👤 Osama Alsmadi

Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W variant associates with reduced low-density lipoprotein/high-density lipoprotein (LDL/HDL) and increased fasting blood glucose (FBG) in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of the R59W variant on the inflammatory activity of ANGPTL8. The ANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-κB activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics. The ANGPTL8 R59W variant was associated with increased circulatory levels of tumor necrosis factor alpha (TNFα) and interleukin 7 (IL7). Our in vitro studies using HepG2 cells revealed an increased phosphorylation of key inflammatory proteins of the NF-κB pathway in individuals with the R59W variant as compared to those with the wild type, and TNFα stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-κB p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-κB activity. ANGPTL8 R59W is associated with increased circulatory TNFα, IL7, and NF-κB p65 activity. Weak transient binding of the ANGPTL8 R59W variant explains its regulatory role on the NF-κB pathway and inflammation. Show less

While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further, consideration of populations such as Arabs, that are characterized by consanguinity and a high level of inbreeding, can lead to identification of novel risk loci. We imputed published GWAS data from two Kuwaiti Arab cohorts (n = 1434 and 1298) to the 1000 Genomes Project haplotypes and performed meta-analysis for associations with 13 metabolic traits. We compared the observed association signals with those established for metabolic traits. Our study highlighted 70 variants from 9 different genes, some of which have established links to metabolic disorders. By relaxing the genome-wide significance threshold, we identified 'novel' risk variants from 11 genes for metabolic traits. Many novel risk variant association signals were observed at or borderline to genome-wide significance. Furthermore, 349 previously established variants from 187 genes were validated in our study. Pleiotropic effect of risk variants on multiple metabolic traits were observed. Fine-mapping illuminated rs7838666/CSMD1 rs1864163/CETP and rs112861901/[INTS10,LPL] as candidate causal variants influencing fasting plasma glucose and high-density lipoprotein levels. Computational functional analysis identified a variety of gene regulatory signals around several variants. This study enlarges the population ancestry diversity of available GWAS and elucidates new variants in an ethnic group burdened with metabolic disorders. Show less

Despite a high prevalence of metabolic trait related diseases in Arabian Peninsula, there is a lack of convincingly identified genetic determinants for metabolic traits in this population. Arab populations are underrepresented in global genome-wide association studies. We genotyped 1965 unrelated Arab individuals from Kuwait using Cardio-MetaboChip, and tested SNP associations with 13 metabolic traits. Models based on recessive mode of inheritance identified Chr15:40531386-rs12440118/ZNF106/W->R as a risk variant associated with glycated-hemoglobin at close to 'genome-wide significant' p-value and five other risk variants 'nominally' associated (p-value ≤ 5.45E-07) with fasting plasma glucose (rs7144734/[OTX2-AS1,RPL3P3]) and triglyceride (rs17501809/PLGRKT; rs11143005/LOC105376072; rs900543/[THSD4,NR2E3]; and Chr12:101494770/IGF1). Furthermore, we identified 33 associations (30 SNPs with 12 traits) with 'suggestive' evidence of association (p-value < 1.0E-05); 20 of these operate under recessive mode of inheritance. Two of these 'suggestive' associations (rs1800775-CETP/HDL; and rs9326246-BUD13/TGL) showed evidence at genome-wide significance in previous studies on Euro-centric populations. Involvement of many of the identified loci in mediating metabolic traits was supported by literature evidences. The identified loci participate in critical metabolic pathways (such as Ceramide signaling, and Mitogen-Activated Protein Kinase/Extracellular Signal Regulated Kinase signaling). Data from Genotype-Tissue Expression database affirmed that 7 of the identified variants differentially regulate the up/downstream genes that mediate metabolic traits. Show less