Phosphatidylinositol 3-kinase p85α regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population

Abstract

Aims/hypothesis Phosphatidylinositol 3-kinase (PI3K) couples the leptin and insulin signalling pathways via the insulin receptor substrates IRS1 and IRS2. Hence, defective activation of PI3K could be a novel mechanism of peripheral leptin or insulin resistance. We investigated associations of tagging single-nucleotide polymorphisms (tSNPs) in the PI3K p85α regulatory subunit gene PIK3R1 with anthropometry, leptin, body fat and insulin sensitivity in a female twin population of European extraction. Materials and methods Eight tSNPs were genotyped in 2,778 women (mean age 47.4±12.5 years) from the St Thomas' UK Adult Twin Registry (Twins UK). Results SNP rs1550805 was associated with serum leptin (p=0.028), BMI (p=0.025), weight (p=0.019), total fat (p=0.004), total fat percentage (p=0.002), waist circumference (p=0.025), central fat (p=0.005) and central fat percentage (p=0.005). SNPs rs7713645 and rs7709243 were associated with BMI (p=0.020 and p=0.029, respectively), rs7709243 with weight, total and central fat (p=0.026, p=0.031 and p=0.023, respectively) and both SNPs with fasting glucose (p=0.003 and p=0.001, respectively) and glucose 2-h post OGTT (p=0.023 and p=0.007, respectively). Subjects with haplotype 222 (frequency 7.2%) showed higher serum leptin concentration (p=0.007) and body fat measures (p≤0.001 for all), and those with haplotype 221 (frequency 38.7%) showed higher fasting and 2-h glucose (p=0.035 and p=0.021, respectively) compared with subjects with the most common haplotype, 111 (frequency 45.5%). Conclusions/interpretation Association of the PIK3R1 SNP rs1550805 with serum leptin and body fat may reflect a diminished ability of PI3K to signal via IRS1 or IRS2 in response to leptin.

Association between Phosphatidylinositol 3-Kinase Regulatory Subunit p85α Met326Ile Genetic Polymorphism and Colon Cancer Risk

“…Others have attempted to evaluate gene-wide association with insulin resistance -related phenotypes or biomarkers using selected sets of tagging single nucleotide polymorphisms, and reported inconsistent results (21 -24). In a large female twin study of eight selected tagging single nucleotide polymorphisms, Jamshidi et al found associations between other single nucleotide polymorphisms in PIK3R1 with serum leptin levels, body fat, and other measures of insulin resistance, but reported no association for the Met326Ile variant (21). An earlier Danish study of 380 young healthy subjects reported a significant association of this variant with insulin sensitivity (22), but the same research group failed to replicate that association in a subsequent study (23).…”

Expression profiling based on coexpressed modules in obese prepubertal children

“…Hence, defective activation of PI3K could be a novel mechanism of peripheral leptin or IR. The association of the PI3KR1 SNPrs1550805 with serum leptin and body fat may reflect a diminished capability of PI3K to signal via IRS-1 or IRS-2 in response to leptin (Jamshidi et al, 2006).…”

The Role of Single Nucleotide Polymorphisms of Untranslated Regions (Utrs) in Insulin Resistance Pathogenesis in Patients with Type 2 Diabetes

“…Described in present study results provide the first evidence for association of SNPs in UTRs of INSR and PIKR1 genes with genes expression rates. So far, all investigated in these genes SNPs were localized mainly in coding regions (Kusari et al, 1991;Baynes et al, 2000;Almind et al, 2002;Jamshidi et al, 2006;Højlund et al, 2006). Presented results stand for the first report where evaluation of SNPs in UTRs of INSR and PIK3R1 genes with gene expression levels was performed in peripheral lymphocytes and adipose tissues.…”