Genetic risk variants for metabolic traits in Arab populations.
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ABSTRACT:
SUBMITTER: Hebbar P
PROVIDER: S-EPMC5247683 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
Genetic risk variants for metabolic traits in Arab populations.
Hebbar Prashantha P Elkum Naser N Alkayal Fadi F John Sumi Elsa SE Thanaraj Thangavel Alphonse TA Alsmadi Osama O
Scientific reports 20170120
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 ...[more]
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Project description: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, PPAR?, 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.
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Project description:The Arabian Peninsula, located at the nexus of Africa, Europe, and Asia, was implicated in early human migration. The Arab population is characterized by consanguinity and endogamy leading to inbreeding. Global genome-wide association (GWA) studies on metabolic traits under-represent the Arab population. Replicability of GWA-identified association signals in the Arab population has not been satisfactorily explored. It is important to assess how well GWA-identified findings generalize if their clinical interpretations are to benefit the target population. Our recent study from Kuwait, which performed genome-wide imputation and meta-analysis, observed 304 (from 151 genes) of the 4746 GWA-identified metabolic risk variants replicable in the Arab population. A recent large GWA study from Qatar found replication of 30 GWA-identified lipid risk variants. These complementing studies from the Peninsula increase the confidence in generalizing metabolic risk loci to the Arab population. However, both the studies reported a low extent of transferability. In this review, we examine the observed low transferability in the context of differences in environment, genetic correlations (allele frequencies, linkage disequilibrium, effect sizes, and heritability), and phenotype variance. We emphasize the need for large-scale GWA studies on deeply phenotyped cohorts of at least 20,000 Arab individuals. The review further presents GWA-identified metabolic risk variants generalizable to the Arab population.
| S-EPMC8535608 | biostudies-literature
Project description:Background: The metabolic syndrome (MetS) is prevalent in Arabian populations. Several small-scale studies have been performed to investigate the genetic basis of MetS. This systematic review and meta-analysis aimed to examine whether candidate gene polymorphisms are associated with MetS susceptibility among ethnic groups of the Arabian world and to suggest possible directions for future research regarding genetic markers and MetS. Methods: A search was conducted for peer-reviewed articles that examined the genetic association of MetS in Arabian populations in the following databases: Medline, Embase, Scopus, Direct Science, Web of Science, ProQuest, and Google Scholar until March 31, 2021. Articles were eligible if they were case-control studies, which investigated MetS as a dichotomous outcome (MetS vs no MetS). To assess the quality of the studies, the Q-Genie tool (Quality of Genetic Association Studies) was used. A non-central chi2 (random-effect) distribution was used to determine the heterogeneity (H) of Q and I (Galassi et al., The American journal of medicine, 2006, 119, 812-819) statistics. Results: Our search strategy identified 36 studies that met our inclusion criteria. In most cases, studies were excluded due to a lack of statistical information such as odds ratios, confidence intervals, and p-values. According to the Q-Genie tool, 12 studies scored poorly (a score of≤35), 13 studies scored moderately ( >35 and≤45), and 12 studies had good quality ( >45 or higher). The most frequently studied genes were FTO and VDR (both included in four studies). Three SNPs indicated increased risk for MetS after calculating the pooled odds ratios: FTO-rs9939609 (odds ratio 1.49, 95% CI: 0.96-2.32); LEP-rs7799039 (odds ratio 1.85, 95% CI: 1.37-2.5); and SERPINA12-rs2236242 (odds ratio 1.65, 95% CI: 1.21-2.24). Meta-analysis studies showed no significant heterogeneity. Conclusion: There were many sources of heterogeneity in the study settings. Most of the studies had low to moderate quality because of sample size and power issues, not considering all potential sources of bias, and not providing details about genotyping methods and results. As most studies were small-scale, aimed to replicate findings from other populations, we did not find any unique genetic association between MetS and Arabian populations.
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Project description:CYP2D6 is a key drug-metabolizing enzyme implicated in the biotransformation of approximately 25% of currently prescribed drugs. Interindividual and interethnic differences in CYP2D6 enzymatic activity, and hence variability in substrate drug efficacy and safety, are attributed to a highly polymorphic corresponding gene. This study aims at reviewing the frequencies of the most clinically relevant CYP2D6 alleles in the Arabs countries. Articles published before May 2021 that reported CYP2D6 genotype and allelic frequencies in the Arab populations of the Middle East and North Africa (MENA) region were retrieved from PubMed and Google Scholar databases. This review included 15 original articles encompassing 2737 individuals from 11 countries of the 22 members of the League of Arab States. Active CYP2D6 gene duplications reached the highest frequencies of 28.3% and 10.4% in Algeria and Saudi Arabia, respectively, and lowest in Egypt (2.41%) and Palestine (4.9%). Frequencies of the loss-of-function allele CYP2D6*4 ranged from 3.5% in Saudi Arabia to 18.8% in Egypt. The disparity in frequencies of the reduced-function CYP2D6*10 allele was perceptible, with the highest frequency reported in Jordan (14.8%) and the lowest in neighboring Palestine (2%), and in Algeria (0%). The reduced-function allele CYP2D6*41 was more prevalent in the Arabian Peninsula countries; Saudi Arabia (18.4%) and the United Arab Emirates (15.2%), in comparison with the Northern Arab-Levantine Syria (9.7%) and Algeria (8.3%). Our study demonstrates heterogeneity of CYP2D6 alleles among Arab populations. The incongruities of the frequencies of alleles in neighboring countries with similar demographic composition emphasize the necessity for harmonizing criteria of genotype assignment and conducting comprehensive studies on larger MENA Arab populations to determine their CYP2D6 allelic makeup and improve therapeutic outcomes of CYP2D6- metabolized drugs.
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Project description:Background: The polymorphisms of the C-C chemokine receptor type 5 (CCR5) and the insulin receptor substrate 1 (IRS1) have been studied as candidates for the susceptibility to develop type 2 diabetes mellitus (T2DM). CCR5 is a chemokine receptor, and the polymorphisms in the promoter region of this receptor are being studied as candidates for the susceptibility to develop T2DM. Also, IRS1 is a critical factor in the signaling pathway for insulin, and mutations in this gene have been reported, which contribute to the ability to develop T2DM. The aim of the current study was to determine the relationship between CCR5 (59029A/G) and IRS1 (rs10498210) polymorphisms with T2DM in Sanandajian patients. Methods: Genomic DNA was isolated from 200 healthy individuals and 220 Kurdish T2DM patients by salt extraction method and the polymorphisms were examined by restriction fragment length polymorphism (RFLP) method and then the results were analyzed using Chi-square test. Results: The frequency of AA genotype in 220 Kurdish patients for both genes CCR5 (OR=1.9, P=0.02) and IRS1 (OR [95% CI]=2.62, P=0.02) were significantly more than controls. There was no significant association between AG or GG genotypes in with T2DM. Conclusion: The presence of AA homozygote alleles in both loci of IRS1 (rs10498210) and CCR5 (59029A/G) genes increased the risk of T2DM.
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Project description:BackgroundThere is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are concerns that the predictive power of GRS will be limited in non-European ancestry populations. GRS for cardiometabolic traits were evaluated in sub-Saharan Africans in comparison with African Americans and European Americans.MethodsWe evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF; n = 5200), African Americans (AA; n = 9139) and European Americans (EUR; n = 9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and the increase in discriminatory ability over traditional risk factors [age, sex and body mass index (BMI)], with adjustment for ancestry-derived principal components.ResultsAcross all traits, GRS showed up to a 5-fold and 20-fold greater predictive utility in EUR relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percentage increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EUR, 26.6% to 65.8% among AA and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EUR relative to AA and up to 44-fold greater in EUR relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EUR.ConclusionsThis work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiple ethnic populations in genomic studies to ensure equitable clinical translation of GRS.
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Project description:Genome-wide association studies are providing new insights into the genetic basis of metabolic and cardiovascular traits. In the past 3 years, common variants in approximately 50 loci have been strongly associated with metabolic and cardiovascular traits. Several of these loci have implicated genes without a previously known connection with metabolism. Further studies will be required to characterize the full impact of these loci on metabolism. Many of the identified loci include multiple independent variants that influence the same metabolic or cardiovascular trait and a few loci harbor independent variants that each influence distinct traits. The total proportion of trait heritability explained by variants identified so far is still modest (typically <10%). Future studies will build on these successes by identifying additional common and rare variants and by determining the functional impact of the underlying alleles and genes.
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Project description:BackgroundGenetic variants may predispose humans to elevated risk of common metabolic morbidities such as obesity and Type 2 Diabetes (T2D). Some of these variants have also been shown to influence elite athletic performance and the response to exercise training. We compared the genotype distribution of five genetic Single Nucleotide Polymorphisms (SNPs) known to be associated with obesity and obesity co-morbidities (IGF2BP2 rs4402960, LPL rs320, LPL rs328, KCJN rs5219, and MTHFR rs1801133) between athletes (all male, n = 461; endurance athletes n = 254, sprint/power athletes n = 207), and controls (all male, n = 544) in Polish and Russian samples. We also examined the association between these SNPs and the athletes' competition level ('elite' and 'national' level). Genotypes were analysed by Single-Base Extension and Real-Time PCR. Multinomial logistic regression analyses were conducted to assess the association between genotypes and athletic status/competition level.ResultsIGF2BP2 rs4402960 and LPL rs320 were significantly associated with athletic status; sprint/power athletes were twice more likely to have the IGF2BP2 rs4402960 risk (T) allele compared to endurance athletes (OR = 2.11, 95% CI = 1.03-4.30, P <0.041), and non-athletic controls were significantly less likely to have the T allele compared to sprint/power athletes (OR = 0.62, 95% CI =0.43-0.89, P <0.0009). The control group was significantly more likely to have the LPL rs320 risk (G) allele compared to endurance athletes (OR = 1.26, 95% CI = 1.05-1.52, P <0.013). Hence, endurance athletes were the "protected" group being significantly (p < 0.05) less likely to have the risk allele compared to sprint/power athletes (IGF2BP2 rs4402960) and significantly (p < 0.05) less likely to have the risk allele compared to controls (LPL rs320). The other 3 SNPs did not show significant differences between the study groups.ConclusionsMale endurance athletes are less likely to have the metabolic risk alleles of IGF2BP2 rs4402960 and LPL rs320, compared to sprint/power athletes and controls, respectively. These results suggest that some SNPs across the human genome have a dual effect and may predispose endurance athletes to reduced risk of developing metabolic morbidities, whereas sprint/power athletes might be predisposed to elevated risk.
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Project description:This is the first genetic anthropology study on Arabs in MENA (Middle East and North Africa) region. The present meta-analysis included 100 populations from 36 Arab and non-Arab communities, comprising 16,006 individuals, and evaluates the genetic profile of Arabs using HLA class I (A, B) and class II (DRB1, DQB1) genes. A total of 56 Arab populations comprising 10,283 individuals were selected from several databases, and were compared with 44 Mediterranean, Asian, and sub-Saharan populations. The most frequent alleles in Arabs are A*01, A*02, B*35, B*51, DRB1*03:01, DRB1*07:01, DQB1*02:01, and DQB1*03:01, while DRB1*03:01-DQB1*02:01 and DRB1*07:01-DQB1*02:02 are the most frequent class II haplotypes. Dendrograms, correspondence analyses, genetic distances, and haplotype analysis indicate that Arabs could be stratified into four groups. The first consists of North Africans (Algerians, Tunisians, Moroccans, and Libyans), and the first Arabian Peninsula cluster (Saudis, Kuwaitis, and Yemenis), who appear to be related to Western Mediterraneans, including Iberians; this might be explained for a massive migration into these areas when Sahara underwent a relatively rapid desiccation, starting about 10,000 years BC. The second includes Levantine Arabs (Palestinians, Jordanians, Lebanese, and Syrians), along with Iraqi and Egyptians, who are related to Eastern Mediterraneans. The third comprises Sudanese and Comorians, who tend to cluster with Sub-Saharans. The fourth comprises the second Arabian Peninsula cluster, made up of Omanis, Emiratis, and Bahrainis. It is noteworthy that the two large minorities (Berbers and Kurds) are indigenous (autochthonous), and are not genetically different from "host" and neighboring populations. In conclusion, this study confirmed high genetic heterogeneity among present-day Arabs, and especially those of the Arabian Peninsula.
| S-EPMC5844529 | biostudies-literature
Project description:Abstract PCOS confers an increased risk for obesity-related comorbidities. It has been challenging to identify precise risk genes associated with the pathogenesis of PCOS. A novel variant located within MYO10 intron 2 (rs9312937) was identified in a PCOS GWAS in the genetically isolated Finnish and related Estonian populations. We identified PCOS risk variants at the MYO10 locus in additional PCOS populations. We hypothesized that PCOS risk variants at the locus were associated with metabolic traits. Women from Iceland (n=1347) and Boston (n=591) were diagnosed with PCOS using the Rotterdam criteria and NIH criteria, respectively, with a non-overlapping replication cohort (n=586) identified using an algorithm incorporating ICD codes and natural language processing. Controls included population controls from Iceland (effective n=1200), well-phenotyped controls from Boston (n=441) and a cohort with no PCOS diagnoses or features in the electronic medical record (EMR; n=749). We performed an association study to identify variants in the MYO10 locus associated with PCOS. We also examined the association of variants in MYO10 and 15 independent phenotypic traits in women of European ethnicity from the Boston PCOS cohort. Data were log-normalized and analyzed using linear regression, then corrected for the false discovery rate using the Benjamini-Hochberg procedure. Two novel risk variants for PCOS were identified within intron 2 of MYO10, rs31506-T (p = 1.6×10-05, OR 0.83 [95% CI 0.77-0.91]) and rs253336-A (p = 2.4×10-06, 0.82 [0.75-0.89]). The rs31506 variant is in moderate linkage disequilibrium with the novel variant rs9312937 (r2 ≥ 0.4) and rs253336 (r2 ≥ 0.4). The variant rs31506 maps to enhancer sites in pancreas, osteoblast and fetal adrenal cells, whereas rs253336 maps to methylation sites in adipose stem cells and ovary (pubs.broadinstitute.org/mammals/haploreg). Neither variant had eQTLs, and expression was highest in lung, thyroid, neurons, breast and ovary (gtexportal.org). Among cases and controls, the variant rs253336 was associated with BMI (β=0.015±0.0057; p=0.01), waist circumference (β=0.011±0.0047; p=0.02), hip circumference β=0.010±0.0035; p=0.003) and triglycerides (β=0.028±0.013; p=0.03). The variant rs31506 was also associated with BMI (β=0.0065±0.0027; p=0.02), waist circumference (β=0.0051±0.0022; p=0.02), hip circumference (β=0.0039±0.0017; p=0.02), HDL (β=-0.0083±0.0037; p=0.02) and triglycerides (β=0.018±0.0063; p=0.003). The association between rs253336 and hip circumference, and rs31506 and triglyceride levels remained significant after correction. There was no association between the variants and BMI in the subjects identified through the EMR. We identified two novel risk variants for PCOS in intron 2 of MYO10 (rs31506 and rs253336), a gene recently implicated within a risk locus for PCOS. We also demonstrated that the variants are associated with hip circumference and triglyceride levels. Previous data demonstrate increased expression of MYO10 in omental adipose of obese type 2 diabetics and an association with lean body mass. The data suggest a potential role for MYO10 in the metabolic etiology of PCOS. Presentation: Sunday, June 12, 2022 11:00 a.m. - 12:30 p.m.
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