Abstract
Due to the high prevalence of metabolic diseases and the role of genetic factors in their susceptibility, the use of basic research in this field can be useful for screening, prevention, and treatment of metabolic disorders. Therefore, in the Immunogenetics group of Endocrinology and Metabolism Research Institute (EMRI), various studies have been conducted to investigate the relationship between genetic markers and the risk of monogenic and complex disorders such as diabetes, obesity, thyroid malignancies, and cardiovascular disease.
Keywords: Type-1 diabetes, Obesity, Monogenic diseases, Type-2 diabetes
Introduction
The molecular and cellular laboratory has been established in Endocrinology and Metabolism Research Institute (EMRI) since 2003 with the aim of evolving cutting edge molecular techniques to conceive translational research studies for understanding the molecular and cellular basis of endocrinology and metabolism disorders. In this regard the main focus of the studies have been on discovering the role of genetic variations in pathogenesis of endocrine disorders in two different entities including monogenic and complex disorders which is described in more details in this article.
Methods and materials
In this review paper, the results of 57 studies that have been conducted in the Immunogenetics group of Endocrinology and Metabolism Research Institute (EMRI) are reviewed and summarized. The main topics of the papers are categorized into three sections: studies on monogenic endocrine and metabolic disorders, genetics of complex endocrine and metabolic disorders including diabetes, obesity, thyroid malignancies, cardiovascular disease and review studies which are summarized in Table 1.
Table 1.
The main topics of research and summury of rsults
| Disease | Gene | Result |
|---|---|---|
| Monogenic Diseases | ||
| Neonatal Diabetes Mellitus | KCNJ11 | Missense mutation c. 679 G/A (E227K) |
| Wolfram Syndrome | WFS1 | c.1185 C > T, c.2433 G > A,c.2565 A > G (neutral), c.997 A > G (I332V),c.1762 T > G (W588G), c.1832 G > A (H611R), andc.1963 G > A (E655K). |
| Wolfram Syndrome | WFS1 | Two missense mutations in G736D and R629W |
| Neonatal Diabetes Mellitus | PDX1 | Novel homozygous mutation in the PDX1 gene (NM_000209.3), p.Phe167Val. |
| Diabetes Mellitus | ND1 | New point mutation (A/G) at position 4093 of the ND1 gene |
| Autoimmune Polyglandular Syndrome Type 1(APS-1) | AIRE | c.1095 + 2 T > A mutation |
| Congenital generalized lipodystrophy (CGL) | APGAT2 | AGPAT2 mutation(rs145169122) |
| H syndrome | SLC29A3 | Frameshift mutation, NM_018344.5:c.122del, p.(Pro41fs) |
| Wolcott-Rallison syndrome (WRS) | Eukaryotic translation initiation factor 2alpha kinase 3 (EIF2AK3). | nonsense (c.679G > T, p. Glu227Ter and c.2476 C > T,p. Arg826Ter), 2 frameshift (c.2589_2593delAAGTT, p. Phe1038fs andc.3112_3113insA, p. Phe1038fs) and 1 missense (c.2866G > C, p.Gly956Arg) variants |
| Type-1 Diabetes | WFS1, SLC19A2, SLC29A3, GCK | Four novel mutations in WFS1, SLC19A2, SLC29A3, GCK. |
| Monogenic Obesity | LEPR | loss-of-function mutation, NM_002303.5:c.464 T > G; p.(Tyr155*) |
| Multiple endocrine neoplasia (MEN) type 1 | MEN1 | Two nucleotide deletion in the exon 2 (c199_200del2) |
| Ectopic Cushing syndrome | MEN1 | Exon 10(R527X) |
| von Hippel-Lindau (vHL) type 2 disease | VHL | Exon 3 of VHL gene c499 C > T |
| Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) | SLC34A3 | 101-bp deletion in intron 9 of the SLC34A3 gene |
|
Genetics of Complex disorders Diabetes | ||
| Diabetic Neuropathy | VEGF |
-7*C/T, -1001*G/C, -1154*G/A and − 2578*C/A |
| Retinopathy ,type 1 diabetes | eNOS | -786*C/T polymorphism |
| Type-1 Diabetes | IGF-I,TGF-β1 | TGF-β1 gene, + 869*T/C and + 915*G/C < 0.05 |
| Type 1 diabetes | TNF-α, IFN-γ | TNF-α − 308*G/A polymorphism ( p = 0.06) |
| Type-2 Diabetes | TCF7L2 | rs7903146 < 0.05 |
| Type-2 Diabetes | CXCL5 | CXCL5 -156G > C < 0.05 |
| Type-2 Diabetes | eNOS | VNTR (intron 4 a/b) variant < 0.05 |
| Diabetic Nephropathy | MTHFR | C677T, 1298A/C, p < 0.05 |
| Diabetic Nephropathy | VDR | rs7975232, rs731236 and rs4516035 haplotypes p < 0.05 |
| Diabetic Nephropathy | MTHFR,CNDP1,CNDP2 | rs2346061, rs7577, rs1801133 > 0.05 |
| Diabetic Nephropathy | ERRFI1 | rs377349 p < 0.05 |
| Diabetic Nephropathy | MYH | rs4821481 p < 0.05 |
| Type-2 diabetes | Adiponectin | + 45T/G, -11391G/A, p < 0.05 |
| Diabetic Foot Ulcer | VDR | FokI, p < 0.05 |
| Diabetic Foot Ulcer | eNOS | Glu 298 Asp p < 0.05 |
| Diabetic Foot Ulcer | VEGF | -7*C/T and − 2578*C/A p < 0.05 |
| Type-2 Diabetes and Depression | MIF | MIF − 173G > C(rs755622) and gene expression, p < 0.05 |
| Type-1 Diabetes | VDR | TaqI, FokI, BsmI and ApaI polymorphism and serum VD level had association with C-Peptid SCP, p < 0.05 |
| Type-1 Diabetes | TGF-β1, IL-23 | TGF-β1, IL-23 gene expression, p < 0.05 |
| Obesity | ||
| Obesity | Adiponectin | -11,391 G/A p = 0.044 with Waist-to-height ratio (WHtR) |
| Obesity | Adiponectin | + 45T/G and − 11391G/A variants ,p < 0.05 |
| Obesity | APOE | APOE showed significant association with BMI and lipid profile,p < 0.05 |
| Obesity | APOE | Association between abdominal obesity and APOE E4,p < 0.05 |
| Obesity | ADA | Significant association of AA genotype, ,p < 0.05 |
| Obesity | MTHFR | No association was observed between rs1801133 and Metabolic syndrome ( p > 0.05) |
| Thyroid Malignancies | ||
| Papillary thyroid carcinoma (PTC) | HLA | HLA-DRB1*04 frequency was ( p = 0.02) |
| Papillary thyroid carcinoma (PTC) | HLA | Significant association between HLACw*4 and HLACw*15 with PTC ( p < 0.05) |
| Papillary thyroid carcinoma (PTC) | Survivin | rs9904341 p < 0.05 |
| Papillary thyroid carcinoma (PTC) | EBNA1 | p < 0.05 |
| Cardiovascular Diseases | ||
| Cardiovascular disease(CAD) | VEGF | Significant association between 2578*C/A and VEGF gene expression( p < 0.05) |
| Cardiovascular disease(CAD) | IL-23, IL-17, TGF-β1 Genes expression | Significant association of IL-23 gene expression( p < 0.05) |
| Cardiovascular disease(CAD) | Rantes | No association between − 403G/A variant and Rantes gene expression with CAD,p > 0.05 |
| Cardiovascular disease(CAD) | TNF-ɑ, IL-1β, IFN-γ | Association of IL-1β with CAD, p < 0.05 |
| Cardiovascular disease(CAD) | eNOS, VNTR | Significant association of -786T > C and eNOS VNTR variants with CAD, p < 0.05 |
| Cardiovascular disease(CAD) | klotho gene (kl-vs) | No association, p > 0.05 |
| Reviews | ||
| Oxidative Stress in Type-2 Diabetes | Role of SNPs within antioxidant enzymes | superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, nitric oxide synthase, and NAD(P)H oxidase |
| antioxidants’ gene varients and T2DM | eNOS, GSTM, GSTT1 | Association of eNOS geen variant, and GSTM1 and GSTT1 null genotypes with Type-2 diabetes confirmed in this study |
| Obesity | Adiponectin, PPARg2, PTP1B, glucokinase, TNF-α, UCP2, MTHFR, β3-adrenoreceptor ,apolipoprotein E | Significant association between adiponectin, PPARg2, PTP1B gene variants and obesity( p < 0.05) |
| Obesity | interleukin-6 (IL-6) | Significant association between IL-6 rs1800797 varinat and obesity |
| Daibetes Mellitus | Signifcant association was observed between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFα and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERα, PPAR-γ2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM | |
| The association of VDR gene with Osteoporosis | VDR gene | Significant association between FOKI and BsmI variants with Osteoporosis (p < 0.05) |
Studies on monogenic endocrine and metabolic disorders
In this group of studies one of the main emphasizes was focused on finding the genetic markers associated with monogenic diabetes. in order to examine the genetic basis of monogenic diabetes in Iranian populations, several investigations were conducted including mutation screening of the KCNJ11 gene in neonatal diabetes [1], report of several novel WFS1 gene mutation in patients with Wolfram syndrome [2, 3] novel homozygous mutation in the PDX1 gene [4], discovery of a new mutation in ND1 gene of a 28 year-old patient with multiple flexion contractures of hands and feet, deafness, diabetes mellitus [5], AIRE gene mutation screening in a family with a clinical diagnosis of autoimmune polyglandular syndrome type 1 (APS-1) [6], APGAT2 mutation in patient with Congenital generalized lipodystrophy (CGL) [7] and a pathogenic frameshift mutation in exon 2 of the SLC29A3 gene in a 4.5 years old girl with H syndrome [8].
Wolcott-Rallison syndrome (WRS) is a very rare autosomal recessive disorder with permanent neonatal diabetes mellitus (PNDM). Mutations in EIF2AK3 gene encoding eukaryotic translation initiation factor 2α kinase 3 results in WRS. The genetic causes of neonatal diabetes in 60 unrelated Iranian subjects with PNDM was examined by a collaboration study with Exeter university, UK. All the probands were screened for KCNJ11, INS, ABCC8 and EIF2AK3. We reported 9 different variants in EIF2AK3 in 11 unrelated Iranian probands, with 5 novel variants which were not reported previously. We observed associated features including short stature, failure to thrive, neurodevelopmental delay, epilepsy and hepatic and renal dysfunction in their clinical follow up together with strong family history of neonatal diabetes and a high mortality rate [9].
Furthermore in another collaborative project with Exeter university in UK in unrelated children with diabetes diagnosed between 9 months and 5, targeted next generation sequencing (tNGS) analysis, serum antibody measurements and SNP analysis revealed that type 1 diabetes genetic risk score can discriminate children with monogenic from Type 1 diabetes and six children with monogenic diabetes, including four novel mutations: homozygous mutations in WFS1 (n = 3), SLC19A2 and SLC29A3 and a heterozygous mutation in GCK were identified. All clinical features were similar in children diagnosed with monogenic diabetes and the rest of the cohort. All children with monogenic diabetes were autoantibody-negative [10].
Another main area of our research is focused on investigating the genetic causes of monogenic obesity in Iran. We are looking at the main obesity genes using various approaches including tNGS and exome sequencing in collaboration with several research centers and recently found a homozygous loss-of-function mutation in the leptin receptor (LEPR) in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia diagnosed as congenital deficiency of the LEPR which is rare cause of severe early-onset obesity [11].
Several other efforts have been carried out looking at genetic cause of various monogenic endocrine disorders including multiple endocrine neoplasia type 1(MEN1). We reported several mutations including presence of two nucleotide deletion in the exon 2 (c199_200del2) resulting in a non-functional gene product [12]. Also we reported mutation in exon 10(R527X) of MEN1 gene in a patient with ectopic cushing syndrome secondary to thymic carcinoid tumor with the presence of clinical manifestations in other family members [13]. A new missense mutation of VHL gene was detected in Von Hippel-Lindau (VHL) type 2 disease in a family with RET negative bilateral malignant pheochromocytoma and retinal angioma [14]. Furthermore for the first time we reported the presence of 101-bp intron 9 deletion in SLC34A3 gene in an Iranian family with Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) presenting with hyperphosphaturia, hypercalciuria, and hypercalcemia [15].
Studies on genetics of complex endocrine and metabolic disorders
Diabetes
Several studies have been conducted to examine the genetic susceptibility of type 1 and type 2 diabetes and their microvascular complications including diabetic nephropathy, retinopathy, neuropathy and diabetic foot ulcer (DFU). In this regard we have investigated the distribution of − 7*C/T, − 1001*G/C, − 1154*G/A and − 2578*C/A variants in VEGF gene with diabetic neuropathy in type 1 diabetic patients and we observed that allele (C) of (− 7*C/T) confer risk to diabetic neuropathy [16]. Furthermore we reported a significant association between the polymorphisms in -786*C/T of eNOS gene and both T1DM and diabetic retinopathy [17]. We also looked at polymorphisms of the IGF-I gene at positions − 383*C/T and − 1089*C/T and two functional TGF-β1 gene polymorphisms, including codons 10 (+ 869*C/T) and 25 (+ 915*G/C). It has been observed that the low producer variant of TGF-β1 gene at codon 25 (allele C) were more frequent in cases than controls which was in line with the anti-inflammatory effect of TGF-β1. Also allele C at codon 10 showed highest frequency in retinopathy while, nephropathy was more frequently presented in carriers of allele T (high producer). In the complication free group, allele G (high producer) frequency of codon 25 polymorphism was to some extent higher than the other subgroups[18]. Functional polymorphisms of TNF-α (− 308*G/A) and IFN-γ gene (+ 874*T/A) were assessed in T1DM patients and healthy controls. There was no significant association between IFN-γ gene polymorphism and T1DM or its complications. However a marginal association was observed between TNF-α − 308*G/A polymorphism in nephropathies compared with healthy controls which might be attributed to survivor factor [19].
In type 2 diabetes we showed for the first time a significant association between TCF7L2 rs7903146 variant in an Iranian population [20]. In another study we reported that patients with type 2 diabetes mellitus had a higher frequency of carrying either the G/C or C/C genotype CXCL5, (epithelial cell-derived neutrophil-activating peptide) (ENA-78) than healthy controls [21].
We also studied the association of eNOS intron 4 VNTR polymorphism and type-2 diabetes in an Iranian population and we observed a significant differences for the frequency of eNOS polymorphism between patients and controls. We also established that frequency of ‘a’ allele was increased significantly in patients with diabetic neuropathy and interestingly both genotype and allele frequencies of eNOS intron 4 VNTR polymorphism were significantly different between patients who were complication free and the controls [22]. Also in type 2 diabetes patients with diabetic neuropathy an study on MTHFR gene C677T and 1298A/C polymorphisms showed a significant association with C677T polymorphism [23].
Several studies have been carried out for genetic association of diabetic nephropathy in patients with type 2 diabetes. Study of VDR rs7975232, rs731236 and rs4516035 variants with DN (diabetic nephropathy) showed no significant association. However the haplotype analysis showed CCC haplotype was significantly more frequent in DN subjects compared to the normal healthy group (HC) and also, TCC haplotype was significantly more frequent in DN group compared to both HC and D (Diabetes) groups[24]. The association of rs2346061 (CNDP1), rs7577 (CNDP2), and rs1801133 (MTHFR) variants and homocysteine level with diabetic nephropathy showed no association with the studied variants[25]. The role of (rs377349) in ERRFI1 gene has been investigated with DN (diabetic nephropathy) which showed significant association [26]. Study of MYH9 gene polymorphism (rs4821481) in diabetic nephropathy showed an association with significantly higher urinary excretion of albumin insignificantly lower GFR values [27]. Another study was carried out to determine the possible association between adiponectin gene polymorphisms + 45T/G and − 11391G/A and type2 diabetes. No significant association was found with diabetes or diabetic complications as diabetic retinopathy, nephropathy and neuropathy. Linkage disequilibrium (LD) analysis did not show a significant LD between those two polymorphisms and we found no significant differences for LD between cases and controls in our study population [28].
In order to study genetic cause of diabetic foot ulcer (DFU) several projects were conducted. The association between vitamin D receptor (VDR) gene FokI polymorphism and DFU in Iranian population indicated a significant association with the presence of allele T which was also significantly related to the higher level of oxidative stress parameters including TBARS [29]. In another study we reported that genotype and allele frequencies of eNOS Glu298Asp polymorphism in exon 7 were significantly different between DFU case and control groups [30]. We also studied the association between − 7*C/T and − 2578*C/A polymorphisms in VEGF gene and DFU (diabetic foot ulcer) in T2DM patients and we observed that the frequency of genotype AA was significantly reduced in patients with DFU in comparison with diabetic subjects without DFU. Also we observed a significant decrease in frequency of A allele in patients with DFU [31].
We have conducted several lines of investigation to study the genetic factors involved in depression associated with diabetes in this regard the association between MIF − 173G > C (rs755622) variant was examined in T2DM patients with and without depression and found some interesting results for the expression of MIF in PBMC of patients and also observed evidence of gender effect in association between MIF gene variant and diabetes related depression [32].
The effect of vitamin D (VD) and its receptor gene polymorphisms on residual ß-cells function in children with T1DM was observed in a study on TaqI, FokI, BsmI and ApaI polymorphisms and serum VD level which showed association with the C-peptide (CP) and SCP(stimulated C-peptide) levels [33].
Finally we have shown the expression level of TGF-β1 and IL-23 gene in unstimulated peripheral blood mononuclear cells (PBMCs) of patients with diabetes and we reported a significant difference in TGF-β1 and IL-23 gene expression in juvenile-onset T1DM and adult-onset T1DM compared to the controls and T2DM patients. In addition we observed an up-regulation of IL-23 in T1DM while it was down-regulated in T2DM[34].
Obesity
As the role of genetic factors in the development of obesity has been demonstrated, another main focuses of our studies were to investigate relationship between obesity anthropometric measures in context of other diseases including diabetes in case-control association studies. Waist-to-height ratio (WHtR) can be regarded as an indicator of abdominal obesity and the risk of T2DM. The serum level of Adiponectin is inversely correlated with body fat percentage and is reduced in obesity and T2DM. In a study 610 subjects with known anthropometric characteristics Adiponectin genotype − 11,391 G/A frequencies showed significant association with WHtR [35]. In another study, for investigating the association of two polymorphisms of Adiponectin gene + 45T/G and − 11391G/A with body mass index (BMI), waist circumferences (WC), and blood pressure in diabetic and non-diabetic individuals from Rafsanjan city the result demonstrated the sex-dependent association of both polymorphisms with BMI and waist circumferences[36].
Apolipoprotein E (apo E) plays a major role in lipid metabolism, obesity and accordingly in development of diabetes and coronary heart disease (CHD). In a cohort study the association of Apolipoprotein E (APOE) as a regulator of blood lipid level was investigated with BMI and lipid profile which showed association with both cholesterol level and BMI [37]. Further studies showed that the likelihood of presenting abdominal obesity in carriers of APOE E4 allele was increased from 0.22 to 8.12 in women and to 3.08 in age ≥ 50 years[38].
In another study the association of Adenosine deaminase (ADA) which contributes to adiposity in T2DM showed the higher frequency of AA genotype in obese people than controls compared to CA and CC genotypes[39].
To examine the association between MTHFR gene C677T polymorphism in diabetes and obesity with serum homocysteine levels, we found no significant differences [28].However in a cross sectionals study the association of MTHFR, rs1801133 variant with metabolic syndrome was investigated which showed positive association [40].
Thyroid malignancies
The study of genetic factors involved in pathogenesis of thyroid cancers has been evaluated by several studies as follow.
HLA-DR antigen frequencies in patients with papillary thyroid carcinoma (PTC) has revealed HLA-DRB1*04 as a risk factor in papillary thyroid carcinoma in Iranian population [41]. In another study we observed that HLACw*4 and HLACw*15 allele frequencies were significantly higher in individuals with PTC compared to the controls [42].
Survivin gene expression has shown correlation with suppression of apoptosis in human solid tumors. In this regard the role of − 31 (G/C) (rs 9,904,341) variant in papillary thyroid carcinoma (PTC) have been investigated which showed that the presence of C allele was significantly associated with the presence of more profound manifestations, including lymph node involvement, vascular involvement and multifocality [43].
The presence of Epstein-Barr Nuclear Antigen 1 (EBNA1) gene have been examined in thyroid cancer. EBNA1 was detected in 65.8 % of patients with papillary thyroid carcinoma which was significantly higher in younger ages. This result suggests that the Epstein-Barr virus (EBV) virus may play a role in papillary thyroid carcinoma especially at younger ages [44].
Cardiovascular disease
Several studies have been conducted to investigate the genetic causes of cardiovascular disorders including gene expression and case control association studies.
VEGF mRNA expression was examined with its 2578*C/A polymorphism in patients who underwent angiography with coronary artery diseases (CAD) and we showed that the frequency of CC genotype was higher in CAD patients compared to the control group. In addition, individuals with AA genotype had lower mRNA levels of VEGF compared to AC and CC genotype indication the role of this variant in mRNA level [45].
In another study, we investigated the association of several cytokines including IL-23, IL-17 and TGF-β1 gene expression in patients with and without CAD which demonstrated the lower expression of IL-23 in patients with CAD compared to the control group as a protective marker[46].
Several other markers have been investigated in CAD patients comprising RANTES (regulation upon activation normal T cell expressed and secreted). The association of RANTES − 403 G/A polymorphism in the promoter region and the mRNA expression did not show a significant association [47].
The association of TNF-α, IL-1β and IFN-γ gene expression in patients with CAD showed a higher level of IL-1β in contrast. Even though the expression of IFN-γ and TNF-α were also higher in CAD patients compared to the control group, the difference were not significant [48].
The expression of the eNOS gene and VNTR polymorphism was also assessed in CAD patients. Although the expression of the eNOS gene was higher in patients than control, it was not statistically significant. However the frequency of aa genotype in eNOS VNTR polymorphism was significantly associated with CAD. In addition, the eNOS expression was lower in patients carrying AA genotype compared to ab or bb genotypes.
In a cross-sectional study we evaluated the role of -786T > C variant in endothelial nitric oxide synthase (eNOS) with the presence of in stent restenosis which showed significant association [49].
We determined for the first time the frequency of klotho gene (kl-vs) variant in 107 patients with CAD and in contrast to previous studies, we observed no mutation in our studied population which may contradict the association and role of gene (kl-vs) in the Iranian population [50].
Review studies
Several reviews and systematic reviews studies were carried out by our team mainly based on previous studies conducted by our group which are briefly presented here.
Oxidative stress has a key role in pathophysiology of type 2 diabetes mellitus (T2DM) and its complications as a most common health problem. A review study has been performed to investigate the mechanism behind the role of Oxidative stress in the development of diabetes mellitus and its complications. The main aim of the review was to focus on the assessment of single-nucleotide polymorphisms within antioxidant enzymes including superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, nitric oxide synthase, and NAD(P)H oxidase and their association with T2DM to understand the mechanisms involved in pathogenesis of disease besides discovering new treatment approaches in management of DM and we presented interesting results [51]. Due to controversial evidence regarding the association between antioxidants’ gene varients and T2DM we conducted another study as a systematic review of the current meta-analyses. As a results of the late study we observed that the variants of eNOS gene were associated with DN (diabetic nephropathy). Separate or combination of GSTM1 and GSTT1 null genotypes (GST gene) were associated with T2DM. GSTM1 and combination of GSTM1/GSTT1 null genotypes were associated with DN. Significant association between C242T variant (NOX) and T2DM or DN, and non-significant association with carotid atherosclerosis were seen. C allele of C47T variant (SOD) was protective against DN, DR and microvascular complications of diabetes [52].
In a systematic review, we investigated the association of genetic variants with obesity. Our study showed that males with TT genotype for + 45T > G variant of adiponectin gene, GG genotype for − 11391G > A polymorphism of adiponectin, GC + GG genotype for Pro12Ala PPARg2 gene variant, 1484 insG carriers of PTP1B and AA genotype of 4223A > C ADA gene variant had significant positive association with obesity in Iranian population. However gene variants of glucokinase, TNF-α, UCP2, MTHFR, β3-adrenoreceptor and apolipoprotein E were not significantly associated with obesity[53].
We also investigated the role of interleukin-6 (IL-6) polymorphisms on risk of obesity in a systematic review and meta-analysis. We found that minor allele of IL-6 rs1800797 polymorphism decreased the risk of obesity/overweight in various models. Allele C showed increased risk of obesity in genetic models containing homozygote model according to BMI and subgroups analysis revealed additional significant results [54].
In another systematic review we investigated the association of genetic variants with diabetes complications in Iranian populations. In 88 included articles we found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFα and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERα, PPAR-γ2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications [55].
We have performed a systematic review for investigating the genetic variations in miRNAs binding site in obesity related cancer risk. The association between miRNA-binding site polymorphisms and colorectal cancer (CRC) was examined. The results showed a population specific association with various SNPs including rs731236, rs3025039, rs17281995, rs712 and rs3212986 in different genetic models with increasing the risk or a protective effect [56].
Lastly in a systematic review we investigated the association of two polymorphisms in VDR gene including Fok1 and osteoporosis and we observed significant relation between Fok1, Bsm1 polymorphisms and osteoporosis [57].
Conclusion
In conclusion we have been able to fulfil the major aim of the immunogenetic research group in endocrinology and metabolism research institute by designing several studies using advanced technologies to screen for the pathogenic markers in clinical samples obtained from patients within the main areas of endocrine and metabolism disorders and established fundamental objects for future studies in this field covering most pioneer aspects of research in various disorders. The long term experience of molecular studies in four main areas of diabetes, obesity, thyroid and cardiovascular disorders and valuable collection of biological samples and clinical data will be helpful for further studies paving the way of new discoveries.
Funding
This work was supported by the Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Declarations
Conflict of interest
The authors declare no conflict of interest.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
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