Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors

Figures & data

Figure 1 Flowchart outlining the literature search process.

Table 1 Association Between Genetic and Prediction of T2DM

Probable Mechanism	Genes	Chromosome Position	SNPs	Population	Allele (Risk/Other)	Ref. No.
Insulin action	KLF14	7q32.3	rs972283	Han Chinese	G/A	[^Citation11]
				Northern Germany	G/A	[^Citation12]
	DUSP9	Xq28	rs5945326	Northern Germany	A/G	[^Citation12]
				Japanese	A/G	[^Citation16]
				Pakistani	A/G	[^Citation17]
				Han Chinese	A/G	[^Citation18]
β-cell function	KCNQ1	11p15.5	rs2237895	Han Chinese	C/A	[^Citation11]
				Japanese, Asian, European	C	[^Citation13]
			rs2237892	Japanese, Asian, European	C	[^Citation13]
			rs2074196	Japanese, Asian, European	G	[^Citation13]
			rs2283228	Eastern Finland	A/C	[^Citation14]
				Asian Indian	A/C	[^Citation15]
			rs231362	Northern Germany	G/A	[^Citation12]
	SLC30A8	8q24.11	rs13266634	Japanese	C/T	[^Citation23]
				Lebanese	–	[^Citation24]
				Tunisian Arabs	–	[^Citation24]
	HNF4A	20q13.12	rs2425637	Finnish	G/T	[^Citation25]
			rs6130608	French-Canadian	T/C	[^Citation26]
			rs736824	French-Canadian	T/C	[^Citation26]
			rs745975	French-Canadian	C/T	[^Citation26]
			rs3212183	French-Canadian	C/T	[^Citation26]
			rs4812829	South Asian	A/G	[^Citation27]
	IGFBP2	3q27	rs4402960	Northen Han Chinese	T/G	[^Citation28]
				Tunisian	T/G	[^Citation29]
			rs1470579	Tunisian Arabs	–	[^Citation24]
				Lebanese	–	[^Citation24]
				Northen Han Chinese	C/A	[^Citation28]
	CDKN2A/B	9p21.3	rs10811661	Indian	T/C	[^Citation30]
				Pakistani	T/C	[^Citation17]
				Mexican	T/C	[^Citation31]
				Chinese She	T/C	[^Citation32]
				Chinese	T/C	[^Citation33]
				Uyghur	T/C	[^Citation34]
				Han Chinese	T/C	[^Citation35]
	TCF7L2	10q.25.2–25.3	rs7903146	Spaniards	T/C	[^Citation36]
				Austrians	T/C	[^Citation37]
				Lebanese	–	[^Citation24]
				Tunisian Arabs	–	[^Citation24]
			rs7901695	African-American	C/T	[^Citation38]
				Italian	C/T	[^Citation39]
			rs7903146	African-American	T/C	[^Citation38]
			rs12255372	European Caucasians	T	[^Citation40]
				Cameroonian	T/G	[^Citation41]
				French	T/G	[^Citation37]
	KCNJ11	11p15.1	rs2285676	Han Chinese	–	[^Citation42]
			rs5215	South Indian	C/T	[^Citation43]
			rs5219	Mauritanian	–	[^Citation44]
				Chinese She	–	[^Citation32]
				Chinese	T/C	[^Citation33]
				Lebanese	–	[^Citation24]
				Tunisian Arabs	–	[^Citation24]
	DNAJC3	13q32.1	–	Turkish	–	[^Citation45]
	CDKAL 1	6p22.3	rs10946398	Han Chinese	C/A	[^Citation47]
			rs775480	Alaska Native	C/A	[^Citation48]
	SLC30A8	8q24.11	rs13266634	Chinese	C/T	[^Citation51]
				Asian, European, African	C/T	[^Citation52]
Obesity	FTO	16q12.2	rs1558902	Japanese	A/T	[^Citation19]
			rs9939609	Scandinavian	A/T	[^Citation20]
				Spaniards	A/T	[^Citation21]
			rs8050136	Finnish	A/C	[^Citation22]
Regulated insulin sensitivity in muscle and liver	ADIPOQ	3q27	rs1501299	Chinese	–	[^Citation46]
			rs7627128	Chinese	–	[^Citation46]
			rs182052	Chinese	–	[^Citation46]
Regulated insulin sensitivity in peripheral tissue	POMC	2p23.3	–	–	A/G	[^Citation49]
Insulin sensitivity	PPARγ2	3p25.2	rs1801282	Caucasian	–	[^Citation50]
Induced oxidative stress via ROS generation	Antioxidant genes	1p13.3	GSTM1del	–	–	[^Citation138]
		22q11.23	GSTT1del	–	–	[^Citation138]
		11q13.2	GSTP1 105I/V(+313A/G)	–	–	[^Citation138]
		11p13, 6q25.3	CAT-21A/T, SOD2 + 47C/T	–	–	[^Citation138]
		3p21.31	GPx1 + 599C/T	–	–	[^Citation138]

Abbreviations: Ref, Reference; SNP, single-nucleotide polymorphism; T2DM, type 2 diabetes mellitus.

Figure 2 Impairments in the regulation of insulin and glucose may cause an increase in hepatic FTO expression.

Abbreviation: TG, triglyceride.

Figure 3 Transcription factor network in the pancreatic β-cell.

Abbreviations: GCK, glucokinase; GLUT-2, glucose transporter-2; L-PK, liver pyruvate kinase.

Figure 4 Probable mechanism of CKN2A/B-antisense noncoding RNA in the INK4 locus (ANRIL) gene product.

Abbreviation: ATM, adipose tissue macrophage.

Figure 5 Possible role of TCF7L2 in the pathogenesis of T2DM.

Abbreviations: GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1.

Figure 6 Mechanism of insulin secretion by the K_ATP channel in pancreatic β-cells. SUR1 and Kir6.2 proteins in the K_ATP channel mediate insulin secretion.

Abbreviations: ATP, adenosine triphosphate; Ca²⁺, calcium ion (composed of α1, α2, β, ɣ, and δ subunits); K⁺, potassium ion; K_ATP, ATP-sensitive potassium channel; Kir6.2, inward rectifier potassium ion channel; SUR1, sulfonylurea receptor-1.

Figure 7 Interaction between ZnT8 expression (A) low ZnT8 and (B) high ZnT8, hormone action, and hepatic insulin clearance.

Kong X , Xing X , Zhang X , Hong J , Yang W . Early-onset type 2 diabetes is associated with genetic variants of beta-cell function in the Chinese Han population. Diabetes Metab Res Rev . 2019;e3214.31465628

 PubMed Web of Science ®Google Scholar

Meigs JB , Shrader P , Sullivan LM , et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med . 2008;359(21):2208–2219. doi:10.1056/NEJMoa0804742 19020323

 PubMed Web of Science ®Google Scholar

Groop L , Forsblom C , Lehtovirta M , et al. Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes . 1996;45(11):1585–1593. doi:10.2337/diab.45.11.1585 8866565

 PubMed Web of Science ®Google Scholar

Herder C , Kowall B , Tabak AG , Rathmann W . The potential of novel biomarkers to improve risk prediction of type 2 diabetes. Diabetologia . 2014;57(1):16–29. doi:10.1007/s00125-013-3061-3 24078135

 PubMed Web of Science ®Google Scholar

Abuissa H , Bel DS , J H O Jr. Strategies to prevent type 2 diabetes. Curr Med Res Opin . 2005;21(7):1107–1114. doi:10.1185/030079905X50606 16004680

 PubMed Web of Science ®Google Scholar

van Hoek M , Dehghan A , Witteman JC , et al. Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study. Diabetes . 2008;57(11):3122–3128. doi:10.2337/db08-0425 18694974

 PubMed Web of Science ®Google Scholar

Cornelis MC , Qi L , Zhang C , et al. Joint effects of common genetic variants on the risk for type 2 diabetes in U.S. men and women of European ancestry. Ann Intern Med . 2009;150(8):541–550. doi:10.7326/0003-4819-150-8-200904210-00008 19380854

 PubMed Web of Science ®Google Scholar

Lyssenko V , Jonsson A , Almgren P , et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med . 2008;359(21):2220–2232. doi:10.1056/NEJMoa0801869 19020324

 PubMed Web of Science ®Google Scholar

Stancakova A , Kuulasmaa T , Paananen J , et al. Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men. Diabetes . 2009;58(9):2129–2136. doi:10.2337/db09-0117 19502414

 PubMed Web of Science ®Google Scholar

Khan IA , Vattam KK , Jahan P , Mukkavali KK , Hasan Q , Rao P . Correlation between KCNQ1 and KCNJ11 gene polymorphisms and type 2 and post-transplant diabetes mellitus in the Asian Indian population. Genes Dis . 2015;2(3):276–282. doi:10.1016/j.gendis.2015.02.009 30258870

 PubMedGoogle Scholar

Fukuda H , Imamura M , Tanaka Y , et al. A single nucleotide polymorphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population. PLoS One . 2012;7(9):e46263. doi:10.1371/journal.pone.0046263 23029454

 PubMed Web of Science ®Google Scholar

Rees SD , Hydrie MZ , Shera AS , et al. Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations. Diabetologia . 2011;54(6):1368–1374. doi:10.1007/s00125-011-2063-2 21350842

 PubMed Web of Science ®Google Scholar

Bao XY , Peng B , Yang MS . Replication study of novel risk variants in six genes with type 2 diabetes and related quantitative traits in the Han Chinese lean individuals. Mol Biol Rep . 2012;39(3):2447–2454. doi:10.1007/s11033-011-0995-8 21643948

 PubMed Web of Science ®Google Scholar

Kamura Y , Iwata M , Maeda S , et al. FTO gene polymorphism is associated with type 2 diabetes through its effect on increasing the maximum BMI in Japanese men. PLoS One . 2016;11(11):e0165523. doi:10.1371/journal.pone.0165523 27820839

 PubMed Web of Science ®Google Scholar

Hertel JK , Johansson S , Sonestedt E , et al. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies. Diabetes . 2011;60(5):1637–1644. doi:10.2337/db10-1340 21398525

 PubMed Web of Science ®Google Scholar

Ortega-Azorin C , Sorli JV , Asensio EM , et al. Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low. Cardiovasc Diabetol . 2012;11:137. doi:10.1186/1475-2840-11-137 23130628

 PubMed Web of Science ®Google Scholar

Scott LJ , Mohlke KL , Bonnycastle LL , et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science . 2007;316(5829):1341–1345. doi:10.1126/science.1142382 17463248

 PubMed Web of Science ®Google Scholar

Tamaki M , Fujitani Y , Hara A , et al. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest . 2013;123(10):4513–4524. doi:10.1172/JCI68807 24051378

 PubMed Web of Science ®Google Scholar

Mtiraoui N , Turki A , Nemr R , et al. Contribution of common variants of ENPP1, IGF2BP2, KCNJ11, MLXIPL, PPARgamma, SLC30A8 and TCF7L2 to the risk of type 2 diabetes in Lebanese and Tunisian Arabs. Diabetes Metab . 2012;38(5):444–449. doi:10.1016/j.diabet.2012.05.002 22749234

 PubMed Web of Science ®Google Scholar

Bonnycastle LL , Willer CJ , Conneely KN , et al. Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns. Diabetes . 2006;55(9):2534–2540. doi:10.2337/db06-0178 16936201

 PubMed Web of Science ®Google Scholar

Marcil V , Amre D , Seidman EG , et al. Hepatocyte nuclear factor 4 alpha polymorphisms and the metabolic syndrome in French-Canadian youth. PLoS One . 2015;10(2):e0117238. doi:10.1371/journal.pone.0117238 25671620

 PubMed Web of Science ®Google Scholar

Kooner JS , Saleheen D , Sim X , et al. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet . 2011;43(10):984–989. doi:10.1038/ng.921 21874001

 PubMed Web of Science ®Google Scholar

Rao P , Wang H , Fang H , et al. Association between IGF2BP2 polymorphisms and type 2 diabetes mellitus: a case-control study and meta-analysis. Int J Environ Res Public Health . 2016;13:6. doi:10.3390/ijerph13060574

 Web of Science ®Google Scholar

Lasram K , Ben Halim N , Benrahma H , et al. Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population. J Diabetes . 2015;7(1):102–113. doi:10.1111/1753-0407.12147 24636221

 PubMed Web of Science ®Google Scholar

Chauhan G , Spurgeon CJ , Tabassum R , et al. Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians. Diabetes . 2010;59(8):2068–2074. doi:10.2337/db09-1386 20424228

 PubMed Web of Science ®Google Scholar

Gamboa-Melendez MA , Huerta-Chagoya A , Moreno-Macias H , et al. Contribution of common genetic variation to the risk of type 2 diabetes in the Mexican Mestizo population. Diabetes . 2012;61(12):3314–3321. doi:10.2337/db11-0550 22923468

 PubMed Web of Science ®Google Scholar

Chen G , Xu Y , Lin Y , et al. Association study of genetic variants of 17 diabetes-related genes/loci and cardiovascular risk and diabetic nephropathy in the Chinese She population. J Diabetes . 2013;5(2):136–145. doi:10.1111/1753-0407.12025 23298195

 PubMed Web of Science ®Google Scholar

Hu C , Zhang R , Wang C , et al. PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population. PLoS One . 2009;4(10):e7643. doi:10.1371/journal.pone.0007643 19862325

 PubMed Web of Science ®Google Scholar

Xiao S , Zeng X , Fan Y , et al. Gene polymorphism association with type 2 diabetes and related gene–gene and gene–environment interactions in a Uyghur Population. Med Sci Monit . 2016;22:474–487. doi:10.12659/msm.895347 26873362

 PubMed Web of Science ®Google Scholar

Wen J , Ronn T , Olsson A , et al. Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort. PLoS One . 2010;5(2):e9153. doi:10.1371/journal.pone.0009153 20161779

 PubMed Web of Science ®Google Scholar

Corella D , Coltell O , Sorli JV , et al. Polymorphism of the transcription factor 7-like 2 gene (TCF7L2) interacts with obesity on type-2 diabetes in the PREDIMED study emphasizing the heterogeneity of genetic variants in type-2 diabetes risk prediction: time for obesity-specific genetic risk scores. Nutrients . 2016;8(12):793.

 PubMed Web of Science ®Google Scholar

Sale MM , Smith SG , Mychaleckyj JC , et al. Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy. Diabetes . 2007;56(10):2638–2642. doi:10.2337/db07-0012 17601994

 PubMed Web of Science ®Google Scholar

Ciccacci C , Di Fusco D , Cacciotti L , et al. TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy. Acta Diabetol . 2013;50(5):789–799. doi:10.1007/s00592-012-0418-x 22843023

 PubMed Web of Science ®Google Scholar

Liu Z , Zhang YW , Feng QP , et al. [Association analysis of 30 type 2 diabetes candidate genes in Chinese Han population]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao . 2006;28(2):124–128.16733889

 PubMedGoogle Scholar

Phani NM , Guddattu V , Bellampalli R , et al. Population specific impact of genetic variants in KCNJ11 gene to type 2 diabetes: a case-control and meta-analysis study. PLoS One . 2014;9(9):e107021. doi:10.1371/journal.pone.0107021 25247988

 PubMed Web of Science ®Google Scholar

Schwingshackl L , Hoffmann G , Lampousi AM , et al. Food groups and risk of type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies. Eur J Epidemiol . 2017;32(5):363–375. doi:10.1007/s10654-017-0246-y 28397016

 PubMed Web of Science ®Google Scholar

Kong X , Zhang X , Xing X , Zhang B , Hong J , Yang W . The association of type 2 diabetes loci identified in genome-wide association studies with metabolic syndrome and its components in a chinese population with type 2 diabetes. PLoS One . 2015;10(11):e0143607. doi:10.1371/journal.pone.0143607 26599349

 PubMed Web of Science ®Google Scholar

Zyriax BC , Salazar R , Hoeppner W , Vettorazzi E , Herder C , Windler E . The association of genetic markers for type 2 diabetes with prediabetic status – cross-sectional data of a diabetes prevention trial. PLoS One . 2013;8(9):e75807. doi:10.1371/journal.pone.0075807 24098730

 PubMed Web of Science ®Google Scholar

Yasuda K , Miyake K , Horikawa Y , et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet . 2008;40(9):1092–1097. doi:10.1038/ng.207 18711367

 PubMed Web of Science ®Google Scholar

Cauchi S , Meyre D , Dina C , et al. Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes . 2006;55(10):2903–2908. doi:10.2337/db06-0474 17003360

 PubMed Web of Science ®Google Scholar

Wang J , Zhang J , Li L , et al. Association of rs12255372 in the TCF7L2 gene with type 2 diabetes mellitus: a meta-analysis. Braz J Med Biol Res . 2013;46(4):382–393. doi:10.1590/1414-431x20132677 23579632

 PubMed Web of Science ®Google Scholar

Nanfa D , Sobngwi E , Atogho-Tiedeu B , et al. Association between the TCF7L2 rs12255372 (G/T) gene polymorphism and type 2 diabetes mellitus in a Cameroonian population: a pilot study. Clin Transl Med . 2015;4:17. doi:10.1186/s40169-015-0058-1 25995831

 PubMedGoogle Scholar

Yao DD , Yang L , Wang Y , et al. Geniposide promotes beta-cell regeneration and survival through regulating beta-catenin/TCF7L2 pathway. Cell Death Dis . 2015;6:e1746. doi:10.1038/cddis.2015.107 25950476

 PubMed Web of Science ®Google Scholar