Gene. 2013 May 15;520(2):166-77.

ACE I/D and MTHFR C677T polymorphisms are significantly associated with type 2 diabetes in Arab ethnicity: a meta-analysis.

Khalid Al-Rubeaan , Amr T.M. Saeb, Khalid Siddiqui, Nyla Nazir, Dhekra Al-Naqeb, Sara Al-Qasim

Strategic Center for Diabetes Research, King Saud University, Saudi Arabia



In this meta-analysis study, SNPs were investigated for their association with type 2 diabetes (T2D) in both Arab and Caucasian ethnicities. A total of 55 SNPs were analyzed, of which 11 fulfilled the selection criteria, and were used for analysis. It was found that TCF7L2 rs7903146 was significantly associated with a pooled OR of 1.155 (95%C.I. = 1.059–1.259), p < 0.0001 and I2 = 78.30% among the Arab population, whereas among Caucasians, the pooled OR was 1.45 (95%C.I. = 1.386–1.516), p < 0.0001 and I2 = 77.20%. KCNJ11 rs5219 was significantly associated in both the populations with a pooled OR of 1.176(1.092–1.268), p < 0.0001 and I2 = 32.40% in Caucasians and a pooled OR of 1.28(1.111–1.475), p = 0.001 among Arabs. The ACE I/D polymorphism was found to be significantly associated with a pooled OR of 1.992 (95%C.I. = 1.774–2.236), p < 0.0001 and I2 = 83.20% among the Arab population, whereas among Caucasians, the pooled OR was 1.078 (95%C.I. = 0.993–1.17), p = 0.073 and I2 = 0%. Similarly, MTHFR C677T polymorphism was also found to be significantly associated among Arabs with a pooled OR of 1.924 (95%C.I. = 1.606–2.304), p < 0.0001 and I2 = 27.20%, whereas among Caucasians, the pooled OR was 0.986 (95%C.I. = 0.868–1.122), p = 0.835 and I2 = 0%. Meanwhile PPARG-2 Pro12Ala, CDKN2A/2B rs10811661, IGF2BP2 rs4402960, HHEX rs7923837, CDKAL1 rs7754840, EXT2 rs1113132 and SLC30A8 rs13266634 were found to have no significant association with T2D among Arabs. In conclusion, it seems from this study that both Arabs and Caucasians have different SNPs associated with T2D. Moreover, this study sheds light on the profound necessity for further investigations addressing the question of the genetic components of T2D in Arabs.

PMID: 23458876



Type 2 diabetes (T2D) is a multi-factorial metabolic syndrome, characterized by high blood glucose level, mainly caused by insulin resistance and relative insulin deficiency (Bonnefond et al., 2010). The prevalence rates of T2D in Arab countries are increasing, and it has reached up to 35% in some Gulf countries. Saudi Arabia, for example, had 23.7% of T2D patients in the year 2004, with an additional 14.1% of pre-diabetic cases, thereby totaling to a prevalence rate of 37.8% (Al-Nozha et al., 2004). To gain an insight into the genes associated with T2D within the Arab population, a systematic literature review was undertaken to acquire a more focused and rigorous view of the bona-fide state of each gene studied within this population. In addition, we wanted to point out the relevant genetic basis of this disease within the different ethnic Arab communities (Tadmouri et al., 2009). This article aims to identify the unique risk of SNPs for T2D that are exclusive to Arab ethnicities, by performing a comparative meta-analysis of previously identified SNPs for the disease among Arabs and Caucasians. At the same time, this meta-analysis will identify SNPs for T2D that are shared by the two ethnicities or unique for either one, or SNPs that are not significant for both ethnicities.

Khalid Al-Rubeaan-1Figure 1.  Shows a Forest plot representation comparing the association of the selected 11 SNPs. Group A — It shows that TCF7L2 and KCNJ11 are with significant association in both Arabs and Caucasians. Group B — Genes ACE and MTHRF are significantly associated in Arabs and non-significant in Caucasians. Group C — Consists of 4 genes namely, CDKAL1, CDKN2 A/B, PPARG2 and IGFBP2 that have no significant association in Arabs but significant in Caucasians. Group D — Includes HHEX, EXT2 & SLC30A8 that showed non-significant association in both Arab and Caucasian populations.

Khalid Al-Rubeaan-fig2

Figure 2 is a comparative scatter plot, demonstrating how these SNPs behave in these ethnicities, according to their groups. The first group, Group ‘A’ where SNPs were significantly positive in both Arabs and Caucasians, which included TCF7L2 rs7903146, showed a score of 22.71 for Arabs and 42.18 for Caucasians with a highly significant score. KCNJ11 rs5219 was also in Group A with 15.14 for Arabs and 23.52 for Caucasians. In Group ‘B’ SNPs, namely, ACE I/D and MTHFR C677T polymorphism, there was a highly significant positive score for the Arab population scoring, as 27.44 and 21.05 respectively, while Caucasian studies revealed a negative score of −3.19 and −4.98 respectively. The third group (Group ‘C’) of SNPs namely, PPARG-2 Pro12Ala, CDKN2A/B rs10811661, CDKAL1 rs7754840 and IGFBP2 rs4402960 were opposite, showing a significantly positive score for Caucasians, reading at 25.56, 28.13, 13 and 25.80 respectively, while the Arab ethnicities had a negative score measuring at−3.45,−12.06,−14.26 and−13.67 respectively. The last group (Group ‘D’) of SNPs namely, HHEX rs7923837, EXT2 rs1113132 and SLC30A8 rs13266634 scored negative for both Arabian and Caucasian populations with scores of −8.13, −12.16 and −11.76 respectively for Arabs and −6.72, −5.98, and −3.91 respectively for Caucasians.


It is clear from this study that we can easily group genes that are associated with Arab ethnic groups as TCF7L2 rs7903146, ACE I/D and MTHFR C677T polymorphisms. Although TCF7L2 rs7903146 is the only SNP found up to this moment to be significantly associated with Arabs and Caucasians, although KCNJ11 rs5219 shows a significant association in Arabs and Caucasians but number of studies is only two in Arabs one shows positive association and other no association. ACE I/D and MTHFR C677T are the most highly significant SNPs among the Arab population. In other SNPs, which were found to be associated with Caucasians namely, PPARG-2 Pro12Ala, CDKN2A/2B rs10811661, KCNJ11 rs5219, IGF2BP2 rs4402960, HHEX rs7923837, EXT2 rs1113132 and SLC30A8 rs13266634were not found to be associated with Arabs. This meta-analysis demonstrates the SNPs associated with T2D among Arab ethnicities, according to what is available at the time of this study. Fig. 2 is more likely to be subject to a lot of changes in the future, when more genetic studies are conducted in these ethnicities.



  1. Al-Nozha, M.M., et al., 2004. Diabetes mellitus in Saudi Arabia. Saudi Med. J. 25, 1603–1610.
  2. Bonnefond, A., Froguel, P., Vaxillaire, M., 2010. The emerging genetics of type 2 diabetes. Trends Mol. Med. 16, 407–416.
  3. Tadmouri, G.O., et al., 2009. Consanguinity and reproductive health among Arabs. Oct 8 Reprod. Health 6, 17.


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