The effects of the renin-angiotensin-aldosterone system gene polymorphisms on insulin resistance in hypertensive families.

Introduction: The hereditability of insulin resistance has been demonstrated in both familial and twin studies. The effects of renin-angiotensin-aldosterone system gene polymorphisms on insulin resistance remain inconclusive.

Methods: This is a sibling-based association study. Polymorphisms of renin-angiotensin-aldosterone system genes were examined in 1113 hypertension and 676 normotension siblings from Chinese and Japanese hypertensive families. The generalized estimation equations method was used to compare the differences in metabolic variables between hypertension and normotensive siblings.

Results: For the G-6A polymorphism of AGT, GG siblings had lower 2-h insulin than siblings carrying the A allele (p=0.006). Siblings with different variants of the angiotensin II type 1 receptor A1166C had no difference in metabolic variables. Siblings carrying the D allele of the angiotensin converting enzyme gene had higher levels of fasting glucose, fasting insulin, area under the curve of insulin levels and the homeostasis model assessment of insulin resistance than II siblings (all p<0.05). Lower levels of fasting glucose and 2-h glucose were observed in siblings with the T allele than their CC homozygotes for the C-344T polymorphism of CYP11B2 (p<0.05). Siblings carrying three high-risk genotypes of the angiotensin converting enzyme, angiotensinogen and CYP11B2 had higher fasting glucose level than siblings carrying no high-risk genotypes (p=0.011).

Conclusion: Our comprehensive analysis of renin-angiotensin-aldosterone system gene polymorphisms demonstrates that the angiotensin converting enzyme and CYP11B2 gene polymorphisms are associated with insulin resistance in hypertensive families.