Abstract
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.
Highlights
Autosomal recessive mode of inheritance[11]
We explore the genome-wide genotypes from a cohort of Arab individuals from Kuwait for gene loci associated with 13 metabolic traits - namely height, weight, waist circumference (WC), waist circumference to height ratio (WcHtR), body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), triglyceride (TGL), high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), systolic blood pressure (SBP), and diastolic blood pressure (DBP)
We identified a total of 30 such SNPs which were involved in 33 associations with metabolic traits of height, weight, BMI, waist circumference (WC), waist circumference to height ratio (WcHtR), HbA1c, FPG, HDL, LDL, TGL, Total Cholesterol, and SBP (Table 4). of these associations were identified by models implementing additive mode of inheritance while 20 were identified by models implementing recessive mode of inheritance
Summary
Autosomal recessive mode of inheritance[11]. Consanguinity can exert an influence on the etiology of complex disorders if rare autosomal recessive alleles (as opposed to alleles that are common in the gene pool) are causally implicated[12]. We explore the genome-wide genotypes from a cohort of Arab individuals from Kuwait for gene loci associated with 13 metabolic traits - namely height, weight, waist circumference (WC), waist circumference to height ratio (WcHtR), body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), triglyceride (TGL), high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) For this purpose, we choose Cardio-MetaboChip genotyping array, which has successfully been employed for fine-mapping of established loci in populations such as Han Chinese[14] and Africans[15]. The results of this study that map disease alleles in the indigenous Arab population can provide important perspectives on the pathogenesis and diagnosis of metabolic trait associated diseases
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