Abstract
The prevalence of Type II Diabetes (T2D) has been increasing and has become a disease of significant public health burden in Jordan. None of the previous genome-wide association studies (GWAS) have specifically investigated the Middle East populations. The Circassian and Chechen communities in Jordan represent unique populations that are genetically distinct from the Arab population and other populations in the Caucasus. Prevalence of T2D is very high in both the Circassian and Chechen communities in Jordan despite low obesity prevalence. We conducted GWAS on T2D in these two populations and further performed meta-analysis of the results. We identified a novel T2D locus at chr20p12.2 at genome-wide significance (rs6134031, P = 1.12 × 10−8) and we replicated the results in the Wellcome Trust Case Control Consortium (WTCCC) dataset. Another locus at chr12q24.31 is associated with T2D at suggestive significance level (top SNP rs4758690, P = 4.20 × 10−5) and it is a robust eQTL for the gene, MLXIP (P = 1.10 × 10−14), and is significantly associated with methylation level in MLXIP, the functions of which involves cellular glucose response. Therefore, in this first GWAS of T2D in Jordan subpopulations, we identified novel and unique susceptibility loci which may help inform the genetic underpinnings of T2D in other populations.
Highlights
Diabetes is among the most common non-communicable diseases globally
SNP rs4758690 is located in the intron of MLXIP, a gene involved in transcriptional regulation of genes in glucose metabolism
These results demonstrate significant genome-wide association study (GWAS) associations to novel T2D susceptibility loci in Jordan subpopulations
Summary
Diabetes is among the most common non-communicable diseases globally. It has been estimated that there are currently about 194 million people at the age of 20 to 79 with diabetes worldwide and that this number will further increase to 333 million by 2025 (Wild et al, 2004). Despite extensive research efforts for more than a decade and some notable successes, much of the genetic basis of common human diseases remains unresolved (Hirschhorn & Daly, 2005). The heritability attributed to these loci remains as low as just 10% (Imamura et al, 2016) These studies have mostly focused on populations of European ancestry and East Asians, with a few studies on South Asians and Mexicans. The genetic determinants of T2D in Middle East populations have not been extensively studied by GWAS and limited evidence suggested that at least some of the reported T2D loci showed differential associations in different populations in the Middle East (Mtiraoui et al, 2012). It has been reported that the presentation of T2D is different between Middle East immigrants and European patients (Glans et al, 2008), implying some different genetic basis between populations. Given the prevalence of the disease in the region, more research is warranted to understand the genetic basis of T2D specific to given Middle Eastern populations
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