European genetic variants associated with type 2 diabetes in North African Arabs

Cauchi, Stéphane; Ezzidi, Intissar; Achhab, Youness El; Mtiraoui, Nabil; Chaieb, L.; Salah, D. Ben; Nejjari, Chakib; Labrune, Yann; Yengo, Loïc; Beury, Delphine; Vaxillaire, Martine; Mahjoub, Touhami; Chikri, Mohamed; Froguel, Philippe

doi:10.1016/j.diabet.2012.02.003

Cited by 58 publications

(53 citation statements)

References 31 publications

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“…The CDKN2A/B locus, at chromosome 9p21, influences diabetes risk across varied ethnicities and geography [1–3], including people of European [4–9], Asian [10–24], Indian [25], Pakistani [26], Mexican [27–29] and Arab [30–32] descent. CDKN2A/B polymorphisms impact risk of gestational diabetes [33–35], early progression to type 2 diabetes after gestational diabetes [36], post-transplant diabetes [37, 38] and cystic fibrosis-related diabetes [39].…”

Section: The Cdkn2a/b Locus Impacts Human Diabetes Riskmentioning

confidence: 99%

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

et al. 2016

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Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16INK4A to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16INK4A) and three other gene products, p14 alternate reading frame (p14ARF), p15INK4B and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.

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Section: The Cdkn2a/b Locus Impacts Human Diabetes Riskmentioning

confidence: 99%

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

et al. 2016

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“…Although few number of T2DM susceptibility genes discovered through candidate gene, linkage analyses, and GWA studies elsewhere have been replicated in African studies [16][17][18][19][20][21] , it must also be emphasized that many other association studies failed to show significant and replicable findings [22][23][24] . Therefore in this study we investigated three genes, namely, TCF7L2, FTO, and ENPP1 as risk factors for T2DM in a South African ethnic population group of Mixed-ancestry (Coloureds) with a unique genetic architecture.…”

Section: Introductionmentioning

confidence: 99%

Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa

et al. 2016

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Background: Transcription factor 7-like 2 gene (TCF7L2), fat mass and obesity-associated gene (FTO), and ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) are known risk loci for type 2 diabetes (T2DM) mostly in European populations. Objectives: To assess the association of these genes with T2DM risk in a South African mixed-ancestry population. Methods: Five hundred and sixty six participants were genotyped for ENPP1-rs997509 and -rs1044498, FTO-9941349 and -rs3751812, TCF7L2-rs12255372 and -rs7903146 polymorphisms using Taqman genotyping assays and validated by automated sequencing to assess the association of the polymorphisms with cardiometabolic traits. Results: In logistic regression models adjusted for age, sex, body mass index (BMI) and insulin resistance, minor allele of rs997509 was associated with a higher risk of prevalent T2DM under a recessive model [odd ratio 4.60 (95% confidence interval: 1.07 to 19.86); p = 0.040].Under additive model, the rs7903146 [1.43 (1.00 to 2.04); p= 0.053] and rs9941349 [1.43 (1.00 to 2.04); p = 0.052] minor alleles showed marginally significant associations with a high risk of T2DM. However, only the rs7903146 alleles (p=0.011) and genotypes (p=0.025) distributions were statistically significantly different between diabetic and non-diabetic individuals. Conclusion: Our findings demonstrate that ENPP1, TCF7L2, and FTO may predispose to T2DM in the mixed-ancestry population.

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“…Thirteen genetic variants associated with T2D risk were reported to be shared among North African Arabs from Tunisia and Morocco and European populations (Cauchi et al, 2012). Such evidence would suggest that black South Africans might also share significant common variant associations for T2D with other ethnicities.…”

Section: Discussionmentioning

confidence: 96%

“…A recent huge meta-analysis of GWAS studies of Europeans, Asians, and Mexicans indicated consistency of T2D risk alleles across these populations (Replication et al, 2014). The Europeans and North African Arabs were noted to have similar disease association patterns for 13 of the genetic variants associated with T2D (Cauchi et al, 2012).…”

Section: Introductionmentioning

confidence: 88%

Common Variants Associated with Type 2 Diabetes in a Black South African Population of Setswana Descent: African Populations Diverge

Chikowore

ConradieKarin

Towers

et al. 2015

OMICS: A Journal of Integrative Biology

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The increasing worldwide prevalence of type 2 diabetes mellitus (T2D) is a serious global health concern. Although T2D has a strong genetic etiology, limited knowledge exists about the common variants associated with it in the black South African population. This study set out to evaluate the association of previously reported common variants in other world populations with T2D susceptibility in a black South African population of Setswana descent. A case-control study design of 178 cases and 178 controls nested in the Prospective Urban Rural Epidemiology (PURE) study was conducted wherein we genotyped for 77 single nucleotide polymorphisms (SNPs). PLINK software was used to evaluate the standard genetic models of disease penetrance for the association of the common variants with impaired glucose tolerance (IGT) while adjusting for age, sex, and body mass index. Only rs1436955 significantly associated with an increase in T2D risk; three other variants, rs831571, rs8050136, and rs7542900, significantly associated with decreased risk of T2D. However, none of the four SNPs had significant associations after correcting for multiple testing (p<0.05). Although further studies are required to confirm these observations, the common variants associated with T2D risk among the Black South Africans of Setswana descent might likely be different than those in the Asian and European populations. This study supports the broader thesis that the genetic background of Africans is diverse and cannot be directly extrapolated using genetic variants from other ethnicities. Therefore there is a need to identify the population-specific variants linked with T2D in Africa.

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European genetic variants associated with type 2 diabetes in North African Arabs

Cited by 58 publications

References 31 publications

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

Islet biology, the CDKN2A/B locus and type 2 diabetes risk

Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa

Common Variants Associated with Type 2 Diabetes in a Black South African Population of Setswana Descent: African Populations Diverge

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