Genomic Landscape of Metabolic Disorders in Saudi Arabian Population

To screen the genetic polymorphisms that could possibly have a deleterious effect in Saudi obese/T2D patients. Also, by identifying the rare homozygous variants that predispose with large effects by whole-genome sequencing Saudi families of extreme obesity and early onset T2D.

Methodology:

The study will include in screening those Saudi that cluster in families and develop early onset T2D ( <35 years of age) and/or represent the top or bottom 10% of the variation in BMI. Pregnant patients, patients with liver failure, cancer patients, patients with advance CKD (stage 5) were excluded from the study. DNA from patients with high prevalence of obesity and/or T2D will be whole-genome sequenced. Sequence variants will be called and annotated and filtered for homo / heterozygous coding mutation (LOF/missense) that segregate with obesity and/or T2D within these families. Selected variants that pass the QC filter will be chosen with respect to the minor allelic frequency rate to be able to identify rare polymorphisms with a deleterious impact. Downstream analysis was done for filtering identifying the genetic associations in familial and sporadic cases.

Results:

Over the study period of one year, all patients were initially screened in the obesity clinic (around 2,100 patients) Of those patients after exclusion 600 patients were approached for recruitment to the study. Screening the 242 Saudi patients out of 377 recruited revealed the associations of a number of variants that were previously reported to affect obesity and/or T2D. A group of six rare variants were identified that are were not reported as pathogenic in prior population studies (MAF < 1%). Also, a group of variants were identified that are not directly linked to obesity or T2D but show their impact to other metabolic disorders, cardiovascular or hematological disorders, etc.

Discussion/Conclusion:

The analysis also revealed the association of rare six variants in our cohort, these variants were categorized as heterozygous LOF. They are linked to metabolic disorder diseases but classified as variants of expected pathogenic or risk factor. Those variants are reported in the following genes RETN, GCK, MRAP2, PPP1R3A, PLIN1 and AIRE. In comparison to deCode 70k database, the frequency of these genes mutations was very low, For RETN, only 3 carriers were found as 2 out of 3 were of American origin. For GCK, one carrier only. MRAP2 showed only 3 carriers while PPP1R3A reveled 5 carriers. Finally, PLIN1 revealed 2 carriers only. The rest of variants that we identified were in three genes ACOXL, PKD2L1 and THSD7B as Homozygous LOF linked to metabolic disorder disease but they are not classified as pathogenic mutation in clinVar.
Other homozygous missense variants were found in two genes LIPE, DLAT of our cohort were previously reported in OMIM database as pathogenic variants and play an important role in regulation of lipids in the body. Mutation in these genes caused excess accumulation of fat association with metabolic disorder that could be linked to diabetes and obesity.