DISCUSSION It is likely that both genetic

DISCUSSIONDiabetes mellitus is a major worldwide public health problem including Saudi Arabia. It has been reported by the World Health Organization (WHO) that Saudi Arabia has the second highest rate of diabetes in the Middle East and the seventh in the world2.  It is likely that both genetic and environmental factors play important role in the disease pathogenesis26.

Various research groups have studied several candidate genes that may induce the susceptibility to T2DM in different populations. However, relatively fewer studies have been conducted in Saudi Arabia to study the association between VDR gene polymorphism and the susceptibility to T2DM.  VDR gene mediates transcription function, and the interaction with its ligand (vitamin D) is known to affect insulin secretion and insulin function34.

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 We have investigated VDR FokI and BsmI gene polymorphisms in a group of Saudi population with T2DM, and matched control subjects for gender and age in Makkah (aka: Mecca) region in western Saudi Arabia.  No significant difference was observed in the genotype distribution and allele frequencies of both SNPs in FokI and BsmI polymorphisms in VDR gene between the control and the patients with T2DM.  An important factor for consideration in our results on VDR polymorphisms is that, this study has been made in Makkah environs of Saudi Arabia, a   region that is known to have two seasonal variations, hot and very hot (Table 3).  The available sunshine throughout the year is fairly high and thus Makkah region can be considered a special reference region for the possible bio-availability of vitamin D throughout the year, unlike many European, North American and even areas in Asian countries that are located in the northern hemisphere such as Hokkaido area of Japan.  Several investigators have studied the association of VDR polymorphism in different populations.

In Polish subjects, Malecki et al have studied the polymorphism of four single nucleotide polymorphisms (SNPs) of VDR gene (BsmI, TaqI, FokI and ApaI) and they found that the genotype and allele distribution is the same in both controls and T2DM35.  Also, in French Caucasian population, Ye et al studied the same SNPs of VDR gene (BsmI, TaqI, FokI and ApaI) and they observed that both the genotype and allele distribution is the same in both controls and T2DM in36.   Furthermore, in Turkish population, Dilmec et al found no significant difference in genotype and allele frequencies of the same four SNPs (BsmI, TaqI, FokI and ApaI) of the VDR gene between both controls and T2DM37. Among European Caucasians, Bertoccini  et al studied the association between VDR FokI polymorphism and T2DM and found no difference of the genotype distributions and allele frequencies between T2DM subjects and controls in Italians38.

 Similarly, in Chinese Han population, Fei Yu et al studied four VDR SNPs and found that VDR FokI and BsmI polymorphism is not related to T2DM risk in Chinese39. In the African continent, for Tunisian subjects, no significant association between VDR FokI polymorphism and T2DM was observed, Mahjoubi et al 40. Thus, all of the above previously reported observations concur and support our results that the reported polymorphisms of VDR gene have no bearing on the diabetes susceptibility. Interestingly, quite the opposite results were obtained by other investigators studying VDR variants and diabetes in different geographical and environmental regions.  For example, in North Indians (Kashmiri population), Malik et al reported VDR TaqI and BsmI polymorphism and they also found that BsmI G allele is associated with T2DM risk41. Similarly in United Arab Emirates population, Safar et al found that the G allele and GG genotype of FokI and T allele and TT genotype of BsmI are associated with T2DM risk in Emirati population42.

  Among the Chinese Han population < 55 years of age; Jia et al reported that FokI polymorphism is associated with T2DM43.  In Saudi population of Riyadh region, Aldaghri et al studied the polymorphism of four SNPs in VDR gene (ApaI, FokI, TaqI and BsmI) and an association of BsmI T allele and C/T genotype and TaqI A/G genotypes and T2DM was observed 31. These findings differ from our observations in Makkah region; which may, among other possibilities, be explained by differences in the genetic background of the participants or due to some unknown environmental factors such as the daily exposure to sunlight and temperature variations. The present study has limitations due to relatively small number of subjects. Further studies will be needed to evaluate the serological levels of the VDR and related metabolites and related genetic analysis in a large T2DM cohort with clinical data.

  These investigations will be important basis to understand the role of VDR in the pathogenesis of T2DM in special geographical and ethnic region.In conclusion, our studies on the VDR gene polymorphisms in Makkah region diabetic patients clearly confirm similar studies in diverse ethnic populations in Tunisian, and Chinese subjects that the FokI and BsmI polymorphisms in the VDR gene show no significant difference in genotype and allele frequency between controls and patients with T2DM. These data strongly suggest that the FokI and BsmI SNPs may not contribute to the susceptibility to T2DM among Saudi population.  ACKNOWLEDGMENT   The authors thank Dr. Abdulrahman Yousuf for his technical support in the research laboratory in Faculty of Dentistry, Um Al-Qura University.  CONFLICT OF INTERESTThe authors declare that no conflict of interest exists.

FUNDINGThis study was funded by the Vice deanship for research, Um Al-Qura  University,  Makkah, Saudi Arabia (No. 43309017).List of Supporting Information: No appendix is presented.


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