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A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians.

ABSTRACT: A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (rs17258746) associated with body mass index (BMI). PFKFB2 encodes 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase isoform 2, which plays a role in glucose metabolism. To follow-up on the GWAS, tag SNPs across PFKFB2 were genotyped in American Indians (AI) who had longitudinal data on BMI (n = 6839), type 2 diabetes (T2D; n = 7710), diabetic nephropathy (DN; n = 2452), % body fat (n = 555) and insulin secretion (n = 298). Two SNPs were further genotyped in urban AI to assess replication for DN (n = 864). PFKFB2 expression was measured in 201 adipose biopsies using real-time RT-PCR and 61 kidney biopsies using the Affymetrix U133 array. Two SNPs (rs17258746 and rs11120137), which capture the same signal, were associated with maximum BMI in adulthood (? = 1.02 per risk allele, P = 7.3 × 10(-4)), maximum BMI z-score in childhood (? = 0.079, P = 0.03) and % body fat in adulthood (? = 3.4%, P = 3 × 10(-7)). The adiposity-increasing allele correlated with lower PFKFB2 adipose expression (? = 0.81, P = 9.4 × 10(-4)). Lower expression of PFKFB2 further correlated with higher % body fat (r = -0.16, P = 0.02) and BMI (r = -0.17, P = 0.02). This allele was also associated with increased risk for DN in both cohorts of AI [odds ratio = 1.64 (1.32-2.02), P = 5.8 × 10(-6)], and similarly correlated with lower PFKFB2 expression in kidney glomeruli (? = 0.87, P = 0.03). The same allele was also associated with lower insulin secretion assessed by acute insulin response (? = 0.78, P = 0.03) and 30-min plasma insulin concentrations (? = 0.78, P = 1.1 × 10(-4)). Variation in PFKFB2 appears to reduce PFKFB2 expression in adipose and kidney tissues, and thereby increase risk for adiposity and DN.

SUBMITTER: Muller YL

PROVIDER: S-EPMC4416128 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians.

Muller Yunhua L YL Piaggi Paolo P Hanson Robert L RL Kobes Sayuko S Bhutta Shujera S Abdussamad Maryam M Leak-Johnson Tennille T Kretzler Matthias M Huang Ke K Weil E Jennifer EJ Nelson Robert G RG Knowler William C WC Bogardus Clifton C Baier Leslie J LJ

Human molecular genetics 20150206 10

A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (rs17258746) associated with body mass index (BMI). PFKFB2 encodes 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase isoform 2, which plays a role in glucose metabolism. To follow-up on the GWAS, tag SNPs across PFKFB2 were genotyped in American Indians (AI) who had longitudinal data on BMI (n = 6839), type 2 diabetes (T2D; n = 7710), diabetic nephropathy (DN; n = 2452), % body fat (n = 555) and in ...[more]

PMID: 25662186

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Project description:BackgroundDiabetes and its complications are more common in American Indians and Alaska Natives (AI/AN) than other US racial/ethnic populations. Prior reports of diabetic retinopathy (DR) prevalence in AI/AN are dated, and research on diabetic macular edema (DME) is limited. This study characterizes the recent prevalence of DR and DME in AI/AN using primary care-based teleophthalmology surveillance.MethodsThis is a multi-site, clinic-based, cross-sectional study of DR and DME. The sample is composed of AI /AN patients with diabetes (n = 53,998), served by the nationally distributed Indian Health Service-Joslin Vision Network Teleophthalmology Program (IHS-JVN) in primary care clinics of US Indian Health Service (IHS), Tribal, and Urban Indian health care facilities (I/T/U) from 1 November 2011 to 31 October 2016. Patients were recruited opportunistically for a retinal examination using the IHS-JVN during their regular diabetes care. The IHS-JVN used clinically validated, non-mydriatic, retinal imaging and retinopathy assessment protocols to identify the severity levels of non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), DME, and sight threatening retinopathy (STR; a composite measure). Key social-demographic (age, gender, IHS area), diabetes-related health (diabetes therapy, duration of diabetes, A1c), and imaging technology variables were examined. The analysis calculated frequencies and percentages of severity levels of disease.ResultsPrevalence of any NPDR, PDR, DME, and STR among AI/AN patients undergoing DR teleophthalmology surveillance by IHS-JVN was 17.7%, 2.3%, 2.3%, and 4.2%, respectively. Prevalence was lowest in Alaska and highest among patients with A1c >/ = 8%, duration of diabetes > 10 years, or using insulin.ConclusionsPrevalence of DR in this cohort was approximately half that in previous reports for AI/AN, and prevalence of DME was less than that reported in non-AI/AN populations. A similar reduction in diabetes related end-stage renal disease in the same population and time period has been reported by other researchers. Since these two diabetic complications share a common microvasculopathic mechanism, this coincident change in prevalence may also share a common basis, possibly related to improved diabetes management.

Project description:Validation of predicted gene expression of human mesangial cells after 24h Tacrolimus stimulus Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies. comparison of gene expression of human mesangial cells after 24h Tacrolimus vs. Ctrl; 4 independent experiments were conducted (4xTacrolimus 24h and 4x ctrl. 24h with Drug solvent (DMSO))

Dataset Information

A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians.

Publications

A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians.

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