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

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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.

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Abbreviations

AUC :

Area under the curve

BMI :

Body mass index

HOMA-B% :

Homeostasis model assessment of percent β-cell function

HOMA IR :

Homeostasis model assessment of insulin resistance

ISI :

Insulin sensitivity index

OGTT :

Oral glucose tolerance test

PC-1 :

Plasma cell-1 glycoprotein

PPAR :

Peroxisome proliferator activated receptor

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Acknowledgements

This research was supported by Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica (MIUR, COFIN 2000, LF) and by Ministero della Salute (Ricerca corrente 2001 and 2002, VT).

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Authors and Affiliations

  1. Department of Internal and Specialist Medicine, University of Catania, Garibaldi Hospital, P.zza S. M. di Gesù, 95123, Catania, Italy

    R. Baratta, D. Spampinato, R. Vigneri & L. Frittitta

  2. Unit of Endocrinology, Scientific Institute CSS, San Giovanni Rotondo, Italy

    R. Di Paola, G. Fini, A. Marucci, A. Coco & V. Trischitta

  3. Department of Clinical Sciences, University La Sapienza, Rome, Italy

    V. Trischitta

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  1. R. Baratta
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  2. R. Di Paola
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  3. D. Spampinato
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  4. G. Fini
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  5. A. Marucci
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  6. A. Coco
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  7. R. Vigneri
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  8. L. Frittitta
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  9. V. Trischitta
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Correspondence to R. Baratta.

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Baratta, R., Di Paola, R., Spampinato, D. et al. Evidence for genetic epistasis in human insulin resistance: the combined effect of PC-1 (K121Q) and PPARγ2 (P12A) polymorphisms. J Mol Med 81, 718–723 (2003). https://doi.org/10.1007/s00109-003-0466-3

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  • DOI: https://doi.org/10.1007/s00109-003-0466-3

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