Circulating amylin in human essential hypertension: heritability and earlyincrease in individuals at genetic risk

Background Human essential hypertension is a complex trait with poorly unde rstood genetic determination. Insulin resistance is frequently associated w ith this trait. Objective To determine whether a potentially pathogenic feature of the insu lin-resistant state, circulating amylin (islet amyloid polypeptide, co-rele ased with insulin from pancreatic islet beta -cells), is already increased in prehypertensive individuals (normotensive persons at genetic risk of hyp ertension because of family history), whether such individuals already diff er in their amylin response to beta -cell stimulation, and whether plasma a mylin concentration is heritable. Such features could establish increased c irculating amylin as a hereditary 'intermediate phenotype' useful in geneti c analyses of hypertension. Methods Plasma amylin and insulin were measured in 283 medication-free indi viduals stratified by blood pressure status (82 hypertensive and 201 normot ensive), and genetic risk (family history) of hypertension. Differences in means were tested by ANOVA, variances by F test and frequency distributions by maximum likelihood analysis. Co-release of amylin and insulin was provo ked by intravenous infusion of mixed amino acids. The effect of antihyperte nsive treatment was evaluated after monotherapy with either angiotensin con verting enzyme inhibition or calcium-channel blockade in hypertension. Results Plasma amylin was increased in hypertension (P = 0.027), and body m ass index was a strong predictor of increased circulating amylin (P = 0.000 1). Plasma amylin and plasma renin activity were not correlated (P = 0.395) , and effective antihypertensive monotherapy with either angiotensin conver ting enzyme inhibition or calcium-channel blockade did not affect either am ylin (P = 0.87-0.97) or insulin (P = 0.55-0.59). Among normotensive individ uals, those at genetic risk of hypertension (with positive family history) already had increased concentrations of amylin (P < 0.001), despite exhibit ing no difference in blood pressure or body mass index compared with the fa mily-history-negative group; however, among normotensive individuals, both family history (P = 0.043) and body mass index (P = 0.0059) were significan t predictors of increased concentrations of amylin. By maximum likelihood a nalysis, plasma amylin was distributed heterogeneously in the normotensive individuals, with two modes best explaining the distribution (<chi>(2) = 77 .4, P < 0.001), and family-history-positive individuals completely accounti ng for the upper mode (<chi>(2) = 4.63, P = 0.031). Family-history-positive normotensive individuals showed greater plasma amylin concentrations both before and during betad-cell stimulation by amino acid infusion (P = 0.014) . Black (n = 111) and white (n = 172) individuals did not differ in mean (P = 0.946) or variance (P = 0.172) of plasma amylin concentrations. Conclusions These results suggest that plasma amylin concentration is in pa rt determined by heredity. Both basal and stimulated plasma amylin excess m ay identify a subgroup of individuals bearing an inherited predisposition t o hypertension. Measurement of amylin might identify a useful 'intermediate phenotype' in the genetic analysis of essential hypertension and its relat ionship to insulin resistance. J Hypertens 18:1611-1620 (C) 2000 Lippincott Williams & Wilkins.