A paired-sibling analysis of the Xbal polymorphism in the muscle glycogen synthase gene

Aims/hypothesis. We have previously shown an association between a XbaI pol ymorphism in the muscle glycogen synthase gene (GYS1) and both Type II (non -insulin-dependent) diabetes mellitus and hypertension. Association studies are, however, hampered by the selection of the control group. To circumven t these problems we addressed the same question using a novel genotype disc ordant paired-sibling approach. Methods. We identified 122 sex-matched sib-pairs discordant for the Xba1 po lymorphism among a new set of 743 Finnish subjects from 227 families with T ype II diabetes and paired analyses were done by McNemar test of symmetry a nd by permutation tests. Results. Paired analysis showed that siblings with the A2 variant had more hypertension (p = 0.0067), obesity (p = 0.033) and microalbuminuria (p = 0. 031) but not significantly more Type II diabetes (p = 0.27) than siblings w ith the A1 variant. Siblings with the A2 variant were more often treated by insulin (p = 0.050) or anti-hypertensive medication (p = 0.0060) or both. Diabetic A2 variant carriers had higher triglyceride (p = 0.023) and lower HDL cholesterol (p = 0.0059) concentrations and an earlier age at onset of diabetes (p = 0.022) than diabetic siblings with the A1 variant. In non-dia betic sib-pairs the presence of the A2 variant was associated with higher d iastolic (p = 0.0014) blood pressure. Finally, the allele frequency of the XbaI polymorphism differed between 216 randomly chosen unrelated Type II di abetic patients and 115 unrelated healthy control spouses without a family history of Type II diabetes (12.7 vs. 6.5%, p = 0.013). Conclusion/interpretation. The A2 allele of the XbaI polymorphism in the GY S1 confers an increased susceptibility to different features of the metabol ic syndrome and Type II diabetes.