Evaluation of the PC-1 K121Q and G2906C variants as independent risk factors for ischaemic stroke

Summary

Overexpression of plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor tyrosine kinase activity and thus favours insulin resistance and atherosclerotic vascular disease. Recent findings indicate that the minor variant K121Q in the PC-1 gene confers an increased risk for early myocardial infarction independent of other established risk factors. We hypothesized that genetic variants in PC-1 may also influence the risk for cerebrovascular disease.

Aim

Therefore, we assessed the association of the PC-1 K121Q variant in the coding region and a polymorphism (G2906C) in the 3’ untranslated region of the PC-1 gene with the risk of stroke.

Patients

We analyzed 1014 patients with a history of ischaemic stroke from the Vienna stroke registry and 1001 control individuals without vascular disease.

Results, conclusion

Genotype frequencies of both genetic variants were similar in patients and controls in the total study population. By multivariate analysis, no interactions were observed between the PC-1 genotype and established vascular risk factors. However, the PC-1 2906C allele was significantly more frequent in patients who suffered from stroke before the age of 40 years. In these patients the risk for ischaemic stroke was increased fourfold.

Zusammenfassung

Vermehrte Expression von Plasma-Zellmembrane-Glykoprotein-1 (PC-1) hemmt die Tyrosinkinase-Aktivität des Insulinrezeptors und begünstigt dadurch die Entstehung von Insulinresistenz und atherosklerotischen Gefäßerkrankungen. Vor kurzem wurde gezeigt, dass die untergeordnete Variante K121Q im PC-1-Gen – unabhängig von anderen etablierten Risikofaktoren – ein erhöhtes Risiko für frühzeitigen Myokardinfarkt bewirkt.

Ziel

Wir vermuteten, dass genetische Varianten in PC-1 auch das Risiko für zerebrovaskuläre Erkrankungen beeinflussen könnten.

Patienten

Wir untersuchten die Assoziation der PC-1-K121Q-Variante in der kodierenden Region und die Rolle des Polymorphismus (G2906C) in der 3’-untranslatierten Region des PC-1-Gens mit dem Schlaganfallrisiko bei 1014 Patienten mit Vorgeschichte eines ischämischen Insults des Wiener Schlaganfall-Registers sowie bei 1001 Kontrollindividuen ohne vaskuläre Erkrankungen.

Ergebnisse, Schlussfolgerungen

Die Genotypfrequenzen beider Polymorphismen waren bei Patienten und Kontrollpersonen bezogen auf die gesamte Studienpopulation vergleichbar. Multivarianzanalysen zeigten keine Interaktionen zwischen PC-1-Genotyp und etablierten vaskulären Risikofaktoren. Allerdings beobachteten wir ein signifikant häufigeres Auftreten des 2906C-Allels bei Patienten, die bereits vor dem 40. Lebensjahr einen Schlaganfall erlitten hatten, verbunden mit einem vierfach erhöhten Schlaganfallrisiko.

Keywords

PC-1 - polymorphism - stroke - vascular disease - risk factor

Schlüsselwörter

PC-1 - Polymorphismus - Schlaganfall - vaskuläre Erkrankungen - Risikofaktoren

• References

• 1 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183-1197.
• 2 The Vienna Stroke Study Group. The Vienna Stroke Registry – objectives and methodology. Wien Klin Wochenschr 2001; 113: 141-147.
• 3 Di Paola R, Caporarello N, Marucci A. et al. ENPP1 affects insulin action and secretion: Evidences from in vitro studies. PLoS One 06: e19462.
• 4 Endler G, Mannhalter C, Sunder-Plassmann H. et al. The K121Q polymorphism in the plasma cell membrane glycoprotein 1 gene predisposes to early myocardial infarction. J Mol Med 2002; 80: 791-795.
• 5 Frittitta L, Ercolino T, Bozzali M. et al. A cluster of three single nucleotide polymorphisms in the 3’-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is associated with increased PC-1 protein content and insulin resistance-related abnormalities. Diabetes 2001; 50: 1952-1955.
• 6 Goldfine ID, Maddux BA, Youngren JF. et al. The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. Endocr Rev 2008; 29: 62-75.
• 7 Grupe A, Alleman J, Goldfine ID. et al. Inhibition of insulin receptor phosphorylation by PC-1 is not mediated by the hydrolysis of adenosine triphosphate or the generation of adenosine. J Biol Chem 1995; 270: 22085-22088.
• 8 Hassan A, Markus HS. Genetics and ischaemic stroke. Brain 2000; 123: 1784-1812.
• 9 Lalouschek W, Schillinger M, Hsieh K. et al. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke 2005; 36: 1405-1409.
• 10 Maddux BA, Goldfine ID. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Diabetes 2000; 49: 13-19.
• 11 Markus HS, Hambley H. Neurology and the blood: haematological abnormalities in ischaemic stroke. J Neurol Neurosurg Psychiatry 1998; 64: 150-159.
• 12 Prudente S, Morini E, Trischitta V. Insulin signaling regulating genes: effect on T2DM and cardiovascular risk. Nat Rev Endocrinol 2009; 05: 682-693.
• 13 Williams RR, Hunt SC, Heiss G. et al. Usefulness of cardiovascular family history data for populationbased preventive medicine and medical research (the Health Family Tree Study and the NHLBI Family Heart Study). Am J Cardiol 2001; 87: 129-135.