Parental History of Type 2 Diabetes Mellitus: A Lurking Genetic Threat

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Sheh Zano
Zil-a- Rubab
Saeeda Baig
Burhanuddin Tahir


Type-2 Diabetes Mellitus (T2DM) is presently the fastest growing disease and has been recognized to be caused by a collision between inherited parental genes and the environment. The current prevalence in Pakistan of type-2 diabetes mellitus is 26.3%. Out of them 19.2% had disease two to three decades back while 7.1% are recently diagnosed cases. Worldwide burden of disease was 415 million in 2015 and this number will increase to 642 million by 2040. Parental history of diabetes mellitus is a chief reason for the development of T2DM in children, but whether this association derives from shared genetic or environmental factors is unclear. Persistent high blood glucose levels can result in drastic outcomes like Diabetic Ketoacidosis and Hyperosmolar non ketotic syndrome. Genome-wide association analyses have uncovered multiple genomic regions associated with T2DM, but identification of the causal variants remains a challenge. This review will discuss the approach of diagnosing T2DM by analyzing the association of gene variants and family history.

Type 2 diabetes mellitus, family history, genetic variant, KCQN1, FTO

Article Details

How to Cite
Zano, S., Rubab, Z.- a-, Baig, S., & Tahir, B. (2020). Parental History of Type 2 Diabetes Mellitus: A Lurking Genetic Threat. Journal of Advances in Medicine and Medical Research, 32(12), 66-75.
Review Article


Umpierrez GE, editor. Therapy for diabetes mellitus and related disorders. American Diabetes Association; 2014.

Meisinger C, Heier M, Loewel H. Sleep disturbance as a predictor of type 2 diabetes mellitus in men and women from the general population. Diabetologia. 2005; 48(2):235-41.

Kelly LA, Lane CJ, Weigensberg MJ. Parental history and risk of type 2 diabetes in overweight Latino adolescents: a longitudinal analysis. Diabetes care. 2007;30:2700-5.

Aljuaid MO, Almutairi AM, Assiri MA, Almalki DM, Alswat K. Diabetes-Related Distress Assessment among Type 2 Diabetes Patients. Journal of Diabetes Research; 2018.

Animaw W, Seyoum Y. Increasing prevalence of diabetes mellitus in a developing country and its related factors. PloS One. 2017;12(11):0187670.


Ding W, Xu L, Zhang L, Han Z, Jiang Q, Wang Z, Jin S. Meta-analysis of association between TCF7L2 polymor-phism rs7903146 and type 2 diabetes mellitus. BMC medical genetics. 2018; 19(1):38.

Yu X, Wang Y, Kristic J, Dong J, Chu X, Ge S, Wang H, Fang H, Gao Q, Liu D, et al. Profiling igg n-glycans as potential biomarker of chronological and biological ages: A community-based study in a han chinese population. Medicine. 2016; 95(28).

Guan Y, Yan LH, Liu XY, Zhu XY, Wang SZ, Chen LM. Correlation of the TCF7L2 (rs7903146) polymorphism with an enhanced risk of type 2 diabetes mellitus: a meta-analysis. Genet Mol Res. 2016; 15(3).

Lascar N, Brown J, Pattison H, Barnett AH, Bailey CJ, Bellary S. Type 2 diabetes in adolescents and young adults. The Lancet Diabetes & Endocrinology. 2018;6(1):69-80.


Adeyemo AA, Tekola-Ayele F, Doumatey AP, Bentley AR, Chen G, Huang H, Zhou J, Shriner D, Fasanmade O, Okafor G, Eghan Jr B. Evaluation of genome wide association study associated type 2 diabetes susceptibility loci in Sub Saharan Africans. Frontiers in Genetics. 2015;6: 335.

Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, Ma C, Fontanillas P, Moutsianas L, McCarthy DJ, Rivas MA. The genetic architecture of type 2 diabetes. Nature. 2016;536(7614): 41.

Baniasadian S, Farajnia S, Jafari B. Frequency of KCNQ1 Variantrs2237892 in Type 2 Diabetes in East Azerbaijan Population, Northwest of Iran. Acta Medica Iranica. 2018;56(2):90-4.

Mahmutovic L, Bego T, Sterner M, Gremsperger G, Ahlqvist E, Velija AZ, Prnjavorac B, Hamad N, Causevic A, Groop L, Semiz S. Association of IRS1 genetic variants with glucose control and insulin resistance in type 2 diabetic patients from Bosnia and Herzegovina. Drug Metabolism and Personalized Therapy; 2019.

Vallee A, Vallée JN, Guillevin R, Lecarpentier Y. Interactions between the canonical WNT/beta-catenin pathway and PPAR gamma on neuroinflammation, demyelination, and remyelination in multiple sclerosis. Cellular and Molecular Neurobiology. 2018;38(4):783-95.

Naaz K, Kumar A, Choudhury I. Assessment of FTO gene polymorphism and its association with type 2 diabetes mellitus in North Indian populations. Indian Journal of Clinical Biochemistry. 2018:1-6.

Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Jentsch TJ, Brown DA. Inhibition of KCNQ1‐4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. The Journal of Physiology. 2000;522(3):349-55.

Liu Y, Wang C, Chen Y, Yuan Z, Yu T, Zhang W, Tang F, Gu J, Xu Q, Chi X, Ding L. A variant in KCNQ1 gene predicts metabolic syndrome among northern urban Han Chinese women. BMC Medical Genetics. 2018;19(1):153.

Kumar S, Aswal VK, Agrawal RP, Quoseena M, Jillellamudi C, Kapur S, Toshan NC. SNP in KCNQ1 Gene is Associated with Susceptibility to Diabetic Nephropathy in Subjects with Type 2 Diabetes in India. Journal of The Association of Physicians of India. 2018; 66:58.

Tulay P, Temel SG, Ergoren MC. Investigation of KCNQ1 polymorphisms as biomarkers for cardiovascular diseases in the Turkish Cypriots for establishing preventative medical measures. International Journal of Biological Macromolecules. 2019;124:537-40.

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature chemical biology. 2011;7(12):885.

Loos RJ, Yeo GS. The bigger picture of FTO—the first GWAS-identified obesity gene. Nature Reviews Endocrinology. 2014;10(1):51.

Taira M, Imamura M, Takahashi A, Kamatani Y, Yamauchi T, Araki SI, Tanaka N, van Zuydam NR, Ahlqvist E, Toyoda M, Umezono T. A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes. PloS One. 2018;13(12): 0208654.

Fawwad A, Siddiqui IA, Basit A, Zeeshan NF, Shahid SM, Nawab SN, Siddiqui S. Common variant within the FTO gene, rs9939609, obesity and type 2 diabetes in population of Karachi, Pakistan. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2016;10(1): 43-7.

Mohammadi H, Shab-Bidar S, Kazemi F, Sadeghi A, Speakman JR, Djafarian K. Association of single nucleotide polymorphisms in the first intron of the Fat mass and obesity associated (FTO) gene with obesity risk in Asians: A meta-analysis. Progress in Nutrition. 2019;21(1): 25-34.

Nakajima T, Fujino S, Nakanishi G, Kim YS, Jetten AM. TIP27: A novel repressor of the nuclear orphan receptor TAK1/TR4. Nucleic acids research. 2004; 32(14):4194-204.

Naruhn S, Meissner W, Adhikary T, Kaddatz K, Klein T, Watzer B, Müller-Brüsselbach S, Müller R. 15-hydroxyeicosatetraenoic acid is a preferential peroxisome proliferator-activated receptor β/δ agonist. Molecular pharmacology. 2010;77(2):171-84.

Park YK, Wang L, Giampietro A, Lai B, Lee JE, Ge K. Distinct roles of transcription factors KLF4, Krox20, and peroxisome proliferator-activated receptor γ in adipogenesis. Molecular and Cellular Biology. 2017;37(2):00554-16.

Liu L, Li J, Yan M, Li J, Chen J, Zhang Y, Zhu X, Wang L, Kang L, Yuan D, Jin T. TCF7L2 polymorphisms and the risk of schizophrenia in the Chinese Han population. Oncotarget. 2017;8(17):28614.

Weeks SE, Metge BJ, Samant RS. The nucleolus: A central response hub for the stressors that drive cancer progression. Cellular and Molecular Life Sciences. 2019:1-4.

Wang J, Wang Z, Wang H, Wanyan Z, Pan Y, Zhu F, Tao Q, Zhai Z. Stress induced premature senescence promotes proliferation by activating SENEX and p16INK4a/Retinoblastoma (Rb) pathway in Diffuse Large B-cell Lymphoma. Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology; 2019.

Taylor NJ, Mitra N, Qian L, Avril MF, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cuellar F, Cust AE, Demenais F. Estimating CDKN2A mutation carrier probability among global familial melanoma cases using Geno MELPREDICT. Journal of the American Academy of Dermatology; 2019.

Deepak Roshan V, Sinto M, Vargees B, Kannan S. Loss of CDKN2A and CDKN2B expression is associated with disease recurrence in oral cancer. Journal of Oral & Maxillofacial Pathology (0973029X). 2019; 23(1).

Herrero-cervera A, Mart S, Ia VE, Es-blasco IA, Piqueras L, Ia MA, Us JE, Tom JO, Real AS, Ascaso JF, Burks DJ. Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus; 2019.

Yousefi B, Mohammadlou M, Abdollahi M, Salek Farrokhi A, Karbalaei M, Keikha M, Kokhaei P, Valizadeh S, Rezaiemanesh A, Arabkari V, Eslami M. Epigenetic changes in gastric cancer induction by Helicobacter pylori. Journal of cellular physiology; 2019.

Jones NL, Arguello D, Holloway RW, Herzog TJ, ElNaggar AC, Winer I, Krivak TC, Mantia-Smaldone GM, Galvan-Turner V, Brown J. Comprehensive genomic profiling of mucinous ovarian carcinoma with comparisons to mucinous colorectal carcinoma. Gynecologic Oncology. 2019;154:63.

Mio C, Grani G, Durante C, Damante G. Molecular defects in thyroid dysgenesis. Clinical Genetics; 21 Aug, 2019.

Alfonso V, Iaccarino L, Ottone T, Cicconi L, Lavorgna S, Divona M, Cairoli R, Cristiano A, Ciardi C, Travaglini S, Falconi G. Early and sensitive detection of PML-A216V mutation by droplet digital PCR in ATO-resistant acute promyelocytic leukemia. Leukemia. 2019; 33(6):1527.

Oh TJ, Kim YG, Kang S, Moon JH, Kwak SH, Choi SH, Lim S, Park KS, Jang HC, Hong JS, Cho NH. Oral Glucose Tolerance Testing Allows Better Prediction of Diabetes in Women with a History of Gestational Diabetes Mellitus. Diabetes & Metabolism Journal. 2019; 43(3):342-9.

Kershaw RM, Roberts D, Wragg J, Shaaban AM, Humphreys E, Halsall J, Price L, Bicknell R, Gaston K, Jayaraman PS. Proline-rich homeodomain protein (PRH/HHEX) is a suppressor of breast tumour growth. Oncogenesis. 2017;6(6): 346.

Sun R, Liu JP, Gao C, Xiong YY, Li M, Wang YP, Su YW, Lin M, Jiang AL, Xiong LF, Xie Y. Two variants on T2DM susceptible gene HHEX are associated with CRC risk in a Chinese population. Oncotarget. 2016;7(20):29770

Galavi H, Mollashahee‐Kohkan F, Saravani R, Sargazi S, Noorzehi N, Shahraki H. HHEX gene polymorphisms and type 2 diabetes mellitus: A case‐ control report from Iran. Journal of Cellular Biochemistry. 2019;120(10): 16445-51

Gu HF. Genetic, epigenetic and biological effects of zinc transporter (SLC30A8) in type 1 and type 2 diabetes. Current Diabetes Reviews. 2016;12:1-9.

Rutter GA, Chimienti F. SLC30A8 mutations in type 2 diabetes. Diabetologia, 2015;58(1):31-36.

Nikitin AG, Potapov VA, Brovkin AN, Lavrikova EY, Khodyrev DS, Shamhalova, MS, Smetanina SA, Suplotova LN, Shestakova MV, Nosikov VV, Averyanov AV. Association of FTO, KCNJ11, SLC30A8, and CDKN2B polymorphisms with type 2 diabetes mellitus. Molecular Biology. 2015;49(1);103-111.

Gomes KFB, Semzezem C, Batista R, Fukui RT, Santos AS, Correia MR, Passos-Bueno MR, da Silva MER. Importance of zinc transporter 8 autoantibody in the diagnosis of type 1 diabetes in Latin Americans. Scientific Reports. 2017;7(1):207.

Wang L, Tong X, Gu F, Zhang L, Chen W, Cheng X, Xie L, Chang Y, Zhang H. The KLF14 transcription factor regulates hepatic gluconeogenesis in mice. Journal of Biological Chemistry. 2017;292(52): 21631-21642.

Li Q, Qiao Y, Wang C, Zhang G, Zhang X Xu L. Associations between two single-nucleotide polymorphisms (rs1801278 and rs2943641) of insulin receptor substrate 1 gene and type 2 diabetes susceptibility: A meta-analysis; 2016.

Yousef AA, Behiry EG, Allah WMA, Hussien AM, Abdelmoneam AA, Imam MH, Hikal DM. irs-1 genetic polymorphism (r. 2963G> A) in type 2 diabetes mellitus patients associated with insulin resistance. The Application of Clinical Genetics, 2018;11:99.

Zhang, Dingyu, Xiaolin Zhang, Dan Liu, Tengfei Liu, Wenzhi Cai, Chenghui Yan, Yaling Han. "Association between insulin receptor substrate-1 polymorphisms and high platelet reactivity with clopidogrel therapy in coronary artery disease patients with type 2 diabetes mellitus." Cardiovas-cular Diabetology. 2016;15(1): 50.

Thangavelu M, Godla UR, Paul SF, Maddaly R. Single-nucleotide polymorphism of INS, INSR, IRS1, IRS2, PPAR-G and CAPN10 genes in the pathogenesis of polycystic ovary syndrome. Journal of genetics, 2017;96(1): 87-96.

Wang L, Tong X, Gu F, Zhang L, Chen W, Cheng X, Xie L, Chang Y, Zhang H. The KLF14 transcription factor regulates hepatic gluconeo- genesis in mice. Journal of Biological Chemistry. 2017;292(52):21631-21642.

Álvarez MF, Gómez MEV, González II, Fernández G, Siewert S. The association between the KLF14 rs4731702 SNP and the lipid profile in type 2 diabetes mellitus patients: A study in San Luis City, San Luis, Argentina. Open Access Library Journal. 2016;3(11):1.