Evidence for genetic epistasis in human insulin resistance:
the combined effect of PC-1 (K121Q) and PPARgamma2 (P12A)
polymorphisms.
Baratta R, Di Paola R, Spampinato D, Fini G, Marucci A, Coco
A, Vigneri R, Frittitta L, Trischitta V. Department of
Internal and Specialist Medicine, University of Catania,
Garibaldi Hospital, P.zza S. M. di Gesu, 95123 Catania,
Italy. [email hidden]
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
PPARgamma2 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 PPARgamma2 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 PPARgamma2 P12P genotype. Among
PPARgamma2 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 PPARgamma2 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. PMID:
14574455 [PubMed - in process]