PROX1 gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease

Abstract

Background:The prevalence of diabetic nephropathy varies according to ethnicity. Environmental as well as genetic factors contribute to the heterogeneity in the presentation of diabetic nephropathy. Our objective was to evaluate this heterogeneity within the Caucasian population.Methods:The geo-ethnic origin of the 3409 genotyped Caucasian type 2 diabetes (T2D) patients of Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation was determined using principal component analysis. Genome-wide association studies analyses of age of onset of T2D were performed for geo-ethnic groups separately and combined.Results:The first principal component separated the Caucasian study participants into Slavic and Celtic ethnic origins. Age of onset of diabetes was significantly lower in Slavic patients (P = 7.3 × 10−20), whereas the prevalence of hypertension (P = 4.9 × 10−31) and albuminuria (5.1 × 10−9) were significantly higher. Age of onset of T2D and albuminuria appear to have an important genetic component as the values of these traits were also different between Slavic and Celtic individuals living in the same countries. Common and geo-ethnic-specific loci were found to be associated to age of onset of diabetes. Among the latter, the PROX1/PROX1-AS1 genes (rs340841) had the highest impact. Single-nucleotide polymorphism rs340841 CC genotype was associated with a 4.4 year earlier onset of T2D in Slavic patients living or not in countries with predominant Slavic populations.Conclusion:These results reveal the presence of distinct genetic architectures between Caucasian ethnic groups that likely have clinical relevance, among them PROX1 gene is a strong candidate of early onset of diabetes with variations depending on ethnicity.

Lymphatic Vasculature in Energy Homeostasis and Obesity

“…Overexpression of Prox1 in immature β-cells promotes acute hyperglycemia (Paul et al, 2016). Consistent with these reports single-nucleotide polymorphisms in PROX1 are associated with higher fasting glucose levels and type 2 diabetes mellitus (Lecompte et al, 2013;Kretowski et al, 2015;Hamet et al, 2017;Adamska-Patruno et al, 2019). Furthermore, hyperinsulinemia is observed in obese Prox1 +/− mice (Harvey et al, 2005).…”

Genetic Susceptibility to Gestational Diabetes Mellitus in a Chinese Population

“…And PROX1 has been shown to be associated with diabetes and its complications in a number of studies (43,44). Recently, a GWA study revealed that PROX1 rs340841 is a strong susceptibility locus of early onset of diabetes with variations depending on ethnicity (45). Here, we present evidence that PROX1 rs340841 conferred an increased GDM risk in a Chinese population.…”

Case-control studies of gene-environment interactions. When a case might not be the case

“…SNP rs7656500 (uLR and pMLE-DX ) locates at the intergenic region between KIAA0922 and TLR2 at Chromosome 4, and is 163k upstream and 144k downstream of rs727153 and rs1466662, respectively, which were reported associated with Alzheimer’s disease in two studies [ 12 , 13 ]. It is also 54k upstream of rs7654093 associated with thrombosis [ 14 ], 30k upstream of rs7659024 associated with Venous thromboembolism [ 15 ], 34k upstream of rs2066865 associated with Venous thromboembolism [ 16 , 17 ], 52k upstream of rs6536024 associated with Venous thromboembolism [ 18 ], and 360k downstream of rs11099942 associated with Type 2 diabetes [ 19 ].…”