Evidence for genetic epistasis in human insulin resistance: The combined effect of PC-1 (K121Q) and PPARγ2 (P12A) polymorphisms

R. Baratta, R. Di Paola, D. Spampinato, G. Fini, A. Marucci, A. Coco, R. Vigneri, L. Frittitta, V. Trischitta

Research output: Contribution to journalArticle

Abstract

Insulin resistance is believed to be under the control of several genes often interacting each other. However, whether genetic epistasis does in fact modulate human insulin sensitivity is unknown. In 338 healthy unrelated subjects from Sicily, all nondiabetic and not morbidly obese, we investigated whether two gene polymorphisms previously associated with insulin resistance (namely PC-1 K121Q and PPARγ2 P12A) affect insulin sensitivity by interacting. PC-1 X121Q subjects showed higher level of fasting glucose, lower insulin sensitivity (by both the Matsuda insulin sensitivity index and M values at clamp, the latter performed in a subgroup of 113 subjects representative of the overall cohort) and higher insulin levels during the oral glucose tolerance test (OGTT) than PC-1 K121K subjects. In contrast, no difference in any of the measured variables was observed between PPARγ2 P12P and X12A individuals. The deleterious effect of the PC-1 X121Q genotype on each of these three variables was significant and entirely dependent upon the coexistence of the PPARγ2 P12P genotype. Among PPARγ2 P12P carriers also fasting insulin and glucose levels during OGTT were higher in PC-1 X121Q than in K121K individuals. In contrast, no deleterious effect of the PC-1 X121Q genotype was observed among PPARγ2 X12A carriers; rather, in these subjects a lower body mass index and consequently lower fasting insulin level was observed in PC-1 X121Q than in K121K carriers. Overall, a significant interaction between the two genes was observed on body mass index, insulin levels (both fasting and after OGTT) and both insulin sensitivity (i.e., insulin sensitivity index and M value) and insulin secretion (i.e., HOMA-B%) indexes.

Original languageEnglish
Pages (from-to)718-723
Number of pages6
JournalJournal of Molecular Medicine
Volume81
Issue number11
DOIs
Publication statusPublished - Nov 2003

Keywords

  • Gene-gene interaction
  • Genetic epistasis
  • Insulin resistance
  • Peroxisome proliferator activated receptor γ2
  • Plasma cell 1 glycoprotein

ASJC Scopus subject areas

  • Medicine(all)

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