Functional allelic heterogeneity and pleiotropy of a repeat polymorphism in tyrosine hydroxylase: prediction of catecholamines and response to stress in twins.
Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, has a common tetranucleotide repeat polymorphism, (TCAT)(n). We asked whether variation at (TCAT)(n) may influence the autonomic nervous system and its response to environmental stress. To understand the role of heredity in such traits, we turned to a human twin study design. Both biochemical and physiological autonomic traits displayed substantial heritability (h(2)), up to h(2) = 56.8 +/- 7.5% (P < 0.0001) for norepinephrine secretion, and h(2) = 61 +/- 6% (P < 0.001) for heart rate. Common (TCAT)(n) alleles, particularly (TCAT)(6) and (TCAT)(10i), predicted such traits (including catecholamine secretion, as well as basal and poststress heart rate) in allele copy number dose-dependent fashion, although in directionally opposite ways, indicating functional allelic heterogeneity. (TCAT)(n) diploid genotypes (e.g., [TCAT](6)/[TCAT](10i)) predicted the same physiological traits but with increased explanatory power for trait variation (in contrast to allele copy number). Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)(10i) allele on both biochemical (norepinephrine) and physiological (heart rate) traits. (TCAT)(6) allele frequencies were lower in normotensive twins at genetic risk of hypertension, consistent with an effect to protect against later development of hypertension, and suggesting that the traits predicted by these variants in still-normotensive subjects are early, heritable, "intermediate phenotypes" in the pathogenetic scheme for later development of sustained hypertension. We conclude that common allelic variation within the tyrosine hydroxylase locus exerts a powerful, heritable effect on autonomic control of the circulation and that such variation may have implications in later development of cardiovascular disease traits such as hypertension.
Zhang
Lian
L
Department of Medicine, University of California at San Diego, 92161, USA.
Rao
Fangwen
F
Wessel
Jennifer
J
Kennedy
Brian P
BP
Rana
Brinda K
BK
Taupenot
Laurent
L
Lillie
Elizabeth O
EO
Cockburn
Myles
M
Schork
Nicholas J
NJ
Ziegler
Michael G
MG
O'Connor
Daniel T
DT
D000225:Adenine / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001341:Autonomic Nervous System / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D002395:Catecholamines / Q000096:biosynthesis*; D003596:Cytosine / Q000378:metabolism; D004171:Diploidy; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D012737:Sex Factors; D013312:Stress, Physiological / Q000201:enzymology / Q000235:genetics*; D013941:Thymine / Q000378:metabolism; D018433:Twin Studies as Topic / Q000379:methods / Q000706:statistics & numerical data; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
D002395:Catecholamines; D003596:Cytosine; D014446:Tyrosine 3-Monooxygenase; D000225:Adenine; D013941:Thymine