A Perception on Genome-Wide Genetic Analysis of Metabolic Traits in Arab Populations

Abstract

Despite dedicated nation-wide efforts to raise awareness against the harmful effects of fast-food consumption and sedentary lifestyle, the Arab population continues to struggle with an increased risk for metabolic disorders. Unlike the European population, the Arab population lacks well-established genetic risk determinants for metabolic disorders, and the transferability of established risk loci to this population has not been satisfactorily demonstrated. The most recent findings have identified over 240 genetic risk loci (with ~400 independent association signals) for type 2 diabetes, but thus far only 25 risk loci (ADAMTS9, ALX4, BCL11A, CDKAL1, CDKN2A/B, COL8A1, DUSP9, FTO, GCK, GNPDA2, HMG20A, HNF1A, HNF1B, HNF4A, IGF2BP2, JAZF1, KCNJ11, KCNQ1, MC4R, PPARγ, SLC30A8, TCF7L2, TFAP2B, TP53INP1, and WFS1) have been replicated in Arab populations. To our knowledge, large-scale population- or family-based association studies are non-existent in this region. Recently, we conducted genome-wide association studies on Arab individuals from Kuwait to delineate the genetic determinants for quantitative traits associated with anthropometry, lipid profile, insulin resistance, and blood pressure levels. Although these studies led to the identification of novel recessive variants, they failed to reproduce the established loci. However, they provided insights into the genetic architecture of the population, the applicability of genetic models based on recessive mode of inheritance, the presence of genetic signatures of inbreeding due to the practice of consanguinity, and the pleiotropic effects of rare disorders on complex metabolic disorders. This perspective presents analysis strategies and study designs for identifying genetic risk variants associated with diabetes and related traits in Arab populations.

Genome-wide association study identifies novel risk variants from RPS6KA1, CADPS, VARS, and DHX58 for fasting plasma glucose in Arab population

“…The risk allele frequencies also differ substantially across the populations (Supplementary Figure S5). In order to identify Arab-population-specific risk variants (that are not polymorphic in continental population), we need to perform large-scale genome-wide surveys (a combination of GWAS, exome, and genome sequencing and imputation) of the Arab population with diabetes 46 .…”

“…(ii) The study cohort is relatively small, a limitation which might have hindered the ability to identify more than just the four reported risk variants and to observe any of the established risk variants for glucose-related traits. There is an urgent need to carry out much larger studies on the genetics of diabetes in Arab populations which are notorious for high prevalence of obesity and diabetes 46 .…”

“…Assessment of allele frequencies at the identified 4 risk variants among the three population substructures of Kuwait. Saudi: Kuwait S subgroup that is predominantly of city-dwelling Saudi Arabian tribe ancestry; Persian: Kuwait P subgroup that is largely of West Asian ancestry, representing Persians; Bedouin: Kuwait B subgroup that is of tent-dwelling Bedouin ancestry46 . (2020) 10:152 | https://doi.org/10.1038/s41598-019-57072-9…”

Molecular Modelling of Islet β-Cell Adaptation to Inflammation in Pregnancy and Gestational Diabetes Mellitus

“…Further support for the important involvement of HMG20A in the islet adaptation process arises from the fact that islets from T2DM donors, in which the adaptation processes have failed, have significantly lower expression of HMG20A when compared with islets from normoglycemic individuals [108]. Moreover, polymorphisms/mutations in the HMG20A gene have been linked to both obesity and T2DM, thus being considered a diabesity gene [109][110][111][112]. In agreement with the role of HMG20A in the adaptation process of β-cells to compensate for an increase in insulin demand, we have observed a transient upregulation of Hmg20a in murine pancreatic β-cells during gestation, with maximal protein expression at gestational day 14.5 [108], correlating with the decrease in PAX4 expression after the initial increase triggered by the gestation [86].…”

Effects of Adenovirus-Mediated Overexpression of JAZF1 on Chronic Inflammation: An In Vitro and In Vivo Study

“…Gluconeogenesis, lipid metabolism, insulin sensitivity, islet β cell function, and inflammatory reactions are regulated by JAZF1 [ 8 – 11 ]. Glucose tolerance and insulin sensitivity are elevated in mice with JAZF1 overexpression, suggesting that this gene affects the regulation of insulin resistance [ 12 ].…”