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Role of telomeres and associated maintenance genes in Type 2 Diabetes Mellitus: A review
Accepted Manuscript Review Role of Telomeres and Associated Maintenance Genes in Type 2 Diabetes Mellitus: A Review Itty Sethi, G.R. Bhat, Vinod Singh, Rakesh Kumar, A.J.S. Bhanwer, Rameshwar N. K. Bamezai, Swarkar Sharma, Ekta Rai PII: DOI: Reference:
S0168-8227(16)30800-2 http://dx.doi.org/10.1016/j.diabres.2016.10.015 DIAB 6779
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
23 February 2016 9 October 2016 16 October 2016
Please cite this article as: I. Sethi, G.R. Bhat, V. Singh, R. Kumar, A.J.S. Bhanwer, R.N. K. Bamezai, S. Sharma, E. Rai, Role of Telomeres and Associated Maintenance Genes in Type 2 Diabetes Mellitus: A Review, Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/j.diabres.2016.10.015
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Role of Telomeres and Associated Maintenance Genes in Type 2 Diabetes Mellitus: A Review Itty Sethia, G.R. Bhata, Vinod Singha, Rakesh Kumara, AJS Bhanwerb, Rameshwar N. K. Bamezaic, Swarkar Sharmaa, Ekta Raia Affiliations: a
Human Genetics Research Group, Department of Biotechnology, Shri Mata Vaishno Devi University Katra, J&K, 182320. b Department of Human Genetics, Guru Nanak Dev University, Amritsar, 143005, Punjab, India. c National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067. Corresponding Authors: Dr. Swarkar Sharma, Ph.D. Human Genetics Research Group, Department of Biotechnology Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, 182320 Tel: 01991-285535 // 285524 // 285634 // 285699 extn: 2533 Email: [email protected] Dr. Ekta Rai Human Genetics Research Group, Department of Biotechnology Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, 182320 Tel: 01991-285535 // 285524 // 285634 // 285699 extn: 2533 Email: [email protected]
Abstract Type 2 Diabetes Mellitus (T2DM), a multifactorial complex disorder, is coming up as a major cause of morbidity, mortality and socio-economic burden across the world. Despite huge efforts in understanding genetics of T2DM, only ~10% of the genetic factors have been identified so far. Telomere attrition, a natural phenomenon, reported to be exacerbated in cases of T2DM, and has recently emerged in understanding the pathophysiology of T2DM. It has been indicated that Telomeres and associated pathways might be the critical components in the disease etiology, though the mechanism(s) involved are not clear. Recent Genome Wide (GWAS) and Candidate Gene Case-Control Association Studies have also indicated an association of Telomere and associated pathways related genes with T2DM. Single Nucleotide Polymorphisms (SNPs) in the telomere maintenance genes: TERT, TERC, TNKS, CSNK2A2, TEP1, ACD, TRF1 and TRF2, have shown strong association with telomere attrition in T2DM and its pathophysiology, in these studies. However, the assessment is made within limited ethnicities (Caucasians, Han Chinese cohort and Punjabi Sikhs from South Asia), warranting the study of such associations in different ethnic groups. Here, we propose the possible mechanisms, in the light of existing knowledge, to understand the association of T2DM with telomeres and associated pathways. KEYWORDS: Type 2 Diabetes Mellitus (T2DM); Telomeres; Telomere attrition; Telomere maintenance genes.
1) Introduction Type 2 diabetes mellitus is a complex multifactorial disease characterized by hyperglycemia, which results from impaired insulin action or secretion [1]. Globally 387 million people have been estimated to suffer from diabetes and the number is expected to increase to 592 million by 2035. India has approximately 66.8 million individuals with diabetes, which may rise to more than 110 million by 2035, plausibly due to unparalleled rates of urbanization and lifestyle factors [2]. Intake of high calorie food, less physical activity and stressful environment have been suggested to be the major contributors [3]. Substantial evidences exist to justify that besides environmental factors, genetic components are critically involved in pathogenesis of T2DM. High concordance rate in monozygotic twins (96%) and general estimates of heritability (0.49) clearly indicate the role of heredity in T2DM [4]. In addition, over 200 genetic loci have been associated with T2DM worldwide, where the majority play a role in at least one of the mechanisms involved in maintaining blood glucose level, such as insulin regulation, insulin secretion, insulin uptake, insulin action, glucose metabolism, lipid metabolism, protein metabolism, mitochondrial function and inflammatory pathways [5]. However, a lot of genetic heterogeneity has been noticed across the populations; and only PPARG, KCNJ11 and TCF7L2 have been identified as genes associated with T2DM in most of the world populations [6]. The advent of Genome Wide Association Studies (GWAS) and Next Generation Sequencing has provided us an opportunity to identify new T2DM genetic loci and metabolic pathways. GWAS in T2DM has contributed ~60 loci robustly associated with T2DM. However, collectively these loci explain only ~10% of variance in disease susceptibility with the majority residing in the non-coding genome, suggesting that there remains a large integral part of genetic makeup yet to be explored for T2DM association [7]. Telomere genetics has recently emerged as an important area in T2DM pathophysiology, and it remains as one of the less explored genetic components. The main focus of this review is to highlight the genetic association of telomere shortening and associated pathways role in T2DM pathophysiology. 2) Telomere Biology Telomeres are protein DNA complexes situated at the terminal ends of the linear chromosomes which mainly function in the maintenance of genomic stability. In humans, telomeres are
guanine rich non-coding (TTAGGG) repeats. These are tandem DNA sequences which lengthen from 9 to 15 kb and terminate in a 50 to 500 nucleotide 3 single strand guanine overhang. The overhang gets folded and intrudes the double-stranded helix of telomere forming a T-loop. This facilitates the formation of a highly ordered structure mediating the end capping of the chromosomes [8]. The stability of the T-loop depends almost entirely on the integrity of the associated telomere maintenance proteins, referred to as the shelterin complex [9]. The telomere maintenance proteins constituting the shelterin complex include, Telomeric Repeat Binding Factor 1 (TRF1), Telomeric Repeat Binding Factor 2 (TRF2), Protection of Telomeres 1 (POT1), Tripeptidyl Peptidase 1 (TPP1), TRF1-Interacting Nuclear Factor 2 (TIN2) and Repressor Activator Protein 1 (RAP1) [10]. TRF1 and TRF2 bind to the double stranded telomeric DNA segment as homodimers. TRF1 acts as negative regulator of telomere length by inhibiting the action of telomerase [8] and TRF2 is involved in the T-loop stability. Disruption of TRF2 results in the activation of Ataxia Telangiectasia Mutated (ATM) protein mediated DNA damage signal which causes end-to-end telomere fusion and telomere homologous recombination, leading to the telomere sister-chromatid exchange (T-SCE) [9]. The repressor activator protein 1 (RAP1) binds directly with the TRF2 protein and is required for the efficient binding of TRF2 protein to the telomeric DNA, improving its efficacy [11]. Whereas, POT1 binds to the single stranded G overhang of telomeric DNA, helping in the formation of T-loop and protecting the chromosome ends from fusion and recombination [12]. The TPP1 binds with the POT1 protein, and helps in the recruitment of telomerase to the telomeric DNA, thus contributing to the protection of telomeres [13]. Disruption of both POT1 and TPP1 is known to result in the activation of ataxia telangiectasia and Rad-3 related (ATR) damage response and telomere fusion [14]. TRF-interacting nuclear factor 2 (TIN2) protein binds with TRF1, TRF2 and TPP1, acting as a central component of the shelterin complex and bridging all these proteins of the shelterin complex together [8]. The shelterin complex has an eminent role in the protection of chromosomes from DNA damagerepair system factors to protect the cells from cell cycle arrest and chromosomal instability [15]. In addition to protect the chromosomal ends, shelterin complex controls the synthesis of telomeric DNA by telomerase through cis-acting effect of TRF1 (Figure 1). Shelterin proteins potentially regulate telomere elongation by recruiting Telomerase, which is a ribonucleoprotein
complex consisting of reverse transcriptase (TERT) and an RNA component (TERC). Telomerase is inactive and suppressed in most of the normal somatic cells. It gets activated during the S phase of cell cycle and promotes the replication of telomeric DNA, which is not replicated by DNA polymerase during the replication process [16]. The telomeric DNA is further synthesized by telomerase through addition of the nucleotides at the 3' end of the telomeric DNA [17]. The mechanism involves Tankyrase or TRF1 Interacting Ankyrin-Related ADP-Ribose Polymerase (TNKS), that acts as antagonist to TRF1 (negative regulator) and positively regulates the telomere length. It has two forms, TNKS1 and TNKS2; both the forms interact with TRF1. TNKS ribosylates the TRF1 protein and causes its degradation. Degradation of TRF1 leads to the disintegration of shelterin complex. Thus the complex is no longer in a position to inhibit Telomerase; and in turn helps in the elongation of telomere length (Figure 2) [18]. During cell cycle progression, phosphorylation of TPP1 enhances the Telomerase recruitment and telomere elongation [16]. Depletion of TPP1 and TIN2 reduces the association of TERT with telomeres and their elongation, indicating that both are required for telomerase recruitment [19], however, its molecular basis still needs to be defined. 3) Telomere Length, Heredity and Diseases Telomere length decreases with each cell division. The decrease in length of the telomeres is by around 30-200 base pairs per cell division [20] and that particular length is usually attained by the Hayflick limit of cell division [21]. This telomere shortening, coinciding with the age of a cell, leads to the process called senescence or cell death. Telomere shortening is not only attributed to the cell division or aging, but also to the DNA damage caused by the oxidative stress. The 3 ׳single strand overhangs of the telomeres, being G rich region, are prone to oxidative damage that cause single strand breaks. During replication process, loss of these single strand break region lead to telomere attrition [22]. The rate of telomere shortening is also dependent on the length of the 3 ׳G rich single strand overhangs as the rate of shortening is directly proportional to the size of the overhang [23]. Physical activity to some extent modulates the telomere length by enhancing the antioxidant enzyme activity, thereby producing adequate antioxidants and down regulating the production of oxidants, stress and inflammation [24]. Other factor contributing to the telomere attrition is obesity, that is one of the leading causes of age related diseases and mortality. The underlying mechanism is the production of reactive oxygen
species (ROS), increased oxidative stress, alteration in the metabolic processes and production of pro-inflammatory cytokines [25]. The attrition of telomeres is greatly influenced by environmental factors and also a sedentary lifestyle, smoking habits, and dietary habits affect the telomere length and accelerate its attrition [24]. Telomere length also varies from individual to individual and it is notably short in older individuals. The variable telomere length is contributed by strong genetic component as suggested by high heritability up to 80%. The high heritability is also supported by a recent study, where closely related individuals of the long-lived persons showed longer lives and also had long telomeres and vice-versa [26]. Telomere length is regulated by the genes involved in telomere biology and variations in such genes have been extensively linked with attrition of telomeres in complex and age related disorders, such as Idiopathic pulmonary fibrosis, Cancers, Cardiovascular diseases, Atherosclerosis and Diabetes (Table 1 and 2)[15]. In age related diseases, telomere shortening increases which may have negative impact on the affected either by increasing the severity of the disease or pre-disposing the individual to other diseases or factors [27]. Interestingly, telomere shortening and T2DM are predisposed to common environmental risk factors, suggesting their strong association with each other. Moreover both are associated with oxidative stress and inflammation. 4) Telomere Attrition and T2DM Genetics Telomere attrition is associated with T2DM and its related conditions, like insulin resistance, impaired glucose tolerance, obesity and inflammation. Telomere attrition in individuals shows inverse correlation with HOMA-IR and Glycated hemoglobin (HbA1c) [28]. In a ~5 year follow up study, individuals who developed diabetes showed a significantly shorter leukocyte telomere length [29]. Cell damage due to hyperglycemia accelerates the shortening and there is pronounced attrition in T2DM individuals with complications of, retinopathy, atherosclerosis and depression. Adiposity in individuals with T2DM is marked with insulin resistance and production of ROS, generating oxidative stress and ultimately contributing to the shortening of telomeres. Short leukocyte telomere length in T2DM has been reported in many studies and is an independent risk factor of T2DM [30, 31]. Individuals with T2DM also show significant decrease of telomere length in the peripheral monocytes and endothelial cells [22]. Two GWAS have been performed in the framework of telomere attrition in T2DM, showing a strong association of telomere attrition with T2DM [32, 33]. Ahmed et al (2012) showed an inverse
relationship between leukocyte telomere length and 2 hour glucose concentration, i.e. longer the leukocyte telomere length lesser the concentration of glucose [34]. In a recent study, it has been shown that the individuals with T2DM have more illustrious signs of vascular ageing due to the shortening of telomeres [35]. The need for insulin production has been shown to increase with the increase in insulin resistance and is accomplished by the expansion in the pancreatic β-cell number. But decline in the pancreatic β-cell mass with the age leads to decrease in insulin production and glucose intolerance followed by T2DM [36]. Pancreatic β-cell dysfunction was related to telomere attrition, as was suggested by the mice model [37] and in the human pancreatic tissues (autopsied) with a
rate of loss in human pancreatic tissue of 36bp/year [38]. Telomere
shortening affects mitochondrial ATP production (less production of ATP) and Calcium regulation that hinders with release of insulin in spite of intact β-cells [37]. Presence of endoplasmic reticulum stress (misfolded protein) and deficiency of telomerase activity evokes the cell apoptosis and β-cell deterioration leading to T2DM [37, 39]. A study on RAP1 deficient mice suggests that RAP1 plays a role in the metabolic regulation leading to obesity and insulin resistance with the advancement of age [40]. Also, TERT is implicated in the signaling pathways that regulate the glucose utilization and is constitutively associated with some glucose transporters (GLUT) [41]. A member of sirtuin family, SIRT1, which is a nictotinamide adenine dinucleotide (NAD)-dependent deacetylase and ADP-ribosyltransferase has been reported recently as a master switch regulating etiology of T2DM [42]. It is involved in the regulation of several processes including metabolism (glucose-lipid metabolism), inflammation, mitochondrial biogenesis, circadian rhythms, stress resistance, autophagy, apoptosis and chromatin silencing [43]. SIRT1 has also been reported to be involved in the positive regulation of telomere length [44], playing an interesting role in both T2DM and telomere biology. In pancreatic β cells, it regulates the insulin secretion and protects the β cells from oxidative stress [45] as there is more production of ROS in aged and obese individuals [46] and the increased oxidative stress is associated with diabetes and metabolic disorders. Functional promoter variant of UCP2 also has been associated with short telomere length in T2DM, that is partly attributed to the increased oxidative stress [47]. Oxidative stress shortens the telomere length and decreases the mRNA level of TERT in adipocytes [48].
Interestingly, the genes: ADAMTS9, BCL2, FTO, and HMGA2, which are associated with T2DM, also show association with telomere independently. ADAMTS9 is a metalloproteinase, associated with decrease in the insulin sensitivity of peripheral tissues and a predictive locus that may represent the leukocyte telomere length [49, 50]. High glucose level regulates the action of BCL family anti-apoptotic and pro-apoptotic proteins, favoring the β-cells’ apoptosis. Bcl-2 in synergistic effect with Bcl-xL suppresses the insulin secretion signaling and is implicated in regulating telomerase activity [51, 52]. FTO is strongly associated with body mass index (BMI), obesity and T2DM and with shorter relative telomere length [53, 54]. HMGA2 is a transcription regulating factor which is involved in the islet functioning and insulin action [55]. It modulates the telomerase activity by regulating the hTERT expression and prevents the shortening of telomeres [56]. The role of T2DM associated genes in telomere biology puts forth to understand the details, whether T2DM is responsible for exacerbated shortening of telomere or telomere shortening predisposes the individual to T2DM. Telomere attrition is also attributed to the genes maintaining the telomere length. In a study, the association of 150 tagging-SNPs (tSNPs) of 11 telomere regulating-pathway genes (TERC, UCP1, TERT, POT1, TNKS, TRF1, TNKS2, TEP1, ACD, TRF2 and TRF2IP) and incidence of T2DM was investigated in 22,715 Caucasian female participants of the prospective Women’s Genome Health Study. The study demonstrated that the genetic heterogeneity within the genes, TRF1, TNKS, TEP1, ACD, and TRF2, in particular, TRF1 and TEP1 were associated with T2DM risk [57]. A study reported an association of TERC haplotype with higher risk of both T2DM and coronary heart disease (Table 2 & 3) [58]. Two GWAS have confirmed the association of telomere genes CSNK2A2 and TERT with T2DM in Punjabi Sikhs Indian population and Han Chinese population respectively (Table 2) [32, 33]. These associations of gene involved in telomere regulation pathway as well as various independent association of genes with both T2DM and telomeres/telomere length, clearly indicate an overlap exists. Further an interesting perspective to explore could be whether the genes are directly affecting the T2DM susceptibility or indirectly through telomeres.
5) Limitations of the previous studies and future perspectives T2DM with a worldwide burden needs to be well studied and explored with great emphasis on the role of genetic factors participating in the causation of the disease. Above 200 loci have been linked with T2DM worldwide, of these ~60 loci have been identified and confirmed by GWAS [7]. However, these loci describe only ~10% variance suggesting that large integral part of genome is yet to be explored for T2DM association. The preset stringent statistical significance level for GWAS i.e. P value < ~110-8 excludes all those genetic risk factors with moderate effect or possibly strong effect in case of particular ethnic groups, towards disease susceptibility. Moreover, GWAS has been limited to common variants that ignore other important risk factors playing role in the pathogenesis of disease. Such limitations of GWAS can be resolved to some extent by evaluating these overlooked associations in different ethnicities. Despite the fact that telomere attrition does play major role in the pathogenesis of T2DM [59], the association of telomere maintenance genes with T2DM is evaluated in limited ethnic groups. Further, functional studies are required to evaluate the role of telomeres and telomere attrition in T2DM, since it is still not clear whether the attrition is a cause or consequence of T2DM. 6) Conclusion Telomere maintenance genes seem to be amongst the overlooked genetic factors in GWAS that are critical to study in well-stratified populations of different ethnic groups by case-control association studies. Studying the role of telomere maintenance genes in T2DM pathogenesis will add to our understanding of genetic landscape of diabetes and may highlight the new pathway, other than the conventional pathways, associated with the disease. Associated genes could then be targeted for development of new therapeutic strategies. Acknowledgment All Authors acknowledge support of their respective institutions. IS acknowledge the financial assistantship from SMVDU for her Ph.D. thesis work. SS and ER acknowledge the Startup Grants from UGC, India and SS acknowledge the SERB-DST India Young Scientist Research Grant Award. Conflict of Interest: none
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Figure legends: Figure 1: Components of Shelterin Complex – TRF1, TRF2, RAP1, POT1, TPP1 and TIN2. Shelterin complex controls the telomeric DNA synthesis. Telomerase consists of subunits namely TERT, TERC and Dyskerin (DKC1). TRF1, TRF2, RAP1 and TIN2 components of Shelterin complex inhibits Telomerase complex from replicating the end of chromosomes. Adopted from [8] Figure 2: Elongation of Telomeres: TNKS Poly (ADP) ribosylates TRF1 protein due to which it gets degraded and the Shelterin complex no longer is able to inhibit the telomerase. Telomerase bind at the 3ˈ end of the overhang and replicates the telomeres. Adopted from [18]
Table1: Telomere Maintenance genes associated with different types of disorders Gene
Role of Gene
SNPs
Role of SNP
Associated Allele
Associated Disease/Phenotype
Population
Sample Size
P-Value
Ref
TERT
Telomere replication
rs2736100
intron variant, UTR 5 variant
A
Idiopathic Pulmonary Fibrosis*
European Cohorts
48,423
4.38×10-19
[60]
C
Glioma*
9,380
110-15
[61]
A
8,610
210-19
[62]
C
Interstitial lung disease* Lung Cancer*
18,130
110-27
[63]
T
Telomere Length*
48,423
2.54×10-31
[60]
C
Chronic Lymphocytic Leukemia* Bladder Cancer*
European Ancestry European Ancestry Han Chinese Ancestry European Cohorts European Ancestry
11,233
210-9
[64]
European Ancestry European Ancestry European Ancestry European Cohorts European Cohort Danish European Cohort
20,837
510-9
[65]
9,112
910-14
[66]
38,135
710-7
[67]
12,409
3.72×10-14
[68]
8,186
1.57×10-4
[69]
1,905 6,014
0.014 1.5×10-14
[70] [71]
European Cohort European Cohort
12,409
2.79×10-12
[68]
6,014
1.6×10-13
[71]
European Cohort Danish
8,186
1.1×10-5
[69]
TERC
Telomere replication
rs10936599
non coding transcript, UTR 5 variant
G
Multiple Myeloma* Multiple Sclerosis
rs12696304
rs16847897
Telomere Length*
C
Age Related Disease* Telomere Length Prostate, Lung, Colorectal & Ovarian Cancer* Telomere Length* Prostate, Lung, Colorectal & Ovarian Cancer* Age Related Disease* Telomere Length
Intron variant
A
1,905
0.011
[70]
rs1317082
Intron Variant Intron variant
G
Telomere Length
European
11,416
110-8
[72]
C
Prostate, Lung, Colorectal & Ovarian Cancer
Caucasian & NonHispanic
3,646
0.009
[73]
Intron variant UTR-5 variant
A
Telomere Length*
48,423
6.9×10-11
[60]
A
8,186
2.33×10-11
[69]
T
Telomere Length/Age Related Disease* Telomere Length
European Cohort European Cohort European
11,416
910-11
[72]
A
Telomere Length*
European Cohort Han Chinese
48,423
4.35×10-16
[60]
3,984
0.012
[74]
Telomere elongation
rs11249943
OBFC1
Activator of DNA polymerase-α primase
rs9420907 rs4387287
rs9419958 Assembly of Telomere Complex
Intron variant
G
rs3772190
TNKS
NAF1
Upstream variant
rs7675998
Intron variant Intron variant
CHD with history of T2DM
CTC1
Telomere maintenance
rs3027234
Intron variant
T
Telomere Length*
European
11,416
210-8
[72]
* GWAS; CHD- Coronary Heart disease
Table2: Association of SNPs in Telomere Maintenance Genes with T2DM. Gene
Role of Gene
SNP
Role of SNP
Associated Allele
Associated Disease/Phenotype
Population
Sample Size
P-Value
Ref
TERT
Telomere replication Telomere replication
rs2736100
UTR-5 variant Upstream variant
C
T2DM*
7,245
4.45×10-6
[32]
G
T2DM
Han Chinese Cohort Han Chinese
4,016
4.5×10-3
[75]
Intron variant Near gene-5, noncoding transcript variant Missense, noncoding transcript variant Intron Variant Intron variant Upstream variant Intron variant Intron variant Missense variant Upstream variant
C
rs7202185
TERC
rs12696304
rs16847897 TEP1
Telomerase Activity
rs3093872
rs3093921
rs1713423 rs1713434 TRF1
Inhibits telomere elongation
rs2010441 rs10099824 rs3863242 rs2291219
TRF2
ACD
TNKS2
CSNK2A2
*GWAS
A
9.5×10-5 T2DM
Caucasian
22,715
0.0369
G
0.0346
A
0.0496
G
0.0291
A
0.0032
A
0.0088
A
0.0083
A
0.0265
A
0.0001
Near gene-3
A
0.0049
0.016
Inhibit telomere elongation Telomere length maintenance Telomere elongation
rs4783704
rs1539041
Intron variant
A
Telomere regulation and maintenance
rs74019828
Intron variant
A
T2DM*
Punjabi Sikhs from South Asia
8,026
4.5×10-8
[57]
[33]
Table3: Association of Haplotypes of Telomere Maintenance Genes with T2DM Gene
Haplotype
Role of SNP
TRF1
rs6982126
Intron variant Intron variant Intron variant UTR 3 variant Missense Intron variant Intron variant Upstream variant Intron variant Intron variant
rs10099824 rs3863243 rs2291220
TEP1
rs2291219 rs1713423 rs4982038
TERC
rs12696304 rs10936601 rs16847897
Associated Allele of Haplotypes A
Associated Phenotype/Disease
Population
Sample Size
P-value
Ref.
T2DM
Caucasian
22,715
0.0054
[57]
A A G A A
0.0375
A G T C
T2DM
European
2,353
0.004
[58]
Highlights The possible role of Telomere Maintenance Genes and associated pathways in Type 2 Diabetes Mellitus is proposed. Mechanism of telomere attrition in Type 2 Diabetes Mellitus is proposed. Understanding the role of telomere maintenance genes in T2DM pathogenesis will add to our understanding of genetic landscape of diabetes.
S0168-8227(16)30800-2 http://dx.doi.org/10.1016/j.diabres.2016.10.015 DIAB 6779
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
23 February 2016 9 October 2016 16 October 2016
Please cite this article as: I. Sethi, G.R. Bhat, V. Singh, R. Kumar, A.J.S. Bhanwer, R.N. K. Bamezai, S. Sharma, E. Rai, Role of Telomeres and Associated Maintenance Genes in Type 2 Diabetes Mellitus: A Review, Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/j.diabres.2016.10.015
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Role of Telomeres and Associated Maintenance Genes in Type 2 Diabetes Mellitus: A Review Itty Sethia, G.R. Bhata, Vinod Singha, Rakesh Kumara, AJS Bhanwerb, Rameshwar N. K. Bamezaic, Swarkar Sharmaa, Ekta Raia Affiliations: a
Human Genetics Research Group, Department of Biotechnology, Shri Mata Vaishno Devi University Katra, J&K, 182320. b Department of Human Genetics, Guru Nanak Dev University, Amritsar, 143005, Punjab, India. c National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067. Corresponding Authors: Dr. Swarkar Sharma, Ph.D. Human Genetics Research Group, Department of Biotechnology Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, 182320 Tel: 01991-285535 // 285524 // 285634 // 285699 extn: 2533 Email: [email protected] Dr. Ekta Rai Human Genetics Research Group, Department of Biotechnology Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, 182320 Tel: 01991-285535 // 285524 // 285634 // 285699 extn: 2533 Email: [email protected]
Abstract Type 2 Diabetes Mellitus (T2DM), a multifactorial complex disorder, is coming up as a major cause of morbidity, mortality and socio-economic burden across the world. Despite huge efforts in understanding genetics of T2DM, only ~10% of the genetic factors have been identified so far. Telomere attrition, a natural phenomenon, reported to be exacerbated in cases of T2DM, and has recently emerged in understanding the pathophysiology of T2DM. It has been indicated that Telomeres and associated pathways might be the critical components in the disease etiology, though the mechanism(s) involved are not clear. Recent Genome Wide (GWAS) and Candidate Gene Case-Control Association Studies have also indicated an association of Telomere and associated pathways related genes with T2DM. Single Nucleotide Polymorphisms (SNPs) in the telomere maintenance genes: TERT, TERC, TNKS, CSNK2A2, TEP1, ACD, TRF1 and TRF2, have shown strong association with telomere attrition in T2DM and its pathophysiology, in these studies. However, the assessment is made within limited ethnicities (Caucasians, Han Chinese cohort and Punjabi Sikhs from South Asia), warranting the study of such associations in different ethnic groups. Here, we propose the possible mechanisms, in the light of existing knowledge, to understand the association of T2DM with telomeres and associated pathways. KEYWORDS: Type 2 Diabetes Mellitus (T2DM); Telomeres; Telomere attrition; Telomere maintenance genes.
1) Introduction Type 2 diabetes mellitus is a complex multifactorial disease characterized by hyperglycemia, which results from impaired insulin action or secretion [1]. Globally 387 million people have been estimated to suffer from diabetes and the number is expected to increase to 592 million by 2035. India has approximately 66.8 million individuals with diabetes, which may rise to more than 110 million by 2035, plausibly due to unparalleled rates of urbanization and lifestyle factors [2]. Intake of high calorie food, less physical activity and stressful environment have been suggested to be the major contributors [3]. Substantial evidences exist to justify that besides environmental factors, genetic components are critically involved in pathogenesis of T2DM. High concordance rate in monozygotic twins (96%) and general estimates of heritability (0.49) clearly indicate the role of heredity in T2DM [4]. In addition, over 200 genetic loci have been associated with T2DM worldwide, where the majority play a role in at least one of the mechanisms involved in maintaining blood glucose level, such as insulin regulation, insulin secretion, insulin uptake, insulin action, glucose metabolism, lipid metabolism, protein metabolism, mitochondrial function and inflammatory pathways [5]. However, a lot of genetic heterogeneity has been noticed across the populations; and only PPARG, KCNJ11 and TCF7L2 have been identified as genes associated with T2DM in most of the world populations [6]. The advent of Genome Wide Association Studies (GWAS) and Next Generation Sequencing has provided us an opportunity to identify new T2DM genetic loci and metabolic pathways. GWAS in T2DM has contributed ~60 loci robustly associated with T2DM. However, collectively these loci explain only ~10% of variance in disease susceptibility with the majority residing in the non-coding genome, suggesting that there remains a large integral part of genetic makeup yet to be explored for T2DM association [7]. Telomere genetics has recently emerged as an important area in T2DM pathophysiology, and it remains as one of the less explored genetic components. The main focus of this review is to highlight the genetic association of telomere shortening and associated pathways role in T2DM pathophysiology. 2) Telomere Biology Telomeres are protein DNA complexes situated at the terminal ends of the linear chromosomes which mainly function in the maintenance of genomic stability. In humans, telomeres are
guanine rich non-coding (TTAGGG) repeats. These are tandem DNA sequences which lengthen from 9 to 15 kb and terminate in a 50 to 500 nucleotide 3 single strand guanine overhang. The overhang gets folded and intrudes the double-stranded helix of telomere forming a T-loop. This facilitates the formation of a highly ordered structure mediating the end capping of the chromosomes [8]. The stability of the T-loop depends almost entirely on the integrity of the associated telomere maintenance proteins, referred to as the shelterin complex [9]. The telomere maintenance proteins constituting the shelterin complex include, Telomeric Repeat Binding Factor 1 (TRF1), Telomeric Repeat Binding Factor 2 (TRF2), Protection of Telomeres 1 (POT1), Tripeptidyl Peptidase 1 (TPP1), TRF1-Interacting Nuclear Factor 2 (TIN2) and Repressor Activator Protein 1 (RAP1) [10]. TRF1 and TRF2 bind to the double stranded telomeric DNA segment as homodimers. TRF1 acts as negative regulator of telomere length by inhibiting the action of telomerase [8] and TRF2 is involved in the T-loop stability. Disruption of TRF2 results in the activation of Ataxia Telangiectasia Mutated (ATM) protein mediated DNA damage signal which causes end-to-end telomere fusion and telomere homologous recombination, leading to the telomere sister-chromatid exchange (T-SCE) [9]. The repressor activator protein 1 (RAP1) binds directly with the TRF2 protein and is required for the efficient binding of TRF2 protein to the telomeric DNA, improving its efficacy [11]. Whereas, POT1 binds to the single stranded G overhang of telomeric DNA, helping in the formation of T-loop and protecting the chromosome ends from fusion and recombination [12]. The TPP1 binds with the POT1 protein, and helps in the recruitment of telomerase to the telomeric DNA, thus contributing to the protection of telomeres [13]. Disruption of both POT1 and TPP1 is known to result in the activation of ataxia telangiectasia and Rad-3 related (ATR) damage response and telomere fusion [14]. TRF-interacting nuclear factor 2 (TIN2) protein binds with TRF1, TRF2 and TPP1, acting as a central component of the shelterin complex and bridging all these proteins of the shelterin complex together [8]. The shelterin complex has an eminent role in the protection of chromosomes from DNA damagerepair system factors to protect the cells from cell cycle arrest and chromosomal instability [15]. In addition to protect the chromosomal ends, shelterin complex controls the synthesis of telomeric DNA by telomerase through cis-acting effect of TRF1 (Figure 1). Shelterin proteins potentially regulate telomere elongation by recruiting Telomerase, which is a ribonucleoprotein
complex consisting of reverse transcriptase (TERT) and an RNA component (TERC). Telomerase is inactive and suppressed in most of the normal somatic cells. It gets activated during the S phase of cell cycle and promotes the replication of telomeric DNA, which is not replicated by DNA polymerase during the replication process [16]. The telomeric DNA is further synthesized by telomerase through addition of the nucleotides at the 3' end of the telomeric DNA [17]. The mechanism involves Tankyrase or TRF1 Interacting Ankyrin-Related ADP-Ribose Polymerase (TNKS), that acts as antagonist to TRF1 (negative regulator) and positively regulates the telomere length. It has two forms, TNKS1 and TNKS2; both the forms interact with TRF1. TNKS ribosylates the TRF1 protein and causes its degradation. Degradation of TRF1 leads to the disintegration of shelterin complex. Thus the complex is no longer in a position to inhibit Telomerase; and in turn helps in the elongation of telomere length (Figure 2) [18]. During cell cycle progression, phosphorylation of TPP1 enhances the Telomerase recruitment and telomere elongation [16]. Depletion of TPP1 and TIN2 reduces the association of TERT with telomeres and their elongation, indicating that both are required for telomerase recruitment [19], however, its molecular basis still needs to be defined. 3) Telomere Length, Heredity and Diseases Telomere length decreases with each cell division. The decrease in length of the telomeres is by around 30-200 base pairs per cell division [20] and that particular length is usually attained by the Hayflick limit of cell division [21]. This telomere shortening, coinciding with the age of a cell, leads to the process called senescence or cell death. Telomere shortening is not only attributed to the cell division or aging, but also to the DNA damage caused by the oxidative stress. The 3 ׳single strand overhangs of the telomeres, being G rich region, are prone to oxidative damage that cause single strand breaks. During replication process, loss of these single strand break region lead to telomere attrition [22]. The rate of telomere shortening is also dependent on the length of the 3 ׳G rich single strand overhangs as the rate of shortening is directly proportional to the size of the overhang [23]. Physical activity to some extent modulates the telomere length by enhancing the antioxidant enzyme activity, thereby producing adequate antioxidants and down regulating the production of oxidants, stress and inflammation [24]. Other factor contributing to the telomere attrition is obesity, that is one of the leading causes of age related diseases and mortality. The underlying mechanism is the production of reactive oxygen
species (ROS), increased oxidative stress, alteration in the metabolic processes and production of pro-inflammatory cytokines [25]. The attrition of telomeres is greatly influenced by environmental factors and also a sedentary lifestyle, smoking habits, and dietary habits affect the telomere length and accelerate its attrition [24]. Telomere length also varies from individual to individual and it is notably short in older individuals. The variable telomere length is contributed by strong genetic component as suggested by high heritability up to 80%. The high heritability is also supported by a recent study, where closely related individuals of the long-lived persons showed longer lives and also had long telomeres and vice-versa [26]. Telomere length is regulated by the genes involved in telomere biology and variations in such genes have been extensively linked with attrition of telomeres in complex and age related disorders, such as Idiopathic pulmonary fibrosis, Cancers, Cardiovascular diseases, Atherosclerosis and Diabetes (Table 1 and 2)[15]. In age related diseases, telomere shortening increases which may have negative impact on the affected either by increasing the severity of the disease or pre-disposing the individual to other diseases or factors [27]. Interestingly, telomere shortening and T2DM are predisposed to common environmental risk factors, suggesting their strong association with each other. Moreover both are associated with oxidative stress and inflammation. 4) Telomere Attrition and T2DM Genetics Telomere attrition is associated with T2DM and its related conditions, like insulin resistance, impaired glucose tolerance, obesity and inflammation. Telomere attrition in individuals shows inverse correlation with HOMA-IR and Glycated hemoglobin (HbA1c) [28]. In a ~5 year follow up study, individuals who developed diabetes showed a significantly shorter leukocyte telomere length [29]. Cell damage due to hyperglycemia accelerates the shortening and there is pronounced attrition in T2DM individuals with complications of, retinopathy, atherosclerosis and depression. Adiposity in individuals with T2DM is marked with insulin resistance and production of ROS, generating oxidative stress and ultimately contributing to the shortening of telomeres. Short leukocyte telomere length in T2DM has been reported in many studies and is an independent risk factor of T2DM [30, 31]. Individuals with T2DM also show significant decrease of telomere length in the peripheral monocytes and endothelial cells [22]. Two GWAS have been performed in the framework of telomere attrition in T2DM, showing a strong association of telomere attrition with T2DM [32, 33]. Ahmed et al (2012) showed an inverse
relationship between leukocyte telomere length and 2 hour glucose concentration, i.e. longer the leukocyte telomere length lesser the concentration of glucose [34]. In a recent study, it has been shown that the individuals with T2DM have more illustrious signs of vascular ageing due to the shortening of telomeres [35]. The need for insulin production has been shown to increase with the increase in insulin resistance and is accomplished by the expansion in the pancreatic β-cell number. But decline in the pancreatic β-cell mass with the age leads to decrease in insulin production and glucose intolerance followed by T2DM [36]. Pancreatic β-cell dysfunction was related to telomere attrition, as was suggested by the mice model [37] and in the human pancreatic tissues (autopsied) with a
rate of loss in human pancreatic tissue of 36bp/year [38]. Telomere
shortening affects mitochondrial ATP production (less production of ATP) and Calcium regulation that hinders with release of insulin in spite of intact β-cells [37]. Presence of endoplasmic reticulum stress (misfolded protein) and deficiency of telomerase activity evokes the cell apoptosis and β-cell deterioration leading to T2DM [37, 39]. A study on RAP1 deficient mice suggests that RAP1 plays a role in the metabolic regulation leading to obesity and insulin resistance with the advancement of age [40]. Also, TERT is implicated in the signaling pathways that regulate the glucose utilization and is constitutively associated with some glucose transporters (GLUT) [41]. A member of sirtuin family, SIRT1, which is a nictotinamide adenine dinucleotide (NAD)-dependent deacetylase and ADP-ribosyltransferase has been reported recently as a master switch regulating etiology of T2DM [42]. It is involved in the regulation of several processes including metabolism (glucose-lipid metabolism), inflammation, mitochondrial biogenesis, circadian rhythms, stress resistance, autophagy, apoptosis and chromatin silencing [43]. SIRT1 has also been reported to be involved in the positive regulation of telomere length [44], playing an interesting role in both T2DM and telomere biology. In pancreatic β cells, it regulates the insulin secretion and protects the β cells from oxidative stress [45] as there is more production of ROS in aged and obese individuals [46] and the increased oxidative stress is associated with diabetes and metabolic disorders. Functional promoter variant of UCP2 also has been associated with short telomere length in T2DM, that is partly attributed to the increased oxidative stress [47]. Oxidative stress shortens the telomere length and decreases the mRNA level of TERT in adipocytes [48].
Interestingly, the genes: ADAMTS9, BCL2, FTO, and HMGA2, which are associated with T2DM, also show association with telomere independently. ADAMTS9 is a metalloproteinase, associated with decrease in the insulin sensitivity of peripheral tissues and a predictive locus that may represent the leukocyte telomere length [49, 50]. High glucose level regulates the action of BCL family anti-apoptotic and pro-apoptotic proteins, favoring the β-cells’ apoptosis. Bcl-2 in synergistic effect with Bcl-xL suppresses the insulin secretion signaling and is implicated in regulating telomerase activity [51, 52]. FTO is strongly associated with body mass index (BMI), obesity and T2DM and with shorter relative telomere length [53, 54]. HMGA2 is a transcription regulating factor which is involved in the islet functioning and insulin action [55]. It modulates the telomerase activity by regulating the hTERT expression and prevents the shortening of telomeres [56]. The role of T2DM associated genes in telomere biology puts forth to understand the details, whether T2DM is responsible for exacerbated shortening of telomere or telomere shortening predisposes the individual to T2DM. Telomere attrition is also attributed to the genes maintaining the telomere length. In a study, the association of 150 tagging-SNPs (tSNPs) of 11 telomere regulating-pathway genes (TERC, UCP1, TERT, POT1, TNKS, TRF1, TNKS2, TEP1, ACD, TRF2 and TRF2IP) and incidence of T2DM was investigated in 22,715 Caucasian female participants of the prospective Women’s Genome Health Study. The study demonstrated that the genetic heterogeneity within the genes, TRF1, TNKS, TEP1, ACD, and TRF2, in particular, TRF1 and TEP1 were associated with T2DM risk [57]. A study reported an association of TERC haplotype with higher risk of both T2DM and coronary heart disease (Table 2 & 3) [58]. Two GWAS have confirmed the association of telomere genes CSNK2A2 and TERT with T2DM in Punjabi Sikhs Indian population and Han Chinese population respectively (Table 2) [32, 33]. These associations of gene involved in telomere regulation pathway as well as various independent association of genes with both T2DM and telomeres/telomere length, clearly indicate an overlap exists. Further an interesting perspective to explore could be whether the genes are directly affecting the T2DM susceptibility or indirectly through telomeres.
5) Limitations of the previous studies and future perspectives T2DM with a worldwide burden needs to be well studied and explored with great emphasis on the role of genetic factors participating in the causation of the disease. Above 200 loci have been linked with T2DM worldwide, of these ~60 loci have been identified and confirmed by GWAS [7]. However, these loci describe only ~10% variance suggesting that large integral part of genome is yet to be explored for T2DM association. The preset stringent statistical significance level for GWAS i.e. P value < ~110-8 excludes all those genetic risk factors with moderate effect or possibly strong effect in case of particular ethnic groups, towards disease susceptibility. Moreover, GWAS has been limited to common variants that ignore other important risk factors playing role in the pathogenesis of disease. Such limitations of GWAS can be resolved to some extent by evaluating these overlooked associations in different ethnicities. Despite the fact that telomere attrition does play major role in the pathogenesis of T2DM [59], the association of telomere maintenance genes with T2DM is evaluated in limited ethnic groups. Further, functional studies are required to evaluate the role of telomeres and telomere attrition in T2DM, since it is still not clear whether the attrition is a cause or consequence of T2DM. 6) Conclusion Telomere maintenance genes seem to be amongst the overlooked genetic factors in GWAS that are critical to study in well-stratified populations of different ethnic groups by case-control association studies. Studying the role of telomere maintenance genes in T2DM pathogenesis will add to our understanding of genetic landscape of diabetes and may highlight the new pathway, other than the conventional pathways, associated with the disease. Associated genes could then be targeted for development of new therapeutic strategies. Acknowledgment All Authors acknowledge support of their respective institutions. IS acknowledge the financial assistantship from SMVDU for her Ph.D. thesis work. SS and ER acknowledge the Startup Grants from UGC, India and SS acknowledge the SERB-DST India Young Scientist Research Grant Award. Conflict of Interest: none
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Figure legends: Figure 1: Components of Shelterin Complex – TRF1, TRF2, RAP1, POT1, TPP1 and TIN2. Shelterin complex controls the telomeric DNA synthesis. Telomerase consists of subunits namely TERT, TERC and Dyskerin (DKC1). TRF1, TRF2, RAP1 and TIN2 components of Shelterin complex inhibits Telomerase complex from replicating the end of chromosomes. Adopted from [8] Figure 2: Elongation of Telomeres: TNKS Poly (ADP) ribosylates TRF1 protein due to which it gets degraded and the Shelterin complex no longer is able to inhibit the telomerase. Telomerase bind at the 3ˈ end of the overhang and replicates the telomeres. Adopted from [18]
Table1: Telomere Maintenance genes associated with different types of disorders Gene
Role of Gene
SNPs
Role of SNP
Associated Allele
Associated Disease/Phenotype
Population
Sample Size
P-Value
Ref
TERT
Telomere replication
rs2736100
intron variant, UTR 5 variant
A
Idiopathic Pulmonary Fibrosis*
European Cohorts
48,423
4.38×10-19
[60]
C
Glioma*
9,380
110-15
[61]
A
8,610
210-19
[62]
C
Interstitial lung disease* Lung Cancer*
18,130
110-27
[63]
T
Telomere Length*
48,423
2.54×10-31
[60]
C
Chronic Lymphocytic Leukemia* Bladder Cancer*
European Ancestry European Ancestry Han Chinese Ancestry European Cohorts European Ancestry
11,233
210-9
[64]
European Ancestry European Ancestry European Ancestry European Cohorts European Cohort Danish European Cohort
20,837
510-9
[65]
9,112
910-14
[66]
38,135
710-7
[67]
12,409
3.72×10-14
[68]
8,186
1.57×10-4
[69]
1,905 6,014
0.014 1.5×10-14
[70] [71]
European Cohort European Cohort
12,409
2.79×10-12
[68]
6,014
1.6×10-13
[71]
European Cohort Danish
8,186
1.1×10-5
[69]
TERC
Telomere replication
rs10936599
non coding transcript, UTR 5 variant
G
Multiple Myeloma* Multiple Sclerosis
rs12696304
rs16847897
Telomere Length*
C
Age Related Disease* Telomere Length Prostate, Lung, Colorectal & Ovarian Cancer* Telomere Length* Prostate, Lung, Colorectal & Ovarian Cancer* Age Related Disease* Telomere Length
Intron variant
A
1,905
0.011
[70]
rs1317082
Intron Variant Intron variant
G
Telomere Length
European
11,416
110-8
[72]
C
Prostate, Lung, Colorectal & Ovarian Cancer
Caucasian & NonHispanic
3,646
0.009
[73]
Intron variant UTR-5 variant
A
Telomere Length*
48,423
6.9×10-11
[60]
A
8,186
2.33×10-11
[69]
T
Telomere Length/Age Related Disease* Telomere Length
European Cohort European Cohort European
11,416
910-11
[72]
A
Telomere Length*
European Cohort Han Chinese
48,423
4.35×10-16
[60]
3,984
0.012
[74]
Telomere elongation
rs11249943
OBFC1
Activator of DNA polymerase-α primase
rs9420907 rs4387287
rs9419958 Assembly of Telomere Complex
Intron variant
G
rs3772190
TNKS
NAF1
Upstream variant
rs7675998
Intron variant Intron variant
CHD with history of T2DM
CTC1
Telomere maintenance
rs3027234
Intron variant
T
Telomere Length*
European
11,416
210-8
[72]
* GWAS; CHD- Coronary Heart disease
Table2: Association of SNPs in Telomere Maintenance Genes with T2DM. Gene
Role of Gene
SNP
Role of SNP
Associated Allele
Associated Disease/Phenotype
Population
Sample Size
P-Value
Ref
TERT
Telomere replication Telomere replication
rs2736100
UTR-5 variant Upstream variant
C
T2DM*
7,245
4.45×10-6
[32]
G
T2DM
Han Chinese Cohort Han Chinese
4,016
4.5×10-3
[75]
Intron variant Near gene-5, noncoding transcript variant Missense, noncoding transcript variant Intron Variant Intron variant Upstream variant Intron variant Intron variant Missense variant Upstream variant
C
rs7202185
TERC
rs12696304
rs16847897 TEP1
Telomerase Activity
rs3093872
rs3093921
rs1713423 rs1713434 TRF1
Inhibits telomere elongation
rs2010441 rs10099824 rs3863242 rs2291219
TRF2
ACD
TNKS2
CSNK2A2
*GWAS
A
9.5×10-5 T2DM
Caucasian
22,715
0.0369
G
0.0346
A
0.0496
G
0.0291
A
0.0032
A
0.0088
A
0.0083
A
0.0265
A
0.0001
Near gene-3
A
0.0049
0.016
Inhibit telomere elongation Telomere length maintenance Telomere elongation
rs4783704
rs1539041
Intron variant
A
Telomere regulation and maintenance
rs74019828
Intron variant
A
T2DM*
Punjabi Sikhs from South Asia
8,026
4.5×10-8
[57]
[33]
Table3: Association of Haplotypes of Telomere Maintenance Genes with T2DM Gene
Haplotype
Role of SNP
TRF1
rs6982126
Intron variant Intron variant Intron variant UTR 3 variant Missense Intron variant Intron variant Upstream variant Intron variant Intron variant
rs10099824 rs3863243 rs2291220
TEP1
rs2291219 rs1713423 rs4982038
TERC
rs12696304 rs10936601 rs16847897
Associated Allele of Haplotypes A
Associated Phenotype/Disease
Population
Sample Size
P-value
Ref.
T2DM
Caucasian
22,715
0.0054
[57]
A A G A A
0.0375
A G T C
T2DM
European
2,353
0.004
[58]
Highlights The possible role of Telomere Maintenance Genes and associated pathways in Type 2 Diabetes Mellitus is proposed. Mechanism of telomere attrition in Type 2 Diabetes Mellitus is proposed. Understanding the role of telomere maintenance genes in T2DM pathogenesis will add to our understanding of genetic landscape of diabetes.