TNF-β polymorphisms TNF α (308) TNF-β (225) D statistic D statistic r 2 statistic TNF α TNF-β TNF α TNF-β TNF α TNF-β (308) (225) (308) (225) (308) (225) TNF α TNF α (308) (308).. TNF-β.. TNF-β.. (225) (225) 98

18 Table 3.5: TNF-α and TNF-β haplotype frequency among RPL cases and controls TNF-α (-308 G/A) (rs ) TNF- (+252 A/G) (rs ) Total Cases Controls Cumulative Frequency G A G G A G A A

19 Table 3.6: Odds ratio (OR) at 95% confidence interval (CI) calculated for TNF-α and TNFβ haplotypes and RPL TNF-α (-308 G/A) (rs ) TNF- (+252 A/G) (rs ) Frequency OR (95 % CI) p value G A 73.81% 1 - G G 21.82% 1.33 ( ) 0.14 A G 4.37% 1.07 ( )

20 Table 3.7: Genotype and allele frequency distributions of TNF-α (-308) polymorphism in different populations of world Population Study group Genotype counts Allele Frequencies Reference GG AA / GA G A Caucasian of UK Cases (N=43) Controls (N=73) 30 (70) 56 (77) 13 (30) 17 (23) 86% 84% 14% 16% Babbage et al. (2001) Brazilian Caucasian Caucasian Cases (N=48) Controls (N=108) Cases (N=168) Controls (N=212) GG AA / GA G A 36 (75) 12 (25) (82) 19 (18) - - GG GA AA G A 133 (79.2) 167 (78.8) 33 (19.6) 41 (19.3) 2 (1.2) 4 (1.9) 88.4% 88.9% 11.6% 11.1% Daher et al. (2003) Pietrowski et al. (2004) Iranian Cases (N=131) Controls (N=143) GG AA / GA G A 117 (89) 122 (85) 14 (11) 21 (15) Kamalli-Sarvestani et al. (2005) Tunisian Cases (N=350) Controls (N=200) GG GA AA G A 305 (87.1) 168 (84) 31 (8.9) 27 (13.5) 14 (4) 5 (2.5) 92% 91% 8% 9% Zammitti et al. (2008) North Indian Cases (N=134) Controls (N=195) GG GA AA G A 122 (91.05) 178 (91.28) 12 (8.95) 17 (8.72) 0 (0) 0 (0) 95.52% 95.64% 4.48% 4.36% Present study 101

21 Table 3.8: Genotype and allele frequency distributions of TNF-β (+252) polymorphism in different populations of world Population Study group Genotype counts Allele Frequencies Reference AA GG / AG A G Iranian Cases (N=137) Kamalli-Sarvestani et Controls 71 (53) 66 (55) - - al. (2005) (N=116) 62 (47) 54 (45) - - Tunisian North Indian Cases (N=350) Controls (N=200) Cases (N=133) Controls (N=197) AA AG GG A G 259 (74) 162 (81) 75 (21.4) 35 (17.5) 16 (4.6) 3 (1.5) 85% 90% 15% 10% AA AG GG A G 77 (57.9) 103 (52.28) 51 (38.35) 77 (39.09) 5 (3.75) 17 (8.63) 77.07% 71.83% 22.93% 28.17% Zammitti et al. (2008) Present study 102

22 Table 3.9: Genotype and allele frequency distributions of IFN-γ (+874) polymorphism in different populations of world Populatio n Caucasian of UK Study group Genotype counts Allele Frequencies Reference Cases (N=41) Controls (N=63) AA AT TT A T 11 (27) 20 (32) 19 (46) 32 (51) 11 (27) 11 (17) 48.81% 57.14% 51.19% 42.86% Babbage et al. (2001) Brazillian Caucasian Cases (N=46) Controls (N=104) AA AT TT A T 16 (35) 39 (38) 18 (39) 50 (48) 12 (26) 15 (14) 54.35% 61.54% 45.65% 38.46% Daher et al. (2003) Iranian Cases (N=132) Controls (N=132) AA AT TT A T 37 (28) 44 (33) 63 (48) 65 (49) 32 (24) 23 (18) 51.89% 57.95% 48.11% 42.05% Kamalli-Sarvestani et al. (2005) North Indian Cases (N=125) Controls (N=186) AA AT TT A T 49 (39.2) 91 (48.92) 51 (40.8) 70 (37.63) 25 (20) 25 (13.45) 59.60% 76.74% 40.40% 32.26% Present study 103

23 Table 3.10: Association findings between TNF-α (-308) cytokine gene polymorphism and RPL in different populations of the world. Population Results Conclusion Reference Caucasian of UK OR = 1.4 ( ), p = 0.4 No significant association Babbage et al. (2001) Caucasian of UK - Increased incidence of TNF-α*G allele among cases Reid et al. (2001) Brazilian OR = 1.61, p = 0.18 Increased frequencies of TNF-α (-308) A/A and A/G Daher et al. (2003) Caucasian genotypes in cases Caucasian OR = 0.9 ( ), p> 0.05 No association Pietrowski et al. (2004) Argentine - No association Prigoshin et al. (2004) Iranian p = 0.42 Non-significant differences by Chi-square test Kamali-Sarvestani et al. (2005) Tunisian OR = 0.78 ( ) No association Zamitti et al. (2008) Tunisian - No association Zamitti et al. (2009) North Indian OR = ( ), p = No association Present study 104

24 Table 3.11: Association findings between TNF-β (+252) cytokine gene polymorphism and RPL in different populations of the world. Population Results Conclusion Reference Iranian p = 0.89 Non-significant differences by Chi-square test Kamali-Sarvestani et al. (2005) Tunisian OR = 1.67 ( Positive association Zamitti et al (2008) Tunisian North Indian Higher prevalence of mutant allele A in cases compared to controls OR 1 = ( ), p = OR 2 = ( ), p = OR 3 = ( , p = OR 4 = ( ), p = OR 5 = ( ), p = Odds ratio calculated for AG vs. AA co-dominant model 2 Odds ratio calculated for GG vs AA co-dominant model 3 Odds ratio calculated for dominant model 4 Odds ratio calculated for recessive model 5 Odds ratio calculated for over- dominant model Positive association Zamitti et al (2009) No association Present study 105

25 Table 3.12: Association findings between IFN-γ (+874) cytokine gene polymorphism and RPL in different populations of the world. Population Results Conclusion Reference Caucasian of UK Brazilian Caucasian Argentine *OR = 1.1 ( ), p = 0.9 *OR = 1.8 ( ), p = 0.3 No significant association Babbage et al. (2001) OR = 1.92, p = 0.04 Positive association Daher et al. (2003) Higher prevalence of AT genotype in cases compared to controls (65% vs 35.8%), p = 0.01 Positive association Prigoshin et al. (2004) Iranian p = 0.35 Non-significant differences by Chi-square test Kamali-Sarvestani North Indian OR 1 = ( ), p = OR 2 = ( ), p = OR 3 = ( ), p = OR 4 = 1.61 ( ), p = OR 5 = ( ), p = * Odds ratio calculated for unspecified models 1 Odds ratio calculated for AT vs. AA co-dominant model 2 Odds ratio calculated for TT vs AA co-dominant model 3 Odds ratio calculated for dominant model 4 Odds ratio calculated for recessive model 5 Odds ratio calculated for over- dominant model Not a significant association et al. (2005) Present study 106

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