International Journal of Diabetes Mellitus
Volume 1, Issue 1 , Pages 32-34, April 2009

Genetics of type 2 diabetes in Arabs: What we know to date

  • Brian F. Meyer

      Affiliations

    • Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
    • Corresponding Author InformationCorresponding author. Tel.: +966 12055162; fax: +966 12055171.
    • ,
  • Osama Alsmadi

      Affiliations

    • Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
    • ,
  • Salma Wakil

      Affiliations

    • Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
    • ,
  • Khalid Al-Rubeaan

      Affiliations

    • Diabetes Center, King Abdulaziz University Hospital, Riyadh, Saudi Arabia

Article Outline

Abstract 

Type 2 diabetes (T2D) is among the most challenging health issues of the 21st century and is associated with an alarming rise in the incidence. The Arab population is no exception to this trend. The pathophysiological processes that lead to development of T2D are still unclear, however impairment in insulin secretion and/or action is clearly indicated. T2D is a complex disease with susceptibility being governed by the interaction of multiple genetic and environmental effects. Previous studies indicated that variants in genes encoding the pancreatic β-cell K+ATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are associated with type 2 diabetes. The common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ gene (PPAR-γ) was confirmed in several studies to be associated with type 2 diabetes as well. More recently, studies reported variants within a novel gene, TCF7L2, as a putative susceptibility gene for type 2 diabetes across many ethnic backgrounds around the world. However, studies to date in Arab cohorts remain limited.

 

The association of type 2 diabetes with the P12A polymorphism of the peroxisome proliferator-activated receptor gene (PPAR-γ) has been established in several populations [1]. While many variants have been identified in this gene, the most prevalent and best studied is the P12A polymorphism. There is considerable interpopulation variance in the incidence of the risk allele (P12). This ranges in frequency from a high of 0.96–0.98 in populations including the Japanese, Chinese, and African Americans to 0.91 in Pima Indians and a low of 0.81 in the Finnish population [2]. In the first Arab study of the P12A polymorphism of PPAR-γ, we observed the P, or risk allele, frequency to be 0.974 and 0.968 in type 2 diabetic and control subjects, respectively and was not statistically significant [3]. However, given the very high incidence of the P allele in this population, the study size was extremely underpowered. The high incidence of the P allele in the Saudi population was confirmed by a neonatal sample set in which frequency of this allele was found to be 0.957 [3]. Clearly the risk allele frequency of the Saudi population was comparable to the Japanese, Chinese, and African Americans and among the highest observed.

Insulin is secreted from pancreatic β-cells in response to nutrients, predominantly glucose but also fatty acids and some amino acids. Glucose metabolism is increased in response to rising cellular glucose levels and results in the production of ATP from ADP. Increased cytosolic ATP:ADP ratios trigger closure of KATP channels and membrane depolarization via reduced K+ efflux and subsequent activation of voltage gated calcium channels giving rise to transient increases in intracellular calcium. This in turn induces the exocytosis of insulin-containing granules [4]. Whilst voltage-gated and calcium-activated potassium channels are involved in membrane repolarisation, KATP channels transduce glucose-mediated metabolic signals into electrical activity which modulates insulin secretion. The KATP channel consists of two types of subunit: an inward-rectifier potassium channel subunit (Kir6.2) [5], [6], and a sulfonylurea receptor subunit (SUR) [7]. The KATP channel is made of 4 Kir6.2 subunits coupled to four high-affinity SUR subunits [5], [8], [9], [10]. The Kir6.2 subunit is encoded by KCNJ11, and the SUR subunit is encoded by ABCC8. Both genes reside adjacent to one another on chromosome 11. The four Kir6.2 subunits form the pore of the channel through which K+ passes and also contain the ATP-binding sites. The four SUR subunits modulate the activity of the channel and contain the binding site of sulfonylurea drugs [7]. Mutations in either KCNJ11 or ABBC8 can dramatically affect KATP channel activity, leading to either increased or decreased insulin release [11], [12], [13], [14], [15].

Common polymorphisms of ABCC8 and KCNJ11, particularly the E23K variant, have been associated with type 2 diabetes in several populations including non-European populations [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Current status of the E23K polymorphism and the implications for type 2 diabetes is discussed by Riedel et al. [27]. Direct effects of polymorphisms in ABCC8 (exon 16-3t/c, exon 18 C/T) have not been demonstrated, however, a functional role is proposed for the E23K variant of KCNJ11 which is reported to stimulate increased pancreatic β-cell activity, thus increasing the ATP threshold for insulin secretion [18]. The E23K variant of KCNJ11 results from a G→A transition in codon 23. Analysis of the E23K variant in several Caucasian populations showed that KK homozygosity had a stronger association with type 2 diabetes relative to EK heterozygosity or EE wild-type homozygosity [19]. We conducted the only study investigating an association between T2D risk and the E23K polymorphism of KCNJ11 in an Arab population to date. Our study confirmed in the Saudi population, association of the E23K allele with type 2 diabetes as seen in several other populations [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. Whilst association with the K allele was evident, sample size did not establish whether the risk was recessive in nature and driven by the KK genotype. Other studies have indicated that association could be driven by KK homozygosity [22], however even with the high consanguinity rate in the Saudi population (∼60%) [28] where recessive effects are likely to be amplified, this was not readily evident.

Researchers at Decode Genetics reported strong association between variants in a novel susceptibility gene called TCF7L2 and type 2 diabetes in Icelandic diabetic patients [29]. TCF7L2 encodes the transcription factor 7-like 2 [30]. The overexpression of this gene in human pancreatic β-cells was shown to associate with impaired insulin secretion both in vivo and in vitro [31]. This gene received attention from many research groups following this report, and similar studies were replicated in samples from several populations. Many studies have confirmed the original findings. Substantial association has been confirmed between variants in TCF7L2 and type 2 diabetes among broad ethnic backgrounds, including for example populations of UK [32], Dutch [33], Amish [34], Finnish [35], Swedish [36], French [37], and US [38], [39], Indian [40], and Japanese [41] origin. It is noteworthy that, as in the original report, there was clear evidence of a gene dosage effect, such that the 10% of individuals with two copies of the susceptibility allele were at almost twice the risk of developing type 2 diabetes compared to those with only one copy [32], [42], [43]. Very recently, lack of association between variants in TCF7L2 and type 2 diabetes has been reported in Pima Indians and Chinese diabetics [43], [44]. In another association study performed in Arabs [45], the authors reported only a marginal association between rs12255372 and type 2 diabetes risk and no association with rs7903146.

Variants in TCF7L2 have been strongly associated with type 2 diabetes risk [46]. In a Saudi cohort rs12255372 and rs7903146 were not or only weakly associated with T2D. Several studies from non-European ethnic backgrounds have reported a positive association between TCF7L2 variants and T2D. The first, an Indian study, investigated 3 TCF7L2 variants (rs7903146, rs12255372, and rs4506565) and reported significant association between all three SNPs and T2D [40]. In a Japanese study, four TCF7L2 SNPs were explored (rs12255372, rs7903146, rs7901695 and rs11196205) and all four SNPs were found to be significantly associated with T2D, with rs12255372 showing the strongest association [41]. The third study was conducted by Cauchi et al. on Moroccans [46]. Significant association between rs7903146 variant of TCF7L2 and T2D risk in this population was concluded. Additionally, positive association was also reported on Indian Asians [47], [48], Pakistanis [49], and Afro-Caribbeans [48]. More recently, a surprising lack of association between TCF7L2 variants and type 2 diabetes was independently reported in two non-European populations including Chinese [43], Pima Indians [44] and in respect to rs7903146 in Emirati Arabs [45]. In a meta analysis conducted by Cauchi et al., the authors reviewed the association of rs7903146 variant with T2D risk by looking at 27 original published association studies (including their own), the authors arrived at a pooled OR of 1.46. There was no overlap between the overall OR and CIs of this meta-analysis and the upper CI of the Saudi cohort (1.27) [50]. However, there is an overlap with three studies included in this meta-analysis [38], [48], [51]. Therefore, even though significant association was not indicated in the Saudi cohort, a weak association could not be ruled out and justifies a larger replication study in Arabs.

Given the limited studies conducted in Arabs to date, two points are clear. Firstly results indicate differences in Arab populations in relation to genetic risk for T2D. Secondly, data presented in the literature to date clearly demand replication studies, ideally with larger numbers to confirm findings reported thus far. Similarly, further T2D association studies either candidate gene based or genome-wide are warranted in Arabs and may reveal novel risk loci for this important global disease.

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References 

  1. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26(1):76–80
  2. Celi FS, Shuldiner AR. The role of peroxisome proliferator-activated receptor gamma in diabetes and obesity. Curr Diab Rep. 2002;2(2):179–185
  3. Wakil SM, Al-Rubeaan K, Alsmadi O, Imtiaz F, Carroll P, Rajab M, et al. The peroxisome proliferator-activated receptor-gamma2 P12A polymorphism and type 2 diabetes in an Arab population. Diab Care. 2006;29(1):171–172
  4. Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol. 1989;54:87–143
  5. Inagaki N, Gonoi T, Clement JPt, Namba N, Inazawa J, Gonzalez G, et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995;270(5239):1166–1170
  6. Sakura H, Ammala C, Smith PA, Gribble F, Ashcroft FM. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett. 1995;377:338–344
  7. Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP, Boyd AE, Gonzalez G, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science. 1995;268:423–426
  8. Markworth E, Schwanstecher C, Schwanstecher M. ATP4-mediates closure of pancreatic beta-cell ATP sensitive potassium channels by interaction with 1 of 4 identical sites. Diabetes. 2003;49:1413–1418
  9. Vanoye CG, MacGregor GG, Dong K, Tang L, Buschmann AS, Hall AE, et al. The carboxyl termini of K(ATP) channels bind nucleotides. J Biol Chem. 2003;277:23260–23270
  10. Trapp S, Haider S, Jones P, Sansom MS, Ashcroft FM. Identification of residues contributing to the ATP binding site of Kir6.2. Embo J. 2003;22:2903–2912
  11. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995;268:426–429
  12. Nestorowicz A, Inagaki N, Gonoi T, Schoor KP, Wilson BA, Glaser B, et al. A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes. 1997;46:1743–1748
  13. Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, et al. Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet. 1998;7:1119–1128
  14. Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG. Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell. 2000;100:645–654
  15. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–1849
  16. Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol 2003;1(1):E20 [Epub 2003 October 13; Erratum in: PLoS Biol 2003;1(3):445].
  17. Gloyn AL, Hashim Y, Ashcroft SJH, Ashfield R, Wiltshire S, Turner RC. Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with type 2 diabetes mellitus (UKPDS 53). Diabetic Med. 2001;18(3):206–212
  18. Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003;52:568–572
  19. Hani EH, Boutin P, Durand E, Hani EH, Boutin P, Durand E, et al. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia. 1998;41:1511–1515
  20. Hansen L, Echwald SM, Hansen T, Urhammer SA, Clausen JO, Pedersen O. Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. Diabetes. 1997;46:508–512
  21. Hansen SK, Nielsen EMD, Andersen J, Ek G, Glumer C, Carstensen B, et al. Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes. J Clin Endocrinol Metab. 2005;90(6):3629–3637
  22. Inoue H, Ferrer J, Warren-Perry M, Zhang YY, Millns H, Turner RC, et al. Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes. 1997;46(3):502–507
  23. Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance – a population-based twin study. Diabetologia. 1999;42(2):139–145
  24. Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM. Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia. 1996;39(10):1233–1336
  25. Van Dam RM, Hoebee B, Seidell JC, Schaap MM, de Bruin TWA, Feskens EJM. Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses. Diabetic Med. 2005;22(5):590–598
  26. Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, et al. Association studies of variants in the genes involved in pancreatic ß-cell function in type 2 diabetes in Japanese subjects. Diabetes. 2006;55:2379–2386
  27. Riedel MJ, Steckley DC, Light PE. Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes. Hum Genet. 2005;116(3):133–145
  28. Teebi AS, Teebi SA. Genetic diversity among the Arabs. Commun Genet. 2005;8:21–26
  29. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320–323
  30. Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem. 2005;280(2):1457–1464
  31. Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007;117(8):2155–2163
  32. Groves CJ, Zeggini E, Minto J, Frayling TM, Weedon MN, Rayner NW, et al. Association analysis of 6736 UK subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes. 2006;55(9):2640–2644
  33. Van Vliet-Ostaptchouk JV, Shiri-Sverdlov R, Zhernakova A, Strengman E, van Haeften TW, Hofker MH, et al. Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort. Diabetologia. 2007;50(1):59–62
  34. Damcott CM, Pollin TI, Reinhard LJ, Ott SH, Shen H, Silver KD, et al. Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes. 2006;55(9):2654–2659
  35. Scott LJ, Bonnycastle C, Willer CJ, Sprau AG, Jackson AU, Narisu N, et al. Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes. 2006;55:2649–2653
  36. Mayans S, Lackovic K, Lindgren P, Ruikka K, Agren A, Eliasson M, et al. TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden. Eur J Hum Genet. 2007;15(3):342–346
  37. Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, et al. Transcription factor TCF7L2 genetic study in the French population: expression in human β-cells and adipose tissue and strong association with type 2 diabetes. Diabetes. 2006;55:2903–2908
  38. Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, et al. Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes. 2006;55:2890–2895
  39. Zhang C, Qi L, Hunter DJ, Meigs JB, Manson JE, van Dam RM, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of US women and men. Diabetes. 2006;55:2645–2668
  40. Chandak GR, Janipalli CS, Bhaskar S, Kulkarni SR, Mohankrishna P, Hattersley AT, et al. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia. 2007;50(1):63–67
  41. Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S. Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia. 2007;50(5):980–984
  42. Florez JC, Sjogren M, Burtt N, Orho-Melander M, Schayer S, Sun M, et al. Association testing in 9000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes. Diabetes. 2004;53(12):3313–3318
  43. Chang YC, Chang TJ, Jiang YD, Kuo SS, Lee KC, Chiu KC, et al. Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes. 2007;56(10):2631–2637
  44. Guo T, Hanson RL, Traurig M, Muller YL, Ma L, Mack J, et al. TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians: analysis of 3501 individuals. Diabetes. 2007;56(12):3082–3088
  45. Saadi H, Nagelkerke N, Carruthers SG, Benedict S, Abdulkhalek S, Reed R, et al. Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects. Diab Res Clin Pract. 2008;80(3):392–398
  46. Cauchi S, El Achhab Y, Choquet H, Dina C, Krempler F, Weitgasser R, et al. TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med. 2007;85(7):777–782
  47. Bodhini D, Radha V, Dhar M, Narayani N, Mohan V. The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians. Metabolism. 2007;56(9):1174–1178
  48. Humphries SE, Gable D, Cooper JA, Ireland H, Stephens JW, Hurel SJ, et al. Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women. J Mol Med. 2006;84(12):1005–1014
  49. Rees SD, Bellary S, Britten AC, O’Hare JP, Kumar S, Barnett AH, et al. Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population. BMC Med Genet. 2008;9:8
  50. Alsmadi O, Al-Rubeaan K, Mohamed G, Alkayal F, Al-Saud H, Abu Al-Saud N, et al. Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population. BMC Med Genet. 2008;9(1):72
  51. Melzer D, Murray A, Hurst AJ, Weedon MN, Bandinelli S, Corsi AM, et al. Effects of the diabetes linked TCF7L2 polymorphism in a representative older population. BMC Med. 2006;4:34

PII: S1877-5934(09)00007-1

doi:10.1016/j.ijdm.2009.03.003

International Journal of Diabetes Mellitus
Volume 1, Issue 1 , Pages 32-34, April 2009

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