The SDF1 A/G Gene Variant: A Susceptibility Variant for Myocardial Infarction

Abstract

Background:

Although environmental factors play an important role in susceptibility to myocardial infarction (MI), genetic determinants also provide a significant contribution. This study aimed to determine whether or not MI susceptibility is influenced by the SDF1-rs1801157A/G and HHEX-rs1111875 A/G polymorphisms in an Iranian population.

Methods:

A total of 120 patients with MI and 120 healthy controls were enrolled. Blood samples were collected from all the participants for genomic DNA extraction and testing. Polymorphism genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism technique.

Results:

Multiple logistic regression analysis revealed that the A allele and AA genotype of the SDF1-rs1111875 polymorphism produce a significant risk of MI both before (crude odds ratio [OR] = 8.83, 95% confidence interval [95% CI] = 1.05-73.76, p = 0.025) and after adjustment (adjusted OR = 8.12, 95% CI = 5.02-19.42, p = 0.04). In contrast, the GG genotype of the SDF1-rs1111875 polymorphism provides a protective effect on MI in a recessive model (GG vs. AA+AG) before (crude OR = 0.57, 95% CI = 0.34-0.97, p = 0.037) and after adjustment (adjusted OR = 0.53, 95% CI = 0.3-0.82, p = 0.021). No association was found between the HHEX-rs1111875 A/G polymorphism alleles and the susceptibility to MI.

Conclusion:

Taken together, the current findings suggest that the SDF1-rs1801157A/G gene variant may play an important role in relation to MI in this Iranian population. Nevertheless, more replication studies and meta-analyses should be carried out in this area.

Introduction

Myocardial infarction (MI), as a late-onset cardiovascular disease, is one of the leading causes of the morbidity and mortality worldwide (Breslow, 1997; Wang, 2005). Although multiple environmental factors are involved in the etiology of MI, genetic variability in human genome can influence the susceptibility to MI in an interacting mechanism with environmental risk factors (Yamada, 2015; Ozaki and Tanaka, 2016). Thus, the achievement of a clear picture on MI pathogenesis needs to conduct multidisciplinary research fields to identify polymorph genetic susceptibility loci that predispose individuals to an increased risk of MI either individually or to an interaction with environmental risk factors (Ozaki and Tanaka, 2016). There are several pieces of evidence from studies on different ethnic populations that claim single-nucleotide polymorphisms (SNPs) can genetically contribute to susceptibility to certain diseases and, thereby, they are clinically significant in the medicine (Kathiresan et al., 2009; Vandenbroeck, 2012; Bastami et al., 2015, 2016; Mansoori et al., 2015a, 2015b; Daraei et al., 2017).

In this regard, recent studies have reported that the rs1801157 G > A SNP in the stromal cell-derived factor (SDF)-1 gene is implicated in susceptibility to MI (Luan et al., 2010; Borghini et al., 2014; Wu et al., 2015). SDF1 gene is located on chromosome 10q11.21 and encodes inflammatory chemokine SDF1 (also called CXCL12) (Wu et al., 2015). It is well known that inflammation is the underlying pathology of MI through migration of inflammatory cells to atherosclerotic human lesions (Madjid and Willerson, 2011; Melamed and Goldhaber, 2014). This is an essential step in the plaque rupture and the occurrence of MI (Borghini et al., 2014; Melamed and Goldhaber, 2014). Chemokines are important actors in this immune-mediated process and lead to the progression of plaque destabilization (Apostolakis et al., 2007). The growing evidence suggests that SDF1 gene plays a considerable role against the development of the MI (Abi-Younes et al., 2000; Ratajczak et al., 2006; Subramanian et al., 2014). The product of this gene generally acts as a chemoattractant to recruit immune leukocyte cells, such as lymphocytes and monocytes, and, in turn, regulates inflammation (Hu et al., 2007).

SDF1 is also involved in other important processes, including hematopoiesis, embryonic development, and organ homeostasis (Abi-Younes et al., 2000). It has been shown that SDF1 gene is overexpressed in atherosclerotic plaques (Borghini et al., 2014). Since lymphocytes and monocytes are implicated in the occurrence of atherosclerosis, it has been conceived that the disruption of SDF1 function plays a central role in the pathogenesis of MI and may be a possible biomarker (Ratajczak et al., 2006; Subramanian et al., 2014). There is evidence that rs1801157 G > A variant in the 3′-untranslated region (3′-UTR) of SDF1 gene results in its overexpression (Borghini et al., 2014). Most importantly, rs1801157 G > A polymorphism was reported to be linked to susceptibility to MI in different populations (Luan et al., 2010; Borghini et al., 2014). However, the SNPs with given associated-phenotypes in a particular population may not hold the same associations in other populations, or may have inverse associations in some cases (Kraft et al., 2009; Rosenberg et al., 2010). On the other hand, no studies have been conducted on Iranian populations to estimate the possible relationship of this SNP with MI risk yet. Therefore, this study was an attempt to determine whether there is a significant association between SDF1-rs1801157A/G SNP and MI.

Moreover, some studies have evaluated the association between hematopoietically expressed homeobox (HHEX)-rs1111875 A/G and different multifactorial diseases (Cai et al., 2010; Gaudet et al., 2010). It has been shown that HHEX gene located on chromosome 10q24 plays a key role in mammalian heart development and encodes a member of the homeobox family transcription factors, called HHEX (Morgutti et al., 2001). Functional studies on avian groups, murine, xenopus, zebrafish, and human models have shown similar roles of HHEX gene for all vertebrate species. It also functions as a transcriptional repressor that is involved in heart-inducing activities (Thomas et al., 1998). In mice, Hhex is expressed in the endothelium of the developing vasculature of the heart and its mutations cause abnormal cardiac development and defective vasculogenesis. Therefore, HHEX gene acts as a key cardiac factor in contributing to mammalian heart development (Morgutti et al., 2001). These findings lead one to hypothesize that rs1111875 A/G polymorphism in the HHEX gene may have an association with MI. Thus, the aim of the present study was to determine whether this variation is associated with susceptibility to MI in an Iranian population.

Materials and Methods

Subjects

An unrelated sample of 120 MI patients and 120 healthy control individuals participated in this study. Both patients and controls were of an Iranian ethnic background. All the enrolled subjects were examined with coronary angiography at Valie-Asr Hospital. The MI diagnosis was accomplished according to the typical electrocardiographic changes and cardiac biomarkers, including serum cardiac enzyme raises, such as creatinine kinase, aspartate aminotransferase, lactate dehydrogenase, and troponin T. In fact, the healthy subjects who did not have any history of MI and had received a previous diagnosis of systemic or cardiovascular disease (corroborated clinically and by electrocardiography) were included in this study as participants of the control group. During the collection of clinical and demographic data, a written informed consent was gained from all the individuals participating in the study. Our study was approved by the Ethics Committee of Fasa University of Medical Sciences. The recorded demographic and clinical data included information on age, gender, weight, height, occupation, smoking habit, hyperlipidemia, hypertension, diabetes mellitus, previous MI, and coronary heart disease (CHD) in first-degree relatives.

DNA isolation and SNP genotyping

Peripheral blood samples were collected by the tubes containing EDTA from the members of both groups. DNA was extracted from white blood cells using the DNG-plus extraction Kit (Cinnagen, Iran) in accordance with the manufacturer's instructions. The extracted DNA was quantified and qualified by Nanodrop and agarose gel electrophoresis, respectively. Polymorphism genotyping was performed through polymerase chain reaction (PCR) and restriction fragment length polymorphism. For SDF1-rs1801157A/G polymorphism, a 302 bp DNA part with the polymorphic site was amplified by PCR via a set of two primers: 5′-CAGTCAACCTGGGCAAAGCC-3′ (Forward) and 5′-AGCTTTGGTCCTGAGAGTCC-3′ (Reverse). The digestion with MspI restriction endonuclease (Fermentas, Lithuania) for 16 h at 37°C led to PCR products, including one fragment of 302 bp for AA genotype, two fragments of 202 and 100 bp for GG genotype, and three fragments of 202, 100, and 302 bp for AG genotype. The products were separated by 2% agarose gel and were stained with sybergreen dye. The genotyping of HHEX-rs1111875 A/G was done using the forward primer (5′-TTCAATTAACTGATCAACAG-3′) and the reverse primer (5′-TTACATGCTCTTTCAAAG-3′). The 224 bp resulting from PCR product was digestion via XbaI restriction nuclease. The resulting digested products were as follows: 224 bp for GG genotype; 249, 135, 141, and 83 bp for AA genotype; and 224, 141, and 83 bp for heterozygous genotype. The enzyme digested products were separated by 3% agarose gels that were stained with sybergreen dye.

Statistical analysis

In the current study, all statistical analyses were evaluated using SPSS version 20.0 (SPSS, Inc., Chicago, IL) and STATA. The data were statistically defined in terms of mean ± standard deviation, range, or frequencies (number of subjects), and percentages when necessary. Student's independent samples t-test was used to determine whether there is any statistically significant difference between MI patients and healthy subjects in terms of demographic and clinical data. Similarly, χ² test analysis or Fisher's exact test was used to find whether there is any significant difference between categorical variables in terms of genotype/allele frequencies and Hardy-Weinberg equilibrium.

The association of SDF1-rs1801157A/G and HHEX-rs1111875 A/G polymorphisms with MI risk was determined by estimating the odds ratio (OR) at the confidence interval of 95% (95% CI) by logistic regression in all genetic models. p < 0.05 was considered as the significance level.

Results

Clinical characteristics

The descriptive details and distributions of the demographic data and clinical characteristics of the subjects are summarized in Table 1. Gender was equally distributed between MI cases and control individuals. However, the cases were older than control subjects (aged 62.90 ± 12.81 years vs. 52.55 ± 9.80 years, p < 0.001). Furthermore, no significant difference was found between the two groups with regard to body mass index (BMI), triglyceride (TG), and total cholesterol (TC) levels (all p > 0.05). In addition, there were significantly higher number of participants in the case group with smoking, hypertension, diabetes, and higher levels of total low density lipoprotein (LDL) compared to the control group (all p < 0.05). The level of high density lipoprotein (HDL) was lower for cases than that for the controls (p < 0.001). Moreover, 54.2% of the case subjects had former MI history and 45.8% of them had no previous MI history.

Table 1.

Basic Characteristics of Participants in Population Study

Variables	Case (n = 120)	Control (n = 120)	p
Age (years)	62.90 ± 12.81	52.55 ± 9.80	<0.001^*
MI age (years)	61.09 ± 12.92	—	—
TG (mg/DL)	207.12 ± 69.25	202.6 ± 77.43	0.49
TC (mg/DL)	235.64 ± 52.26	226.55 ± 48.99	0.17
HDL (mg/DL)	48.92 ± 6.35	51.84 ± 6.29	0.001^*
LDL (mg/DL)	141.89 ± 31.89	133.84 ± 28.33	0.028^*
BMI (kg/m²)	26.05 ± 2.31	26.32 ± 1.87	0.33
Gender (%)			0.43
M	74 (61.7%)	68 (56.7%)
F	46 (38.3%)	52 (43.3%)
MI history	65 (54.2%)	—	—
BP	71 (59.2%)	27 (22.5%)	<0.001^*
Smoking	45 (37.5%)	10 (8.3%)	<0.001^*
Diabetes	36 (30%)	16 (13.3%)	<0.002^*

Represents significance of the difference between two groups (p < 0.05).

The results are presented as n (%) or median. Continuous factors are expressed as mean ± standard deviation. Continuous factors were compared by independent sample t-tests.

BMI, body mass index; BP, blood pressure; HDL, high density lipoprotein; LDL, low density lipoprotein; MI, myocardial infarction; TC, total cholesterol; TG, triglyceride.

Distribution of the genotypes and alleles of SDF1-rs1801157A/G polymorphism

Table 2 shows the distribution of each genotype and allele of SDF1-rs1801157A/G polymorphism in MI case and control groups with regard to the three genetic models. There were significant differences in the genotype and allele frequencies of SDF1-rs1801157A/G between cases and controls. The A allele of polymorphisms was found to be significantly more frequent in patients with MI than controls. Furthermore, AA genotype took up the frequency of 5.8% in the case group while this value equaled 0.8% in the control group (p = 0.023 Fisher's exact test). Genetic models have shown that the dominant model (AA vs. AG+GG) of SDF1-rs1801157A/G was slightly more frequent in patients than control subjects (total: 5.8% vs. 0.8%; p = 0.067 Fisher's exact); however, its recessive model (GG vs. AA+AG) was significantly lower among MI patients than that in controls (total: 50.8% vs. 64.2%; p = 0.037).

Table 2.

Genotype and Allele Frequencies of SDF1-RS1801157A/G and HHEX-RS1111875 A/G Polymorphisms in the Myocardial Infarction Cases and Control Subjects

Gene variants	Case (n = 120)	Control (n = 120)	p
HHEX
AA	33 (27.5%)	38 (31.7%)	0.215
GG	11 (9.2%)	18 (15%)
AG	76 (63.3%)	64 (53.3%)
Dominant model
AA	33	38	0.48
AG+GG	87	82
Recessive model
GG	11	18	0.16
AA+AG	109	102
Additive model
AG	76	64	0.12
AA+GG	44	56
Allele
A	142 (59.2%)	140 (58.3%)	0.85
G	98 (40.8%)	100 (41.7)
SDF1
AA	7 (5.8%)	1 (0.8%)	0.023 ^a
GG	61 (50.8%)	77 (64.2%)
AG	52 (43.3%)	42 (35%)
Dominant model
AA	7	1	0.067^a
AG+GG	113	119
Recessive model
GG	61	77	0.037 ^b
AA+AG	59	43
Additive model
AG	52	42	0.19
AA+GG	68	78
Allele
A	66 (27.5%)	44 (18.3%)	0.017 ^b
G	174 (72.5%)	19 (81.7%)

p values in bold represent significance of the difference in allele/genotype frequencies between cases and controls.

By Fisher's exact test.

By χ² test analysis.

Furthermore, the association between SDF1-rs1801157A/G polymorphism and risk of MI was analyzed by logistic regression analysis (adjustment for age, gender, TG, TC, HDL, LDL, blood pressure (BP), diabetes mellitus (DM), BMI, and smoking). Crude and adjusted ORs for MI in relation to each genotype and allele are shown in Table 3. Logistic regression analysis also showed that A allele and AA genotype were statistically associated with increased MI risk after adjustment with conventional MI risk factors (AA genotype OR = 8.12, 95% CI 5.02-19.42; p = 0.04 and A allele OR = 1.72, 95% CI 1.31-2.73; p = 0.03). This suggests that allele and genotype are the independent determinants of MI risk. Logistic regression adjustment for recessive model (GG vs. AA+AG) also produced no change in the result and led to a significantly lower risk of GG genotype (OR = 0.53, 95% CI 0.3-0.82; p = 0.021). This shows that the presence of GG genotype was an independent atheroprotective factor. In this regard, the subjects carrying GG genotype appear to be less susceptible to MI compared to those with AA genotype. The above findings suggest that genotype specific manner of SDF1-rs1801157A/G polymorphism influences MI risk wherein AA genotype acts as a higher susceptibility factor for MI compared to the genotypes carrying at least one copy of G allele (AA and AG). However, GG genotype shows a protective influencer on MI.

Table 3.

Multiple Logistic Regression Analysis on the Associations of the Two Polymorphisms Between Myocardial Infarction Cases and Controls

Genetic models	OR_crude (95% CI)	p	OR_adjusted (95% CI)	p
HHEX
AA	1.42 (0.58-3.43)	0.43	1.59 (0.5-5.04)	0.41
AG	1.94 (0.85-4.41)	0.11	2.37 (0.8-6.95)	0.12
GG	1 (ref.)	—	1 (ref.)	—
Dominant model
AA vs. AG+GG	0.82 (0.47-1.42)	0.48	0.76 (0.37-1.56)	0.45
Recessive model
GG vs. AA+AG	0.57 (0.26-1.27)	0.16	0.48 (0.17-1.37)	0.17
Additive model
AG vs. AA+GG	1.51 (0.9-2.5)	0.12	1.71 (0.87-3.35)	0.11
Allele
A	1.03 (0.72-1.49)	0.85	0.92 (0.47-1.78)	0.80
G	0.97 (0.67-1.39)	0.85	1.08 (0.55-2.11)	0.80
SDF1
AA	8.83 (1.05-73.76)	0.025	8.12 (5.02-19.42)	0.04^*
AG	1.56 (0.92-2.65)	0.09	1.48 (0.75-2.93)	0.25
GG	1 (ref)	—		—
Dominant model
AA vs. AG+GG	7.37 (0.89-60.86)	0.06^a	12.73 (0.91-77.45)	0.058^a
Recessive model
GG vs. AA+AG	0.57 (0.34-0.97)	0.037	0.53 (0.3-0.82)	0.021^*
Additive model
AG vs. AA+GG	1.42 (0.84-2.39)	0.186	1.37 (0.69-2.7)	0.36
Allele
A	1.69 (1.09-2.6)	0.017	1.72 (1.31-2.73)	0.03^*
G	0.59 (0.38-0.91)	0.017	0.57 (0.41-0.88)	0.03^*

Value with a significance level (p < 0.05).

ORs were adjusted by gender, age, smoking, DM, BMI, BP, TC, TG, HDL and LDL.

By Fisher's exact test.

95% CI, 95% confidence interval; DM, diabetes mellitus; OR, odds ratio.

Distribution of the genotypes and alleles of HHEX-rs1111875 A/G polymorphism

Concerning this polymorphism, no statistically significant difference was observed in allelic or genotypic frequencies between the cases and controls (Table 2). Similarly, there was no significant difference in genotype distribution between the two groups under all genetic models and also no association was found between the two groups by multiple logistic regression analysis (Table 3).

Discussion

In this study, it was demonstrated that AA genotype of SDF1-rs1801157A/G polymorphism was a significant genetic risk factor for MI susceptibility independently of conventional MI risk factors in the Iranian population. In addition, it was found that there was a protective association of its GG genotype against MI, which suggested a protective effect of this genotype form of SDF1. However, no association was obtained between HHEX-rs1111875 A/G gene polymorphism and MI in the current population. To the best of the researchers' knowledge, this is the first report on the association between SDF1-rs1801157A/G gene variant and MI in an Iranian population.

The polymorphic alleles of SDF1 gene are of considerable interest in light of their possible roles in affecting the product rates and function of SDF1 (Winkler et al., 1998). There is an emerging body of literature demonstrating that SDF1 gene shows protection against MI disease by its anti-inflammatory and matrix-stabilizing effects (Damås et al., 2002; Hu et al., 2007). In fact, SDF1 gene product usually acts as a cytokine that prevents recruiting white blood immune cells in inflamed region during inflammation and, in turn, governs the inflammation-related process (Poznansky et al., 2000). SDF1 protein has been shown to be highly produced in endothelial cells and macrophages of human atherosclerotic plaques compared with normal vessels. This suggests its protective role in the pathogenesis of atherosclerosis and MI (Abi-Younes et al., 2000). In addition, SDF1 expression has been shown to experience an increase in the experimental rat and mouse models of infarction under the hypoxic state (Hu et al., 2007). According to the data obtained from different studies, the rs1801157A/G SNP in 3′-UTR of SDF1 gene can influence MI risk (Luan et al., 2010; Borghini et al., 2014). Furthermore, experimental data have shown that A allele of this polymorphism upregulates the expression of SDF1 compared with G allele; therefore, it is linked to high production of SDF1 (Borghini et al., 2014).

So far, different studies have reported the existence of some associations between SDF1-rs1801157A/G gene variant and atherosclerotic disease (Szalai et al., 2001; Coll et al., 2005, 2007; Apostolakis et al., 2007; Ghilardi et al., 2008; Luan et al., 2010; Borghini et al., 2014). From among these, some replication studies have reported that A allele carriers of SDF1-rs1801157A/G polymorphism have a significant decreased risk of MI (Luan et al., 2010; Borghini et al., 2014). For example, Luan et al. (2010) conducted a study on a Chinese population on SDF1-rs1801157A/G polymorphisms. They reported that AA genotype is correlated with reduced MI risk in comparison with GG genotype (Luan et al., 2010). In another study conducted on an Italian population, Borghini et al. (2014) found a significant association between AA genotype of SDF1-rs1801157A/G polymorphism and reduced risk of MI (Borghini et al., 2014). Coll et al. reported that HIV patients with SDF1-rs1801157A allele showed a significant lower intima media thickness in comparison to the patients who had G wild-type allele (Coll et al., 2005). These authors also showed that A allele had a protective effect on the progression of subclinical carotid atherosclerosis in HIV-infected subjects (Coll et al., 2007). Furthermore, a meta-analysis has shown that SDF1-rs1801157A/G SNP is associated with decreased risk of MI and does not have any association with CHD susceptibility (Wu et al., 2015). In contrast, the results of the present study were indicative of the availability of the risk association between A allele and AA genotype of SDF1-rs1801157A/G. This finding is not consistent with the results of above-mentioned studies.

Nonetheless, in agreement with the present study, Ghilardi et al. reported a significant link between A allele of SDF1-rs1801157 polymorphism and increased risk of developing internal carotid artery occlusive disease compared with homozygous of the G allele (Ghilardi et al., 2008). In contrast to the finding of this study and that of the above studies, two studies did not observe any significant association between allele/genotype of SDF1-rs1801157 polymorphism and coronary artery disease (Szalai et al., 2001; Apostolakis et al., 2007).

Thus, according to these findings, it can be concluded that SDF1-rs1801157A/G gene variant in the current population and other different ethnic populations may have a direct or an inverse influence on MI risk. This issue may be due to the ethnic and genetic background similarities or differences between the current population and other studied populations, the role of the environmental factors, and/or the different research designs taken for the purpose of the studies, for example, the inadequate number of subjects. These factors may have caused this polymorphism to exert a different or similar influence on MI disease. It is evident, however, that SDF1-rs1801157A/G polymorphism is apparently not the only factor that influences the susceptibility to MI. In fact, other polymorphisms in other genes and certain genetic structures certainly contribute to this event. Apparently, further investigations are required to elucidate these inconsistent findings between our population and other populations. In addition, the present study had some limitations that must be addressed: The low number of participants, unavailability of the subjects with similar age in the two groups of patients and controls, and lack of evaluation for other genes and SNPs that may be linked to MI disease in our population.

Taken together, the current study revealed a different influence of SDF1-rs1801157A/G polymorphism on a subset of Iranian population; indeed, it has different effects on the risk of MI disease depending on each genotype. It is required to conduct further replication studies on larger and different populations to evaluate the relationship between SDF1-rs1801157A/G gene variant and the risk of MI.

Footnotes

Acknowledgments

We would like to thank all personnel of Valie-asr Hospital who felt committed to the recruitment of participants with their excellent sampling assistance. This study was financially supported by the Vice Chancellor for Research of Fasa University of Medical Sciences (Grant No.: 90027).

Author Disclosure Statement

No competing financial interests exist.

References

Abi-Younes

, Sauty

, Mach

, et al. (2000) The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res, 86:131-138.

Apostolakis

, Baritaki

, Kochiadakis

, et al. (2007) Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease. Thromb Res, 119:63-71.

Bastami

, Ghaderian

, Omrani

, et al. (2015) Evaluating the association of common UBE2Z variants with coronary artery disease in an Iranian population. Cell Mol Biol (Noisy-le-Grand), 61:50-54.

Bastami

, Ghaderian

, Omrani

, et al. (2016) MiRNA-related polymorphisms in miR-146a and TCF21 are associated with increased susceptibility to coronary artery disease in an Iranian Population. Genet Test Mol Biomarkers, 20:241-248.

Borghini

, Sbrana

, Vecoli

, et al. (2014) Stromal cell-derived factor-1-3′ A polymorphism is associated with decreased risk of myocardial infarction and early endothelial disturbance. J Cardiovasc Med, 15:710-716.

Breslow

(1997) Cardiovascular disease burden increases, NIH funding decreases. Nat Med, 3:600-601.

Cai

, Yi

, Ma

, et al. (2010) Meta-analysis of the effect of HHEX gene polymorphism on the risk of type 2 diabetes. Mutagenesis, 26:309-314.

Coll

, Alonso-Villaverde

, Parra

, et al. (2005) The stromal derived factor-1 mutated allele (SDF1-3′ A) is associated with a lower incidence of atherosclerosis in HIV-infected patients. AIDS, 19:1877-1883.

Coll

, Parra

, Alonso-Villaverde

, et al. (2007) The role of immunity and inflammation in the progression of atherosclerosis in patients with HIV infection. Stroke, 38:2477-2484.

10.

Damås J

, Wæhre

, Yndestad

, et al. (2002) Stromal cell-derived factor-1α in unstable angina. Circulation, 106:36-42.

11.

Daraei

, Mansoori

, Zendebad

, et al. (2017) Influences of IL-1b-3953 C>T and MMP-9-1562C >T gene variants on myocardial infarction susceptibility in a subset of the Iranian population. Genet Test Mol Biomarkers, 21:33-38.

12.

Gaudet

, Yang

, Bosquet

, et al. (2010) No association between FTO or HHEX and endometrial cancer risk. Cancer Epidemiol Biomarkers Prev, 19:2106-2109.

13.

Ghilardi

, Biondi

, Turri

, et al. (2008) Genetic control of chemokines in severe human internal carotid artery stenosis. Cytokine, 41:24-28.

14.

, Dai

, Wu

W-J

, et al. (2007) Stromal cell-derived factor-1α confers protection against myocardial ischemia/reperfusion injury role of the cardiac stromal cell-derived factor-1α-CXCR4 axis. Circulation, 116:654-663.

15.

Kathiresan

, Voight

, Purcell

, et al. (2009) Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet, 41:334-341.

16.

Kraft

, Zeggini

, Ioannidis

(2009) Replication in genome-wide association studies. Stat Sci, 24:561-573.

17.

Luan

, Han

, Zhang

, et al. (2010) Association of the SDF1-3′ A polymorphism with susceptibility to myocardial infarction in Chinese Han population. Mol Biol Rep, 37:399-403.

18.

Madjid

, Willerson

(2011) Inflammatory markers in coronary heart disease. Br Med Bull, 100: 23-38.

19.

Mansoori

, Daraei

, Naghizadeh

, et al. (2015a) The HHEX rs1111875A/G gene polymorphism is associated with susceptibility to type 2 diabetes in the Iranian population. Mol Biol, 49:535-542.

20.

Mansoori

, Daraei

, Naghizadeh

, et al. (2015b) Significance of a common variant in the CDKAL1 gene with susceptibility to type 2 diabetes mellitus in Iranian population. Adv Biomed Res, 4:45-51.

21.

Melamed

, Goldhaber

(2014) Inflammation and myocardial infarction. Circulation, 130:e334-e336.

22.

Morgutti

, Demori

, Pecile

, et al. (2001) Genomic organization and chromosome mapping of the human homeobox gene HHEX. Cytogenet Genome Res, 94:30-32.

23.

Ozaki

, Tanaka

(2016) Molecular genetics of coronary artery disease. J Hum Genet, 61:71-77.

24.

Poznansky

, Olszak

, Foxall

, et al. (2000) Active movement of T cells away from a chemokine. Nat Med, 6:543-548.

25.

Ratajczak

, Zuba-Surma

, Kucia

, et al. (2006) The pleiotropic effects of the SDF-CXCR1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia, 20:1915-1924.

26.

Rosenberg

, Huang

, Jewett

, et al. (2010) Genome-wide association studies in diverse populations. Nat Rev Genet, 11:356-366.

27.

Subramanian

, Liu

, Aviv

, et al. (2014) Stromal cell-derived factor 1 as a biomarker of heart failure and mortality risk. Arterioscler Thromb Vasc Biol, 34:2100-2105.

28.

Szalai

, Duba

, Prohászka

, et al. (2001) Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp (a) and MCP-1− 2518 G/G genotype in CAD patients. Atherosclerosis, 158:233-239.

29.

Thomas

, Brown

, Beddington

(1998) Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. Development, 125:85-94.

30.

Vandenbroeck

(2012) Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies. J Interferon Cytokine Res, 32:139-151.

31.

Wang

(2005) Molecular genetics of coronary artery disease. Curr Opin Cardiol, 20: 182-188.

32.

Winkler

, Modi

, Smith

, et al. (1998) Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science, 279:389-393.

33.

, Zhang

, Jia

, et al. (2015) Lack of an association between the SDF-1 rs1801157 polymorphism and coronary heart disease: a meta-analysis. Sci Rep, 5:1-9.

34.

Yamada

(2015) Molecular genetics of coronary artery disease and ischemic stroke. Personal Med Universe, 4:4-12.