title: 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 (β = 1.02 per risk allele, P = 7.3 × 10(-4)), maximum BMI z-score in childhood (β = 0.079, P = 0.03) and % body fat in adulthood (β = 3.4%, P = 3 × 10(-7)). The adiposity-increasing allele correlated with lower PFKFB2 adipose expression (β = 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 (β = 0.87, P = 0.03). The same allele was also associated with lower insulin secretion assessed by acute insulin response (β = 0.78, P = 0.03) and 30-min plasma insulin concentrations (β = 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.
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Yunhua L
authors: YL
authors: Muller
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Paolo
authors: P
authors: Piaggi
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Robert L
authors: RL
authors: Hanson
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Sayuko
authors: S
authors: Kobes
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Shujera
authors: S
authors: Bhutta
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Maryam
authors: M
authors: Abdussamad
authors: Department of Internal Medicine and Computational Medicine, University of Michigan, Ann Arbor, MI, USA.
authors: Tennille
authors: T
authors: Leak-Johnson
authors: Department of Internal Medicine and Computational Medicine, University of Michigan, Ann Arbor, MI, USA.
authors: Matthias
authors: M
authors: Kretzler
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Ke
authors: K
authors: Huang
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: E Jennifer
authors: EJ
authors: Weil
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Robert G
authors: RG
authors: Nelson
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: William C
authors: WC
authors: Knowler
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and.
authors: Clifton
authors: C
authors: Bogardus
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, AZ, USA and lbaier@phx.niddk.nih.gov.
authors: Leslie J
authors: LJ
authors: Baier
mesh_terms: D000273:Adipose Tissue; D050154:Adiposity / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007668:Kidney; D008297:Male; D008875:Middle Aged; D025481:Phosphofructokinase-2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D055815:Young Adult
chemical_list: D007328:Insulin; C555744:PFKFB2 protein, human; D025481:Phosphofructokinase-2