Publication Date:
2015-04-23
Description:
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 x 10 –4 ), maximum BMI z-score in childhood ( β = 0.079, P = 0.03) and % body fat in adulthood ( β = 3.4%, P = 3 x 10 –7 ). The adiposity-increasing allele correlated with lower PFKFB2 adipose expression ( β = 0.81, P = 9.4 x 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 x 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 x 10 –4 ). Variation in PFKFB2 appears to reduce PFKFB2 expression in adipose and kidney tissues, and thereby increase risk for adiposity and DN.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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