From the Clinical Pharmacology Unit, University of Cambridge,
Addenbrooke's Hospital; and the MRC Biostatistics Unit (D.C.),
Cambridge, UK.
Abstract—Despite advances in the
understanding of monogenic hypertensive disorders, the genetic
contribution to essential hypertension has yet to be elucidated. The
position of tyrosine hydroxylase (TH) as the rate-limiting enzyme in
catecholamine biosynthesis renders it a candidate gene for
the etiology of hypertension. The TH gene contains an internal,
informative microsatellite marker (TCAT)9. We undertook (1)
an association study in a group of well-characterized hypertensive
subjects (HT) and control subjects (NT) and (2) an affected sibling
pair (ASP) study using sibships from our local family practices. Two
hundred twenty-seven hypertensive patients (pretreatment
systolic/diastolic blood pressure [BP] range,
139/94 to 237/133 mm Hg; age range [SD], 30 to 71 [8.5]
years) were age- and gender-matched with 206 control subjects (BP
range, 96/62 to 153/86 mm Hg; age range, 40 to 70 [7.6] years).
One hundred thirty-six affected sibling pairs were recruited for our
linkage study; 73 young borderline hypertensive subjects (YHT)
(pretreatment BP range, 123/76 to 197/107 mm Hg; age range, 20 to
51 [9.4] years) were also recruited in whom recent pretreatment
norepinephrine and epinephrine levels were
available. All subjects were white. The TH short tandem repeat (STR)
was amplified using specific polymerase chain reaction cycling
conditions in all subjects, and products were run on an ABI 373A
sequencer. TH alleles were assigned using Genescan and
Genotyper software. Five TH alleles were present and
designated A through E. Allele frequencies in the NT population (A,
B, C, D, and E: 0.24, 0.17, 0.13, 0.20, and 0.26, respectively) were
significantly different from the HT cohort (A, B, C, D, and E: 0.24,
0.19, 0.11, 0.11, and 0.35, respectively), P<0.0005
(Pearson's test
© 1998 American Heart Association, Inc.
Scientific Contributions
Positive Association of Tyrosine Hydroxylase Microsatellite Marker to Essential Hypertension
2=19.94; 4 df). The E
allele appears overrepresented in the HT group, whereas
the D allele appears to be overrepresented in the NT
group. TH genotype frequencies were also significantly
different between cases and controls (P<0.001;
2=36.57; 14 df). Both groups were in
Hardy-Weinberg proportion. There was a trend (NS) for the D allele
to be associated with a lower BP when BP was analyzed as a
quantitative trait. ASP linkage data was analyzed using Splink,
a nonparametric program. Expected values for sharing 0, 1,
and 2 alleles (Z0, Z1, and Z2,
respectively) may be expected to be 25%, 50%, and 25%, respectively,
by chance (assuming identity by descent). These probabilities were
calculated by Splink as 34, 68, and 34, respectively, and compared with
observed values of 36.8, 67.9, and 31.3, respectively; thus, there was
no excess sharing of TH alleles among affected sibling pairs
(P=0.59; logarithm of odds ratio score, 0.0). TH
allele frequencies in our YHT group (A, B, C, D, and E: 0.24, 0.20,
0.12, 0.15, and 0.29, respectively) were similar to those of our NT
cohort (P>0.05). There was a trend for lower
pretreatment plasma norepinephrine levels with the D
allele in this YHT cohort. A common and potentially functional
variant at codon 81Val
Met within exon 2 of the TH gene
(which we show to be in linkage disequilibrium with TH-STR) was also
typed in our YHT but did not associate with catecholamine
levels and is therefore unlikely to account for our findings with D and
E TH-STR. In conclusion, the TH locus strongly associates with
essential hypertension in a case-control model using well-characterized
hypertensive and control groups. An ASP linkage model was negative,
presumably because of lack of power. This study suggests that the TH
gene, or a nearby gene, may be involved in the etiology of
essential hypertension.
Key Words: hypertension, essential • genetics • catecholamines • molecular biology • tyrosine hydroxylase • microsatellite marker
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