The relationship between five widely-evaluated variants in CDKN2A/B and CDKAL1 genes and the risk of type 2 diabetes: A meta-analysis

Peng, Feng; Hu, Dan; Gu, Chaohao; Li, Xiaobo; Li, Yuqiong; Nan, Jun; Chu, Shaoli; Lin, Jinxiu; Niu, Wenquan

doi:10.1016/j.gene.2013.08.075

Cited by 30 publications

(19 citation statements)

References 53 publications

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“…Age influences the association between CDKN2A/B polymorphism rs10811661 and type 2 diabetes, consistent with the known interaction between age and p16 INK4A activity in islets [204]. The rs10811661 `T' (risk) allele is associated with reduced insulin secretion after both oral and intravenous glucose challenge [205, 206].…”

Section: Evidence That Human Cdkn2a/b-related Type 2 Diabetes Risk Inmentioning

confidence: 53%

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: Evidence That Human Cdkn2a/b-related Type 2 Diabetes Risk Inmentioning

confidence: 53%

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

et al. 2016

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“…GWAS studies have linked CDKAL1 with susceptibility to type 2 diabetes. [31] Although CDKAL1 is highly expressed in artery tissue (online supplementary table S3B), we did not detect differential expression in the blood of BAVM cases compared to controls. [29] Interestingly, CDKN2B–AS1 is a non-coding RNA located within the CDKN2A–CDKN2B gene cluster on 9p21, the strongest genetic locus for cardiovascular diseases and linked to intracranial aneurysm.…”

Section: Discussionmentioning

confidence: 87%

Genome-wide association study of sporadic brain arteriovenous malformations

Weinsheimer

Bendjilali

Nelson

et al. 2016

J Neurol Neurosurg Psychiatry

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Background-The pathogenesis of sporadic brain arteriovenous malformations (BAVM) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single-nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicenter Genetics of Arteriovenous Malformation (GEN-AVM) consortium.

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“…Based on stratified analyses, the CC genotype was significantly associated with T2D in overweight and obese women, as well as in men regardless of their BMI. Several studies have provided evidence for the significant contribution of CDKAL1 rs10946398 to T2D risk 13,14,16,22,23 . According to findings from a global meta-analysis, 8 studies have reported a trend of elevated ORs for the C risk allele, whereas only two studies have found no associations 14 .…”

Section: Discussionmentioning

confidence: 99%

“…Stratification of samples helps to clarify the role of BMI in modulating pancreatic beta-cell function possibly influenced by the rs10946398 variant. So far, such stratifications have not been widely considered in Asian populations 13 . Our study is limited in that we used a nonrandom or purposive sampling technique; hence, results may not be fully reflective of the general population.…”

Section: Discussionmentioning

confidence: 99%

Body mass index modulates the association between CDKAL1 rs10946398 variant and type 2 diabetes among Taiwanese women

Nfor

Lee

et al. 2018

Sci Rep

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CDKAL1 rs10946398 is a type 2 diabetes (T2D)-associated variant. It is a new body mass index (BMI)-associated variant in Asian populations. We investigated the association between rs10946398 and T2D among 9908 participants aged 30–70 years based on BMI: normal weight; 18.5 ≤ BMI < 24 kg/m2, overweight; 24 ≤ BMI < 27 kg/m2, and obesity; BMI ≥27 kg/m2. The CC genotype conferred a higher risk of T2D than the CA genotype. The odds ratios (ORs) were 1.83; 95% confidence interval (CI) 1.49–2.26 and 1.20; 95% CI 1.02–1.40, respectively. The C allele was the significant risk allele compared with A allele (OR = 1.32; 95% CI 1.19–1.47). For normal, overweight and obese participants with CC genotype, the ORs were respectively 1.69; 95% CI 1.02–2.81, 2.34; 95% CI 1.50–3.66, and 1.58; 95% CI 1.02–2.45 among men and 1.22; 95% CI 0.67–2.22, 2.42; 95% CI 1.30–4.52, and 2.3; 95% CI 1.19–4.50 among women. The C allele ORs were higher in obese and overweight women. In conclusion, the rs10946398 CC/CA genotypes, as well as the C allele increased the risk of T2D. The ORs were higher in women who were overweight and obese than in those with normal weight. Nonetheless, significant results were prominent only among those with CC genotype and C allele.

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The relationship between five widely-evaluated variants in CDKN2A/B and CDKAL1 genes and the risk of type 2 diabetes: A meta-analysis

Cited by 30 publications

References 53 publications

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

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

Genome-wide association study of sporadic brain arteriovenous malformations

Body mass index modulates the association between CDKAL1 rs10946398 variant and type 2 diabetes among Taiwanese women

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