Genetic risk variants for metabolic traits in Arab populations

Glycated haemoglobin (HbA1c) is widely used as a biomarker for the diagnosis of diabetes, for population-level screening, and for monitoring the glycaemic status during medical treatment. Although the heritability of HbA1c has been estimated at ~55–75%, a much smaller proportion of phenotypic variance is explained by the HbA1c-associated variants identified so far. To search for novel loci influencing the HbA1c levels, we conducted a genome-wide meta-analysis of 2 non-diabetic Japanese populations (n = 7,704 subjects in total). We identified 2 novel loci that achieved genome-wide significance: TMC6–TMC8 (P = 5.3 × 10−20) and SIX3–SIX2 (P = 8.6 × 10−9). Data from the largest-scale European GWAS conducted for HbA1c supported an association between the novel TMC6–TMC8 locus and HbA1c (P = 2.7 × 10−3). The association analysis with glycated albumin and glycation gap conducted using our Japanese population indicated that the TMC6–TMC8 and SIX3–SIX2 loci may influence the HbA1c level through non-glycaemic and glycaemic pathways, respectively. In addition, the pathway-based analysis suggested that the linoleic acid metabolic and 14-3-3-mediated signalling pathways were associated with HbA1c. These findings provide novel insights into the molecular mechanisms that modulate the HbA1c level in non-diabetic subjects.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6–TMC8 and SIX3–SIX2 loci associated with HbA1c

Hachiya

Komaki

Ohmomo

et al. 2017

“…To capture the extent of exome variation in the entire Kuwaiti population, 291 healthy, unrelated native Kuwaiti individuals from the study cohorts used in our earlier studies were selected 24 , 36 , 69 , 70 . At the time of recruitment, all participants in this study were healthy and deemed free of Mendelian or rare genetic disorders, cognition or physical disability, mental retardation or chronic disorders, such as cancer.…”

Section: Methodsmentioning

confidence: 99%

Assessment of coding region variants in Kuwaiti population: implications for medical genetics and population genomics

John

Antony

Eaaswarkhanth

et al. 2018

Self Cite

Consanguineous populations of the Arabian Peninsula have been underrepresented in global efforts that catalogue human exome variability. We sequenced 291 whole exomes of unrelated, healthy native Arab individuals from Kuwait to a median coverage of 45X and characterised 170,508 single-nucleotide variants (SNVs), of which 21.7% were ‘personal’. Up to 12% of the SNVs were novel and 36% were population-specific. Half of the SNVs were rare and 54% were missense variants. The study complemented the Greater Middle East Variome by way of reporting many additional Arabian exome variants. The study corroborated Kuwaiti population genetic substructures previously derived using genome-wide genotype data and illustrated the genetic relatedness among Kuwaiti population subgroups, Middle Eastern, European and Ashkenazi Jewish populations. The study mapped 112 rare and frequent functional variants relating to pharmacogenomics and disorders (recessive and common) to the phenotypic characteristics of Arab population. Comparative allele frequency data and carrier distributions of known Arab mutations for 23 disorders seen among Arabs, of putative OMIM-listed causal mutations for 12 disorders observed among Arabs but not yet characterized for genetic basis in Arabs, and of 17 additional putative mutations for disorders characterized for genetic basis in Arab populations are presented for testing in future Arab studies.

“…Consideration of ethnic populations in association studies is supposed to help in enlarging the global catalog of risk loci by way of indicating novel risk loci (not seen in major continental populations). Previous studies from the region on Arab cohorts demonstrated this aspect by way of identifying novel risk loci for type 2 diabetes (T2DM) at either genome-wide significant or suggestive p-values for associations -such loci include KIF12, Table S5) [41][42][43][44][45] . Our study now adds RPS6KA1, CADPS, (VARS, VWA7), and DHX58 to this list of novel T2DM risk loci in Arab population.…”

Section: Aif1 Prrc2a Apom Bag6 C6orf47 Csnk2b Gpank1 Ly6g5b Lmentioning

confidence: 99%

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

Hebbar

Abu‐Farha

Alkayal

et al. 2020

Self Cite

Consanguineous populations of the Arabian Peninsula, which has seen an uncontrolled rise in type 2 diabetes incidence, are underrepresented in global studies on diabetes genetics. We performed a genome-wide association study on the quantitative trait of fasting plasma glucose (FPG) in unrelated Arab individuals from Kuwait (discovery-cohort:n = 1,353; replication-cohort:n = 1,196). Genome-wide genotyping in discovery phase was performed for 632,375 markers from Illumina HumanOmniExpress Beadchip; and top-associating markers were replicated using candidate genotyping. Genetic models based on additive and recessive transmission modes were used in statistical tests for associations in discovery phase, replication phase, and meta-analysis that combines data from both the phases. A genome-wide significant association with high FPG was found at rs1002487 (RPS6KA1) (p-discovery = 1.64E-08, p-replication = 3.71E-04, p-combined = 5.72E-11; β-discovery = 8.315; β-replication = 3.442; β-combined = 6.551). Further, three suggestive associations (p-values < 8.2E-06) with high FPG were observed at rs487321 (CADPS), rs707927 (VARS and 2Kb upstream of VWA7), and rs12600570 (DHX58); the first two markers reached genome-wide significance in the combined analysis (p-combined = 1.83E-12 and 3.07E-09, respectively). Significant interactions of diabetes traits (serum triglycerides, FPG, and glycated hemoglobin) with homeostatic model assessment of insulin resistance were identified for genotypes heterozygous or homozygous for the risk allele. Literature reports support the involvement of these gene loci in type 2 diabetes etiology. A large number of genome-wide association studies have been conducted in various populations (mostly on Europeans, Americans, and East Asians), resulting in the identification of more than 100 loci conferring susceptibility to type 2 diabetes mellitus 1-4. Meta-analysis and genotype imputations from diverse ethnic populations help identify novel markers and causal loci. However, despite the observed high prevalence of type 2 diabetes in Arab countries 5,6 , their populations were not included in global studies. The Arabian Peninsula is at the nexus of Africa, Europe, and Asia; and has been assumed to be an early human migration route out of Africa. Consanguineous marriage (especially among first or second cousins) is an established practice among the Arabian Peninsula population. Consanguinity results in increased homozygosity, and accumulation of deleterious recessive alleles in the gene pool, creating the potential for certain variants to become