Diabetes mellitus, as the most prevalent metabolic disorder, is characterized by chronic hyperglycemia due to defect in insulin secretion by beta cells of Langerhans islets or resistance against insulin action [
A systematic review showed that between years 1996 and 2004 the prevalence of type 2 diabetes in Iran was 24% and the risk was 1.7% greater in women. According to this report the prevalence of T2DM in Iran seems to be highest amongst developing countries. Previous reports on total urban population of Middle Eastern countries show the prevalence of T2DM as 3.4% in Sudan, 20% in United Arab Emirates, 8.5% in Bahrain, and 12.1% in India [
Diabetes Mellitus is categorized into the following groups.
Type 1 diabetes mellitus (T1DM) includes 5–10% of diabetic patients. Cellular-mediated autoimmune destruction of the beta-cells of the pancreas results in T1DM. It classically occurs in juveniles and affected patients are dependent on insulin injection in their lifetime and are very prone to ketosis [
T2DM includes 90–95% of patients with diabetes. Patients with type 2 diabetes may be asymptomatic for long period of time. Vascular complications such as nephropathy, neuropathy, retinopathy, and cardiovascular disease may develop in these patients. The impact of genetic component appears to be stronger in T2DM compared to T1DM [
Gestational diabetes mellitus (GDM) is another type which is observed during pregnancy and the prevalence may range from 1 to 14% in all pregnancies [
MODY (maturity onset diabetes of young) is monogenic form of diabetes comprised of several types with various features which is consisting of 1–5% of patients diagnosed as T2DM. The onset of this type of diabetes is normally before 25 years and its treatment is independent of insulin. MODY in its different forms is inherited in autosomal dominant pattern and presents as a result of mutation in transcription factors genes including
There are also other types of diabetes which are considered as secondary to other conditions, for example, any damage to pancreas such as removal of pancreatic tissue, trauma, pancreatic carcinoma, and infection, or underlying diseases including endocrine diseases that alter different hormones secretion which are antagonist to insulin resulting in various clinical manifestations such as acromegaly, Cushing’s syndrome, pheochromocytoma, glucagonoma, somatostatinoma, and diabetes. Diabetes (or carbohydrate intolerance) is also found in increased frequency with a large number of genetic syndromes such as Wolfram syndrome, which causes diabetes mellitus, diabetes insipidus, and other neurodegenerative disorders, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) which is presented with myopathy and encephalopathy caused by mitochondrial mutation, MIDD (maternally inherited diabetes and deafness) which causes diabetes, and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome) which is X-linked and alters immune system and causes multiple endocrine problems [
Diabetes mellitus is a multifactorial disease with both environmental and genetic causes affecting its presence and incidence. Genome wide association studies revealed the genetic heterogeneity of diabetes and the fact that difference in ethnicity can result in different susceptible genes associated with diabetes [
There is no inclusive information for genetic association studies of diabetes in Middle Eastern population including Iranian population. In order to make a comprehensive approach, we aimed to collectively investigate and gather data for association between genetic variants and type 2 diabetes in Iranian population in a systematic review study.
This study is reported according to PRISMA (preferred reporting items for systematic reviews and meta-analyses) guideline [
We systematically searched international web databases: Google Scholar, PubMed, Scopus, and Persian web databases; IranMedex; and Magiran to investigate the association of genetic variants with diabetes and its complications in Iranian population up to January 2014. The search terms were “gene,” “polymorphism,” “diabetes,” “diabetes’ complications,” nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery disease) and their MeSH terms and Persian equivalents with diabetes. At least three emails were sent to the corresponding author of articles which were not accessible as full text or had insufficient data. Duplicate articles and multiple publications from the same population were excluded and the most relevant data were used for the investigation. The references of all selected articles were investigated.
We included all observational population-based studies ≥100 sample size, which were conducted as case-control, cohort, or cross sectional. According to WHO criteria, diabetes mellitus was defined as FBS ≥ 7 mmol/L (126 mg/dL) or 2 h plasma glucose ≥11.1 mmol/L (200 mg/dL) [
The following data were extracted and presented in an excel sheet: author(s), year, genes and SNPs, patients’ characteristics (sample size, age, and sex), city, study design, genotyping method, and significant association. Six selected items from the STROBE (strengthening the reporting of observational studies in epidemiology) checklist [
Due to heterogeneity in genotyping techniques and also differences in genetic variants studied in assessed included articles performing a meta-analysis was impossible.
A summary of the literature review process performed in this study is presented in a flow chart in Figure
Characteristics of included articles in systematic review.
Reference | Genes/ |
Patients’ characteristics | City | Study design | Method | Significant association |
---|---|---|---|---|---|---|
T1DM and complications | ||||||
Ahmadi et al., 2013 [ |
CTLA-4/ |
60 T1DM, 56 T2DM, and 107 healthy, male (M)/female (F) | Kurdistan | Case control | PCR-RFLP | Positive significant association between AG carriers and T1DM ( |
Karamizadeh et al., 2013 [ |
(i) Osteopontin/ |
87 T1DM and 86 healthy, <20 yr, M/F | Shiraz | Case control | PCR-RFLP | Nonsignificance |
Rahbani-Nabar et al., 2013 [ |
IL-18/ |
104 T1DM and 92 healthy, 9–32 yr, M/F | Tabriz | Case control | SS-PCR | Positive significant association between GG carriers and T1DM ( |
Bonakdaran et al., 2012 [ |
(i) VDR/ |
69 T1DM and 45 healthy, <35 yr, M/F | Mashhad | Case control | PCR-RFLP | Positive significant association between Aa ( |
Mohammadnejad et al., 2012 [ |
(i) VDR/ |
87 T1DM and 100 healthy, 17–38 yr, M/F | Mashhad | Case control | PCR-RFLP | (i) Negative significant association between TT carriers and T1DM ( |
Afshari et al., 2011 [ |
(i) TAP2/ |
87 T1DM and 104 healthy, <30 yr, M/F | Mashhad | Case control | ARMS-PCR | (i) Significant association between Ile379Val and T1DM ( |
Massoud et al., 2009 [ |
(i) IL-18/ |
75 T1DM and 88 healthy, <30 yr, M/F | Tehran | Case control | PCR-SSP | (i) Positive significant association between GG carriers and T1DM ( |
Masoud et al., 2007 [ |
TGF |
75 T1DM and 88 healthy, <30 yr, M/F | Tehran | Case control | PCR-SSP | Nonsignificance |
Masoud et al., 2007 [ |
IL-12/ |
75 T1DM and 88 healthy, <30 yr, M/F | Tehran | Case control | PCR-SSP | Significant association between AA and AC genotype and T1DM ( |
Mojtahedi et al., 2006 [ |
IL-18/ |
112 T1DM and 194 non-DM, <15 and >15 yr, M/F | Shiraz | Case control | PCR-SSP | −137CC and −607AA/−137CC significant association with T1DM in onset >15 yr ( |
Mojtahedi et al., 2005 [ |
CTLA-4/ |
109 T1DM and 331 healthy, 0–37 yr, M/F | Shiraz | Case control | PCR-SSP |
(i) Positive significant association between AG carriers and T1DM ( |
Zamani et al., 2005 [ |
CD4/ |
92 T1DM and 108 healthy, >35 yr, M/F | Tehran | Case control | PCR | Negative significant association between A3 allele and T1DM ( |
|
||||||
MODY | ||||||
Taghavi et al., 2009 [ |
HNF |
30 MODY, 21 relatives, and 50 healthy, 25–35 yr, M/F | Mashhad | Case control | PCR-FLP |
The mutation was found in patients and relatives but not in controls |
|
||||||
T2DM and complications | ||||||
Ahmadi et al., 2013 [ |
CTLA-4/ |
Said above | Said above | Said above | Said above | Nonsignificance |
Amiri et al., 2013 [ |
Haptoglobin/ |
134 T2DM with MVCs, 71 T2DM without MVCs, 46–72 yr, M/F | Sari | Case control | PCR | Hp2-2 highly significant for T2DM ( |
Andalib et al., 2013 [ |
Paraoxonase 2/ |
100 T2DM and 100 healthy, 51 yr, M/F | Isfahan | Case control | PCR-RFLP | Positive significant association of Cys/Cys and Cys/Ser carriers and negative significant association of Ser/Ser carriers with T2DM ( |
Kohan et al., 2013 [ |
Leptin/ |
100 T2DM and 100 healthy, 44–66 yr, M/F | Arsanjan | Case control | PCR-RFLP | Positive significant association between GG carriers and T2DM ( |
Alami et al., 2013 [ |
TCF7L2/ |
233T2DM and 233 controls, >40 yr, M/F | Gorgan | Case control | PCR-RFLP | CC and CT genotypes significant difference between T2DM and controls ( |
Mahmazi et al., 2013 [ |
Calreticulin | 120 T2DM and 530 controls, 43–66 yr, M/F | Zanjan | Case control | PCR-SCA | 9 bp deletion of 397–399 codons |
Mohammadi et al., 2013 [ |
(i) ER |
174 T2DM and 174 ND, 35–65 yr, M/F | Jahrom | Case control | PCR-RFLP | (i) Significant association with T2DM ( |
Motavallian et al., 2013 [ |
PPAR- |
100 T2DM and 100 healthy, 51 yr, M/F | Isfahan | Case control | PCR-RFLP | Negative significant association between Ala/Ala carriers ( |
Sepahi et al., 2013 [ |
HNF-1 |
100 T2DM and 50 healthy controls, ≤35 and >35 yr, M/F | Mashhad | Case control | PCR-RFLP | Nonsignificance |
Sheikhha et al., 2013 [ |
APOA1/ |
200 T2DM and 200 healthy, 41.8 yr, M/F | Yazd | Case control | PCR-RFLP | Nonsignificance |
Yaghoubi et al., 2013 [ |
CXCL5/ |
100 T2DM, 54 yr and 100 healthy, 56 yr, M/F | Ardabil | Case control | PCR-RFLP | Positive significant association of GC carriers ( |
Bahreini et al., 2012 [ |
Calpain-10/ |
102 T2DM and 100 healthy, 40–70 yr, M | East Azerbayjan | Case control | PCR-RFLP | G allele as risk factor of T2DM ( |
Derakhshan et al., 2012 [ |
SDF-1 |
200 T2DM and 200 healthy, 40 yr, M/F | Rafsanjan | Case control | PCR-RFLP | Nonsignificance |
Haghani et al., 2012 [ |
(i) IRS-1/ |
336 T2DM and 341 healthy, 44–63 yr, M/F | Ilam and Kermanshah | Case control | PCR-RFLP | (i) Positive significant association of GR ( |
Alami et al., 2012 [ |
TCF7L2/ |
236 T2DM and 255 healthy, >37 yr, M/F | Gorgan | Case control | PCR-RFLP | Positive significant association between TT carriers and T2DM ( |
Meshkani et al., 2012 [ |
(i) ER |
155 T2DM and 377 controls, 23–79 yr, M/F | Tehran | Case control | PCR-RFLP | (i) Positive significant association of pooled Pp + pp male carriers ( |
Moasser et al., 2012 [ |
GSTM1 |
171 T2DM and 169 healthy, 25–65 yr, M/F | Shiraz | Case control | PCR-RFLP | GSTM1-null ( |
Mohaddes et al., 2012 [ |
SLC30A8/ |
125 T2DM and 125 controls, 40–70 yr, M/F | Azarbayjan | Case control | PCR-RFLP | Nonsignificance |
Oladi et al., 2012 [ |
Glucokinase/ |
542 subjects, 18–65 yr, M/F | Mashhad | Cross sectional | PCR-RFLP | Nonsignificance |
Palizban et al., 2012 [ |
TCF7L2/ |
110 T2DM and 80 healthy, 46–67 yr, M/F | Isfahan | Case control | PCR-RFLP | Positive significant association between TT carriers and T2DM ( |
Tabatabaei-Malazy et al., 2012 [ |
ApoE/ |
156 T2DM and 155 healthy, 25–65, M/F | Tehran | Case control | PCR-RFLP | Nonsignificance |
Ghasemi et al., 2012 [ |
KCNJ11/ |
358 T2DM and 388 healthy, 41–69 yr, M/F | Rasht | Case control | Real time PCR | Positive significant association between KK carriers and obese T2DM ( |
Ranjbar et al., 2011 [ |
Adiponectin/ |
244 T2DM and 99 healthy, 37–65 yr, M/F | Rafsanjan | Case control | PCR-RFLP | Nonsignificant |
Mehrab-Mohseni et al., 2011 [ |
eNOS VNTR/ |
220 T2DM and 96 healthy, 53 ± 15 yr, M/F | Rafsanjan | Case control | PCR | Positive significant association between aa or ab carriers and T2DM ( |
Nosratabadi et al., 2011 [ |
(i) VDR/ |
100 T2DM and 100 healthy, 40 yr, M/F | Rafsanjan | Case control | PCR-RFLP | (i) Positive significant association between Tt carriers and T2DM ( |
Saberi et al., 2011 [ |
ENPP1/ |
155 T2DM and 377 healthy, 23–79 yr, M/F | Tehran | Case control | PCR-RFLP | Nonsignificance |
Fallah et al., 2010 [ |
SUMO4/ |
50 T2DM and 50 healthy, 25–45 yr, M/F | Tehran | Case control | PCR-RFLP | Nonsignificance |
Heidari et al., 2010 [ |
UCP2/ |
75 T2DM, 75 ND obese and 75 ND nonobese, 35–76 yr, M/F | Tehran | Case control | PCR-RFLP | Nonsignificance |
Nazem et al., 2010 [ |
5HTTLPR/ |
90 T2DM and 90 healthy, 54–66 yr, M/F | Shiraz | Case control | PCR | Nonsignificance |
Bazzaz et al., 2010 [ |
MTHFR/ |
401 T2DM, 74 ND obese and 207 ND nonobese, 30–63 yr, M/F | Tehran | Case control | PCR-RFLP | Nonsignificance |
Emamgholipour et al., 2009 [ |
resistin/ |
47 T2DM and 66 healthy, 58 ± 9 yr, M/F | Tehran | Case control | PCR-RFLP | Positive significant association between CC carriers and T2DM ( |
Hasani-Ranjbar et al., 2009 [ |
CXCL5/ |
230 T2DM and 120 healthy, 40–63 yr, M/F | Rafsanjan | Case control | PCR-RFLP | Positive significant association between GC or CC carriers and T2DM ( |
Kazemi Arababadi et al., 2009 [ |
IL-4/ |
160 T2DM and 160 healthy, 38 ± 9 yr, M/F | Rafsanjan | Case control | PCR-RFLP |
Nonsignificance |
Arababadi et al., 2009 [ |
CCR5/ |
200 T2DM and 300 healthy, 40 ± 9 yr, M/F | Rafsanjan | Case control | Gap-PCR | Nonsignificance |
Kazemi et al., 2009 [ |
INSR | 128 T2DM, >40 yr, M/F | Tehran | Case control | PCR |
Following mutations were found only in T2DM |
Mirzaei et al., 2009 [ |
PPAR |
78 normal, 78 obese, 78 T2DM, and 78 obese T2DM, 25–64 yr, M/F | Tehran | Cross sectional | PCR-RFLP | Nonsignificance |
Nikzamir et al., 2008 [ |
ACE/ |
170 T2DM and 144 healthy, M/F | Tehran | Case control | PCR | Positive significant association between DD carriers and T2DM ( |
Sharifi et al., 2008 [ |
HFE/ |
101 T2DM and 101 healthy, 55 ± 11 yr, M/F | Zanjan | Case control | PCR | Nonsignificance |
Besharati et al., 2007 [ |
(i) ApoA-I/ |
215 subjects, 26–64 yr, M/F | Tehran | Cross sectional | PCR-RFLP | (i) Nonsignificant association between G-75A carriers and T2DM |
Hasani-Ranjbar et al., 2007 [ |
Adiponectin/ |
80 T2DM obese, 72 T2DM nonobese, and 70 healthy, 25–64 yr, M/F | Tehran | Case control | PCR-RFLP | Positive significant association between TT carriers and nonobese T2DM ( |
Meshkani et al., 2007 [ |
PTPN1/ |
174 T2DM and 412 healthy, 23–79, M/F | Tehran | Case control | PCR sequencing |
Nonsignificance |
Meshkani et al., 2007 [ |
PPAR |
412 T2DM and 284 healthy, 23–79 yr, M/F | Tehran | Case control | PCR-RFLP | Negative significant association between Pro/Ala or Ala/Ala carriers and T2DM ( |
|
||||||
T2DM patients and insulin resistance | ||||||
Namvaran et al., 2012 [ |
(i) Adiponectin/ |
101 T2DM and 128 healthy, 30–70 yr, M/F | Shiraz | Case control | PCR-RFLP | (i) Positive significant association between TG carriers and T2DM ( |
Namvaran et al., 2011 [ |
PPAR |
101 T2DM and 128 healthy, 30–70 yr, M/F | Shiraz | Case control | Real time PCR | Positive significant association between Ala allele carriers and T2DM ( |
Hossein-nezhad et al., 2009 [ |
VDR/ |
105 T2DM, 55 ± 10 yr, M/F | Tehran | Case series | PCR-RFLP | Positive significant association between ff carriers and insulin resistance index ( |
Moosapoor et al., 2007 [ |
PTPN1/ |
71 T2DM and 264 ND, 20–80 yr, M/F | Tehran | Case control | PCR-RFLP | Negative significant association between 148insG carriers and insulin resistance index ( |
|
||||||
T2DM patients and heart diseases | ||||||
Bayatmakoo et al., 2013 [ |
Paraoxonase 1/ |
105 CAD/DM and 95 CAD/ND, <85 yr, M/F | Tabriz | Case control | PCR-RFLP | Nonsignificance |
Bayatmakoo et al., 2012 [ |
Paraoxonase 1/ |
105 DM/CAD and 95 CAD/ND, <85 yr, M/F | Tabriz | Case control | PCR-RFLP | Positive significant association between RR carriers and CAD/DM ( |
Esteghamati et al., 2012 [ |
(i) Adiponectin/ |
114 CAD/DM and 127 DM, 42–71 yr, M/F | Tehran | Case control | PCR-RFLP | (i) Negative significant association between 45TT carriers and CAD ( |
Rahimi et al., 2012 [ |
eNOS/ |
102 CAD/DM, 105 CAD/ND, 101 DM, and 92 ND, 45–66 yr, M/F | Kermanshah | Case control | PCR-RFLP | Positive significant association of concomitant presence of NOS3 T allele and CEPT B1 allele with T2DM ( |
Assali et al., 2011 [ |
AT1R/ |
145 CAD/DM and 164 CAD, <50 and ≥50 yr, M/F | Mashhad | Case control | PCR-RFLP | Positive significant association of AC and CC carriers with DM ( |
Emamgholipour et al., 2009 [ |
Resistin/ |
113 CAD with and without DM, |
Tehran | Cross sectional | PCR-RFLP | Positive significant association between CC carriers and DM ( |
Fallah et al., 2010 [ |
MMP-3/ |
305 CAD/DM and 313 DM, |
Tehran | Case control | PCR-RFLP | Positive significant association between 6A/6A carriers and CAS ( |
Vaisi-Raygani et al., 2010 [ |
BChE K/ |
118 DM, 162 CAD/ND, 172 DM/CAD, and 179 healthy, 42–68 yr, M/F | Kermanshah | Case control | PCR-RFLP | Positive significant association of GA, AA, and E4 carriers with CAD and DM ( |
Rahimi et al., 2009 [ |
Factor V |
65 CAD/DM, 52 CAD/ND, and 59 healthy, 46064 yr, M/F | Kermanshah | Case control | PCR-RFLP | Nonsignificance |
Nakhjavani et al., 2007 [ |
ACE/ |
82 DM with hypertension and 87 DM without hypertension, 49–63 yr, M/F | Tehran | Case control | PCR | Positive significant association between DD carriers and hypertension ( |
Vaisi-Raygani et al., 2007 [ |
Apolipoprotein/ |
152 CAD/DM, 262 CAD/ND, and 300 healthy, 35–73 yr, M/F | Kermanshah | Case control | PCR-RFLP | Positive significant association of E2 and E4 allele carriers with CAD ( |
|
||||||
T2DM patients and nephropathy | ||||||
Rahimi et al., 2013 [ |
eNOS/ |
63T2DM/microalbuminuria, 57T2DM/macroalbuminuria, 52T2DM/normoalbuminuria, 121 DN, and 101 healthy, 45–66 yr, M/F | Kermanshah | Case control | PCR |
Positive significant association of 4a or 894T allele carriers and macro- ( |
Rahimi et al., 2013 [ |
AT2R/ |
28T2DM/microalbuminuria, 22T2DM/macroalbuminuria, 20T2DM/normoalbuminuria, and 112 healthy, 43–63 yr, M/F | Kermanshah | Case control | PCR-RFLP | Positive significant association between AA carriers and nephropathy ( |
Shahsavar et al., 2013 [ |
SUMO4/ |
50 T2D/DN and 50 T2DM non-DN, 25–45 yr, M/F | Tehran | Case control | PCR-RFLP | Positive significant association between AA carriers and nephropathy ( |
Arababadi et al., 2012 [ |
IL-10/ |
100 T2DM/non-DN, 100 T2DM/DN and 100 healthy, 31–49 yr, M/F | Rafsanjan | Case control | PCR-RFLP | Positive significant association between CC carriers and DN ( |
Nikzamir et al., 2012 [ |
VEGF/ |
255 T2DM/microalbuminuria and 235 T2DM/nonalbuminuric, 50–67 yr, M/F | Tehran | Case control | PCR-RFLP | Positive significant association between GG carriers and albuminuria ( |
Rahimi et al., 2012 [ |
MTHFR/ |
72T2DM/MicAlb, 68T2DM/MacAlband 72 T2DM/non-DN, 46–65 yr, M/F | Kermanshah | Case control | PCR-RFLP |
Positive significant association of ACE D/677T ( |
Rahimi et al., 2012 [ |
eNOS/ |
72T2DM/microalbuminuria, 68T2DM/macroalbuminuria and 72 T2DM/non-DN, 46–65 yr, M/F | Kermanshah | Case control | PCR-RFLP |
Positive significant association between ACE D carriers and macroalbuminuria ( |
Felehgari et al., 2011 [ |
ACE/ |
68 T2DM/macroalbuminuria and 72 T2Dm/normoalbuminuria, 46–65 yr, M/F | Kermanshah | Case control | PCR | Nonsignificance |
Jafari et al., 2011 [ |
eNOS/ |
72T2DM/microalbuminuria, 68T2DM/macroalbuminuria and 72 T2DM/non-DN, 46–65 yr, M/F | Kermanshah | Case control | PCR-RFLP | (i) Positive significant association of eNOS T/1298 C and eNOS T/677 T carriers with macroalbuminuria ( |
Rahimi et al., 2011 [ |
ACE/ |
217/mean 55/both | Kermanshah | Case control | PCR |
Nonsignificance |
Arababadi, 2010 [ |
IL-4/ |
100 T2DM/DN and 150 healthy, 33–47 yr, M/F | Rafsanjan | Case control | PCR | Positive significant association between CT carriers and DN ( |
Nosratabadi et al., 2010 [ |
(i) VDR/ |
100 T2DM/non-DN, 100 T2DM/DN, and 100 healthy, 31–49 yr, M/F | Rafsanjan | Case control | PCR-RFLP | (i) Positive significant association between Tt carriers and DN ( |
Rahimi et al., 2010 [ |
MTHFR/ |
72T2DM/microlbumiunira, 68T2DM/macroalbuminuria, and 72 T2DM/non-DN, 46–65 yr, M/F | Kermanshah | Case control | PCR-RFLP | (i) Positive significant association of 677T, 1298C and 677T/1298C carriers with macroalbuminoria ( |
Nikzamir et al., 2009 [ |
ACE/ |
129T2DM/microlbumiunira, 48T2DM/macroalbuminuria, and 145T2DM/normoalbuminuria, 59.4 ± 8.5 yr, M/F | Tehran | Cross sectional | PCR | Positive significant association between DD carriers and progression of albuminuria ( |
Nikzamir et al., 2006 [ |
ACE/ |
85 T2DM/DN, 85 T2DM/non-DN, and 91 healthy, 37–67 yr, M/F | Tehran | Case control | PCR | Positive significant association between DD carriers and T2DM ( |
|
||||||
T2DM patients and retinopathy | ||||||
Abbasi et al., 2013 [ |
GSTM1/ |
80 DR and 80 healthy, 30–70 yr, M/F | Rasht | Case control | ARMS-PCR | Null genotype significant association, |
Dadbinpour et al., 2013 [ |
(i) GSTM1/ |
57 DR and 58 non-DR, 35–65 yr, M/F | Yazd | Case control | Multiplex PCR | (i) Null genotype of GSTM1 or GSTT1 significant association ( |
Feghhi et al., 2011 [ |
VEGF/ |
119 diabetics with PDR and 279 diabetics with NPDR, 47–66 yr, M/F | Ahvaz | Case control | PCR-RFLP | Positive significant association between GG carriers and diabetic retinopathy ( |
|
||||||
T2DM patients and foot ulcer | ||||||
Amoli et al., 2011 [ |
(i) VEGF/ |
247 T2DM with DFU, 241 T2DM without DFU, and 98 healthy, 43–64, M/F | Tehran | Case control | ARMS-PCR | (i) Nonsignificant association of −7C/T carriers with DFU |
SNP, single nucleotide polymorphism; T1DM, type 1 diabetes mellitus; CTLA-4, cytotoxic T lymphocyte associated antigen 4; T2DM, type 2 diabetes mellitus; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; IL, interleukin; SS-PCR, sequence specific PCR; VDR, vitamin D receptor; TAP2, transporter 2 ATP-binding cassette; ARMS-PCR, amplification refractory mutation system PCR; PCR-SSP, PCR single specific primer; TGF
Flow diagram of study selection process.
Overall 27,396 diabetics and healthy subjects were studied in this systematic review. All of the subjects were recruited from total urban population. T2DM was the most investigated type of diabetes (42 studies) [
Details of the included studies are described as below.
All the studies in this subgroup including 12 studies [
Association of interleukins including IL-18 (interleukin) and IL-12 with T1DM revealed that the −137C/G polymorphism of IL-18 had significant association with T1DM (
In 2 studies the association of +49A/G variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investigated and it was revealed that there was a positive significant association between AG genotype and T1DM (
Vitamin D receptor (VDR) was investigated in 2 studies [
Different polymorphisms of TAP2 and their association with T1DM were investigated in 191 subjects. It was shown that Ile379Val and Stop687Gln had significant association with T1DM (
Association of alleles A2–A9 of CD4 with T1DM was assessed in 200 subjects. It was revealed that A3 allele had negative (
Association of some other genes including osteopontin (rs1126772 polymorphism), integrin
In this category only one study was found [
In this subgroup 42 studies were assessed and all of them were designed as case control association studies [
Association between two polymorphisms of TCF7L2 including rs7903146 (C/T) and rs12255372 (G/T) was assessed in three studies [
Investigating the association of calreticulin with T2DM in 650 subjects showed two mutations, only in case group, 9 bp deletion of 397–399 codons and G>T mutation at IVSII-142 [
Association of estrogen receptor
Association of Pro12Ala polymorphism of PPAR
Association of different polymorphisms of
Two studies assessed the association of −156G>C polymorphism of CXCL5 with T2DM [
Adiponectin and its association with T2DM were investigated in two studies [
In one study that investigated insulin receptor gene, the following mutations were found only in T2DM: 511C>A, 514T>G, 586, and 628T>A on exon 2, 694G>C, 680G>A on exon 3, 1627A>T on exon 8, AT>TG on intron 9, 2007C>C/T on exon 9, 2595C>C/T and 2669G>C/G on exon 13, 2706 and 2717C>G, 2752C>T, and 2753C>G on exon 14, and 3471T>A and 3516T>G on exon 19. These mutations were not seen in control subjects [
Other variants which had significant association with T2DM included haptoglobin (allele 2-2), leptin (G-2548A polymorphism), paraoxonase 2 (Ser311Cys polymorphism), GST (glutathione-S-transferase) M1 and GSTM1/GSTT1 interaction, calpain-10 (SNP (single nucleotide polymorphism) 43), IRS-1 (G972R polymorphism) and IRS-2 (G1057D polymorphism), VDR (vitamin D receptor) (TaqI polymorphism), KCNJ11 (E23K polymorphism), eNOS (endothelial nitric oxide synthase) VNTR (intron 4 a/b polymorphism), resistin (−420C/G polymorphism), and ACE (Insertion/Deletion) [
In contrast to above variants, CTLA4 (+49A/G polymorphism), HNF-1
In this subgroup, four studies were assessed and all were designed as case-control association studies. Three studies used PCR-RFL [
The studies assessed in this subgroup showed a positive association of TG carriers of +45T/G polymorphism of adiponectin (
Design of all 11 studies in this subgroup was case-control association study [
Paraoxonase 1 (163T/A polymorphism) was the only variant in this subgroup which was not significantly associated with atherosclerosis risk in T2DM [
Investigating B1 and B2 alleles of CETP
Investigation of apolipoprotein E (E2, E3, and E4) alleles showed the association of E2 and E4 alleles with CAD (
Adiponectin +276G/T and +45T/G were significantly associated with CAD (
In addition A1166C polymorphism of AT1R (angiotensin I receptor) and −420C/G polymorphism of resistin in diabetic patients with CAD revealed significant association with diabetes,
Another study showed insertion(I)/deletion(D) polymorphism of angiotensin converting enzyme (ACE) DD genotype was significantly associated with higher blood pressure (
Factor V Leiden (G1691A polymorphism), prothrombin (G20210A polymorphism), and MTHFR (methylenetetrahydrofolate reductase) (C677T polymorphism) were the variants which were not significantly associated with CAD and T2DM in this subgroup [
All of 15 studies in this subgroup were designed as case-control association studies [
Studying the association of 163A/G polymorphism of SUMO4 showed a positive significant association between AA carriers and diabetic nephropathy (
Studying the interaction of eNOS/4a/b and G894T revealed positive significant association between 4a or 894T allele carriers and macro- and microalbuminuria (
It has also been shown that interaction of eNOS (G894T polymorphisms) and MTHFR (C677T and A1298C polymorphisms), eNOS T/1298 C, and eNOS T/677 T carriers had positive significant association with macroalbuminuria. In addition significant association of eNOS GT+TT carriers with lipid profile (
C677T and A1298C polymorphisms of MTHFR were also investigated in another study revealing that 677T, 1298C, and 677T/1298C carriers were significantly associated with macroalbuminuria (
ACE (I/D alleles) polymorphisms were investigated in three studies. In one study positive significant association (
Association of interleukins including IL-4 and IL-10 with diabetic nephropathy was also investigated in two studies. Study of −592C/A polymorphism of IL-10 revealed positive significant association between CC carriers and nephropathy (
Other significant associations between variants and diabetic nephropathy included AT2R (angiotensin II receptor) (−1332G/A polymorphism), VEGF (vascular epithelium growth factor) (+405G/C polymorphism), and VDR (
All of the 3 studies in this subgroup were conducted as case-control association studies [
Investigating null/positive genotype of GSTM1 in a study, which used ARMS-PCR for genotyping, revealed that null genotype is significantly associated with diabetic retinopathy (
Investigating +405G/C polymorphism of VEGF also revealed positive significant association between GG carriers and diabetic retinopathy (
In this subgroup only one study was found [
Diabetes mellitus is the eighth most frequent disease leading cause of death throughout the world and now ranks the fifth, following communicable diseases, cardiovascular disease, cancer, and injuries [
Type 2 diabetes is the most frequent type of diabetes mellitus [
MTHFR is another important gene in association with T2DM and other related complications. No association of C677T polymorphism of MTHFR gene was found in Africans, Asians, and Caucasians [
Interleukins especially IL-10 are shown to have significant association with T2DM in different ethnic groups. Significant association between −592C/A and −819C/T polymorphisms of IL-10 and T2DM risk in Africans was shown [
Investigation of different polymorphisms of adiponectin and their association with T2DM in a meta-analysis study revealed −11391G>A and −11426A>G polymorphisms of adiponectin as risk factor for T2DM in Europeans and −11377C>G variant of adiponectin as risk factor of T2DM in Europeans and Asians [
Among candidate genes in association with T2DM, TCF7L2 is one of the strongest genes related to diabetes. In a meta-analysis study after pooling all data of European, African, and Asian populations, it has been revealed that rs12255372 polymorphism of TCF7L2 significantly increases the risk of T2DM. However no data from Iranian population as a type of Asian population was included in this meta-analysis [
Pro12Ala polymorphism of PPAR
Type 1 diabetes mellitus is another type of diabetes in which HLA (human lymphocyte antigen), IR1R1 (interleukin-1 receptor type 1), CTLA-4, and VDR are some important genes studied in association with T1DM [
Among diabetic complications, CAD and DN are the most studied complications. Meta-analysis studies showed that rs2010963 and rs3025039 polymorphisms of VEGF, 4b/a, T-786C, and G894T polymorphisms of eNOS and ACE are associated with DN [
The most investigated genes in association with CAD include PPAR
Overall it seems that more studies are needed to identify diabetes susceptibility genes in Iranian population. Investigation of candidate genes is one way to understand these genes, but the method with the least expenses and error is GWAS which scans a set of loci in association with a disease in many people. GWAS in different populations such as Americans, Caucasians, Australians, West Africans, and Europeans revealed multiple loci in association with T2DM [
However, there are some strength and some limitations in our study. Firstly, this systematic review, for the first time, assessed the association between genetic variants and diabetes in Iranian population. Moreover, the studies included in this systematic review were assessed for quality and selected as high quality (scored ≥ 3). For limitations it should be considered that all included studies were observational, which does not allow reliable inferences about causality. Moreover due to methodological heterogeneity, we were not able to pool the data and perform the meta-analysis.
Our study showed significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM. HNF
Insufficient data might cause the conflicting results; therefore GWAS on defined population with large sample size is suggested as a more comprehensive approach answering many more questions.
The authors declare that they have no conflict of interests.