Circulating amylin in human essential hypertension: heritability and early increase in individuals at genetic risk.
BACKGROUND
Human essential hypertension is a complex trait with poorly understood genetic determination. Insulin resistance is frequently associated with this trait.


OBJECTIVE
To determine whether a potentially pathogenic feature of the insulin-resistant state, circulating amylin (islet amyloid polypeptide, co-released with insulin from pancreatic islet beta-cells), is already increased in prehypertensive individuals (normotensive persons at genetic risk of hypertension because of family history), whether such individuals already differ in their amylin response to beta-cell stimulation, and whether plasma amylin concentration is heritable. Such features could establish increased circulating amylin as a hereditary 'intermediate phenotype' useful in genetic analyses of hypertension.


METHODS
Plasma amylin and insulin were measured in 283 medication-free individuals stratified by blood pressure status (82 hypertensive and 201 normotensive), 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 provoked by intravenous infusion of mixed amino acids. The effect of antihypertensive treatment was evaluated after monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade in hypertension.


RESULTS
Plasma amylin was increased in hypertension (P= 0.027), and body mass index was a strong predictor of increased circulating amylin (P = 0.0001). Plasma amylin and plasma renin activity were not correlated (P = 0.395), and effective antihypertensive monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade did not affect either amylin (P = 0.87-0.97) or insulin (P= 0.55-0.59). Among normotensive individuals, those at genetic risk of hypertension (with positive family history) already had increased concentrations of amylin (P< 0.001), despite exhibiting no difference in blood pressure or body mass index compared with the family-history-negative group; however, among normotensive individuals, both family history (P = 0.043) and body mass index (P= 0.0059) were significant predictors of increased concentrations of amylin. By maximum likelihood analysis, plasma amylin was distributed heterogeneously in the normotensive individuals, with two modes best explaining the distribution (chi2 = 77.4, P< 0.001), and family-history-positive individuals completely accounting for the upper mode (chi2 = 4.63, P = 0.031). Family-history-positive normotensive individuals showed greater plasma amylin concentrations both before and during beta-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 part determined by heredity. Both basal and stimulated plasma amylin excess may identify a subgroup of individuals bearing an inherited predisposition to hypertension. Measurement of amylin might identify a useful 'intermediate phenotype' in the genetic analysis of essential hypertension and its relationship to insulin resistance.
Kailasam
M T
MT
Department of Medicine and Center for Molecular Genetics, University of California and VA San Diego Healthcare System, 92161, USA.
Parmer
R J
RJ
Tyrell
E A
EA
Henry
R R
RR
O'Connor
D T
DT
D000328:Adult; D000596:Amino Acids; D000682:Amyloid / Q000097:blood*; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001794:Blood Pressure; D015992:Body Mass Index; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D058228:Islet Amyloid Polypeptide; D008297:Male; D008875:Middle Aged; D017257:Ramipril / Q000008:administration & dosage; D012307:Risk Factors
D000596:Amino Acids; D000682:Amyloid; D000959:Antihypertensive Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D017257:Ramipril