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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0373
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 11 5985-5990
Copyright © 2005 by The Endocrine Society

Aggregation of High-Normal Thyroid-Stimulating Hormone in Hypertensive Families

Olga Gumieniak, Shelley Hurwitz, Todd S. Perlstein, U. Chioma Ngumezi, Paul N. Hopkins, Xavier Jeunemaitre and Gordon H. Williams

Endocrinology, Diabetes, and Hypertension Division (O.G., S.H., U.C.N., G.H.W.), and Division of Cardiology (T.S.P.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; Cardiovascular Genetics, Cardiology Division, University of Utah (P.N.H.), Salt Lake City, Utah 84108; and Department of Genetics and Clinical Investigation Center, Hôpital Européen Georges Pompidou (X.J.), Paris 75908, France

Address all correspondence and requests for reprints to: Dr. Gordon H. Williams, Endocrinology, Diabetes, and Hypertension Division, 221 Longwood Avenue, RFB-2, Boston, Massachusetts 02115. E-mail: gwilliams{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Studies suggest that there are genetic variants that influence both blood pressure regulation and serum TSH levels. We investigated whether high-normal TSH values aggregate in hypertensive families. The influence of hypertension family history on serum TSH levels in healthy normotensive individuals was also examined.

Methods: All subjects were euthyroid (TSH, 0.5–5.0 mIU/liter). The study subjects were 333 hypertensives, including 229 members of multiple sibling families. The subjects had blood samples for serum TSH determination drawn in the morning after overnight bed rest. High-normal TSH was defined as values above 2.0 mIU/liter and equal to or less than 5.0 mIU/liter. Thirty-one healthy normotensives provided information about their family history of hypertension by telephone.

Results: The concordance for high-normal TSH values among hypertensive, multiple sibling families was greater than expected by chance (P = 0.009). There were nearly twice as many families concordant for high-normal TSH status as expected (13.2% vs. 7.0%), whereas the observed proportion concordant for normal TSH status was similar to that expected (58.3% vs. 54.1%). Family membership explained a significant proportion of variance in TSH status (P = 0.038). Healthy normotensives with a family history of hypertension had significantly higher TSH values (2.2 ± 1.2 mIU/liter) than those with a negative family history of hypertension (TSH 1.3 ± 0.7 mIU/liter) independent of other characteristics (P = 0.025).

Conclusions: There is familial aggregation of high-normal TSH values in hypertensive families, and a hypertension family history influences serum TSH levels in healthy individuals. These findings are consistent with the existence of genetic variants affecting both blood pressure regulation and serum TSH levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROID HORMONE HAS multiple effects on the cardiovascular system, including modulation of vascular tone (1, 2, 3). Overt (4, 5) and subclinical (6, 7, 8, 9) hypothyroidism are associated with an increase in systemic vascular resistance and hypertension. Variation in serum thyroid hormone concentrations within the euthyroid range also influences cardiovascular health (10, 11, 12, 13, 14), including endothelium-dependent vasodilation (15) and hypertension (16, 17).

Studies conducted to identify genetic underpinnings of essential hypertension have been challenged by the heterogeneity of this complex trait. A number of genetic and environmental factors influence blood pressure, and individual hypertensive patients have unique combinations of genes that contribute to blood pressure elevation (18, 19, 20, 21). Genes of the hypothalamic-pituitary-thyroid pathway received little attention in investigating genetic determinants of essential hypertension. There is evidence, however, to suggest that these genes may be involved in blood pressure regulation.

In the spontaneously hypertensive rat (SHR), blood pressure elevation is at least in part mediated by TRH (22, 23, 24, 25). This animal model of essential hypertension also has high-normal TSH concentrations compared with controls (24, 26, 27), which appear to also be driven by TRH (24). It is not known whether the subtle TSH changes in the SHR have physiological consequences or simply mark TRH-mediated hypertension. In humans, a promoter region single nucleotide polymorphism of the TRH receptor gene was associated with essential hypertension (28). The authors of this study did not report participants’ thyroid status (28). However, other investigators observed subtle differences in thyroid function, resembling those in the SHR, in euthyroid hypertensive individuals compared with normotensive controls (16, 17).

To address the hypothesis that there are genetic variants that influence both blood pressure regulation and serum TSH levels, we performed familial aggregation studies of high-normal TSH levels in hypertensive, multiple sibling families. The influence of hypertension family history on serum TSH in healthy normotensives was also investigated.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Three hundred thirty-three hypertensive subjects were studied by the international HyperPath (hypertensive pathotype) group. All subjects were generally healthy, community-dwelling, hypertensive individuals. Among 333 hypertensive subjects studied were 229 members of 109 multiple sibling families. There were 99 sibling pairs, nine sibling trios, and one family with four siblings. Subjects were studied at the General Clinical Research Centers of the Brigham and Women’s Hospital (Boston, MA), the Hospital Brussais (Paris, France), and University of Utah (Salt Lake City, UT). All subjects had serum TSH values within the normal reference range and were not receiving thyroid hormone therapy.

Hypertension in a proband was defined as a diastolic blood pressure (DBP) of 100 mm Hg or higher off medications or 90 mm Hg or higher while taking one or more medications, or treatment with more than two medications. Hypertensive siblings had to have a DBP of 90 mm Hg or higher off medication, or a DBP of 80 mm Hg or higher while taking one antihypertensive medication, or be treated with two or more agents. All subjects had a screening history, physical examination, and laboratory tests. Those with secondary forms of hypertension, diabetes mellitus, obesity [body mass index (BMI), >34 kg/m2], renal insufficiency, alcohol intake greater than 12 oz/wk, or any significant medical or psychiatric illnesses were excluded. Subjects were between 18 and 65 yr of age. All antihypertensive medications were stopped 2–4 wk before the study.

To determine the influence of hypertension family history on serum TSH values, information about hypertension family history was obtained by telephone in healthy normotensive subjects enrolled in the Partners/Roche Type 2 Diabetes Project. All subjects were generally healthy, without any significant medical or psychiatric illness. Subjects were excluded if they had blood pressure greater than 140/90 mm Hg, hypertension, heart disease, depression, or current treatment with antihypertensive, cardiovascular (with the exception of lipid-lowering agents), or psychiatric medications. Other reasons for exclusion were treatment with thyroid hormone, age greater than 65 yr, or BMI greater than 34 kg/m2. These exclusion criteria were chosen to match the inclusion/exclusion criteria for the HyperPath study. Of 55 eligible subjects, it was possible to contact 31; all provided information about family history of hypertension in first degree relatives.

Protocol

All hypertensive subjects underwent an identical protocol, described in detail previously (29, 30). The institutional review boards of the respective institutions approved the study, and all subjects gave written informed consent before enrollment.

Subjects had a 200 mmol or higher/24 h sodium diet, which they consumed as out-patients for 4–7 d. Blood samples for thyroid function testing were obtained in the morning of the high-salt study day after overnight bed rest. All thyroid function tests were performed in the central laboratory. Reported systolic blood pressure (SBP) and DBP values are means of three consecutive readings (by Dinamap, Critikon, Inc., Tampa, FL) separated by 5 min each, measured at bed rest in the morning of the high-salt study day.

To determine the influence of hypertension family history on serum TSH values in healthy normotensive subjects, information about hypertension family history was obtained by telephone. Frozen serum samples were used to perform thyroid function assays at the Brigham and Women’s Hospital core laboratory.

Because free T4 measurements were not available, the free T4 index (FTI) was calculated by multiplying total T4 by the thyroid hormone binding ratio (THBR).

Laboratory procedures

Details of most laboratory assays have been described previously (30, 31). TSH, T4, and THBR assays were performed centrally at Brigham and Women’s Hospital core laboratory. For hypertensive subjects, serum TSH measurements were performed using an Access chemiluminescence analyzer (Beckman Coulter, Inc., Fullerton, CA; n = 73) or TSH RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA; n = 260). The reference range for serum TSH was 0.5–5.0 mIU/liter. These methods demonstrated good agreement with a slope of 0.8514, an intercept of –0.1234, and a correlation coefficient of 0.9984. There were no differences in proportions of hypertensives with high-normal and normal TSH status by the TSH assay method (79.6% of hypertensives in the high-normal TSH group and 77.6% of hypertensives in the normal TSH group had serum TSH assay determined by Nichols Institute TSH RIA). For the Beckman Access chemiluminescence analyzer, the interassay coefficient of variation (CV) of a human serum pool with a TSH concentration of 0.09 mIU/liter was 4.9%; at concentrations of 8.3 and 30.7 mIU/liter, the CVs were 5.5 and 7.7%, respectively. For the Nichols Institute TSH RIA, the interassay CV with a concentration of 0.17 mIU/liter was 20.0%; at concentrations of 6.8 and 23.2 mIU/liter, the CVs were 3.4 and 3.5%, respectively.

Serum T4 measurements were performed with the Access Immunoassay System (Beckman Coulter, Inc.) or the Coat-a-Count RIA (Diagnostic Products Corp., Los Angeles, CA). These methods had good agreement, with a slope of 0.8628, an intercept of 0.7895, and a correlation coefficient of 0.9072. There were no differences in proportions of hypertensives with high-normal and normal TSH status by the T4 assay method (79.6% of hypertensives in the high-normal TSH group and 77.6% of hypertensives in the normal TSH group had serum T4 assay determined by Diagnostic Products Corp. Coat-a-Count RIA). The Coat-a-Count RIA was used for THBR measurements.

For normotensive subjects, all serum TSH measurements were performed using the Access chemiluminescence analyzer (Beckman Coulter, Inc.), and T4 was measured with the Access Immunoassay System (Beckman Coulter, Inc.).

Statistical analyses

High-normal TSH was defined as serum TSH levels greater than 2.0 mIU/liter (15, 32, 33). The hypothesis that high-normal TSH clustered significantly within hypertensive families was tested by two approaches, without assuming any particular ordering of the siblings within families. First, mixed models logistic regressions were performed, with high-normal TSH as the binary outcome and family membership as the random effect. Generalized logistic regression also allowed the testing of individual baseline characteristics for predicting high-normal TSH. These analyses were conducted using all 333 subjects. The second approach was to test whether the observed familial aggregation for high-normal TSH exceeded the aggregation that would occur by chance. The expected proportions of sibling pairs that would be concordant high-normal TSH, concordant normal TSH, and discordant were estimated using the unrestricted database of 333 individuals. {chi}2 analysis was used to test the significance of the excess aggregation in 229 subjects from multiple sibling families, where each family received equal weight. In the separate normotensive database, individuals with and without a family history of hypertension were compared in terms of baseline characteristics using unpaired t tests and Fisher’s exact tests. Regression methods were used to adjust for potential confounders. Serum TSH was natural log transformed for analysis. SAS version 8.2 (SAS Institute, Inc., Cary, NC) was used for all analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The baseline characteristics of 333 hypertensives (229 hypertensive members of multisibling families and 104 hypertensive singletons) are shown in Table 1Go. Subjects with high-normal and normal TSH levels were similar in age, BMI, and gender distribution. Whites were slightly overrepresented among high-normal TSH hypertensives. As anticipated, FTI was somewhat lower in those with high-normal TSH. Fasting plasma glucose and insulin concentrations were similar in the two groups (Table 1Go). Two subjects in the normal TSH group and one subject with high-normal TSH had fasting glucose values greater than 200 mg/dl on the study day, with normal random plasma glucose values at screening.


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  		TABLE 1. Characteristics of hypertensive subjects

 
The intraclass correlation coefficient for the concentration of log-transformed serum TSH was 0.34, indicating that approximately 34% of the total variance in serum TSH values can be explained by family membership. This is very similar to reported intraclass correlation in dizygotic twins (34). In contrast, serum FTI explained only 2% of the variance in serum TSH.

The proportion of high-normal TSH among all hypertensives was 26.4%. The observed proportion of multiple sibling families concordant for high-normal TSH status, concordant for normal TSH status, and discordant differed from the proportions expected by chance (P = 0.009). The observed proportion of multisibling families concordant for high-normal TSH status was 13.2%, 1.9 times the expected 7.0% (Fig. 1Go). The observed proportion of multisibling families concordant for normal TSH status was similar to that expected (58.3% vs. 54.1%). The observed proportion of families discordant for TSH status was less than that expected (28.5% vs. 38.9%). This suggests that there is an excess aggregation of high-normal TSH values in hypertensive families. The largest racial group was the white race, with 193 members in 92 multiple sibling families. Familial aggregation of high-normal TSH remained significant when analysis was repeated in this subgroup (P = 0.044). The observed proportion of families concordant for high-normal TSH status was 1.7 times that expected (14.5% vs. 8.5%). Results were unchanged when the analyses were restricted to the subgroup of 260 hypertensives with serum TSH measured using the Nichols Institute TSH RIA. The observed proportion of families concordant for high-normal TSH status was 15.2%, 2.1 times the expected 7.3% (P = 0.002).



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  		FIG. 1. Ratio of observed to expected proportions of multiple sibling families concordant for high-normal TSH status, discordant, and concordant for normal TSH. The observed proportions differed significantly from expected (P = 0.009). The observed frequency of multisibling families concordant for high-normal TSH status was 1.9 times that expected, whereas the observed frequency of families concordant for normal TSH status was similar to that expected. Expected proportions were based on population estimates of high-normal TSH status in the full database of 333 hypertensive subjects.

 
Using mixed models logistic regression, family membership explained a significant proportion of variance in TSH status (P = 0.038). The significant family membership random effect indicated that the probability of high-normal TSH was not constant, but depended on the family, and thus on some unobserved latent factor unique to the family, such as heredity or immediate environment. Table 2Go shows the odds ratios and confidence intervals for fixed effects of age, gender, and race with and without accounting for family membership. When familial aggregation was ignored, the probability of high-normal TSH was a constant 0.26. The significant family membership random effect indicated that the effect of an individual covariate on high-normal TSH status was not constant across families. Furthermore, race seemed to be associated with high-normal TSH status when ignoring family membership, but the effect was weakened by accounting for the clustering (Table 2Go).


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  		TABLE 2. Mixed models logistic regression predicting high-normal TSH status by individual covariates

 
Table 3Go shows characteristics of healthy normotensives with and without history of hypertension in first degree relatives. Nineteen subjects reported no first degree relatives with hypertension, whereas 12 reported having at least one hypertensive first degree relative. All subjects were euthyroid. There was a trend toward higher BMI and blood pressure in individuals without a family history of hypertension (Table 3Go). When adjusted for BMI, blood pressure differences between groups disappeared. The mean SBP and DBP in normotensives with a family history of hypertension, adjusted for BMI, were 110 and 73 mm Hg, respectively. The mean SBP and DBP in normotensives without a family history of hypertension, adjusted for BMI, were 113 and 73 mm Hg, respectively (P = 0.48 for comparison of mean SBP; P = 0.99 for comparison of mean DBP).


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  		TABLE 3. Characteristics of healthy normotensives with and without history of hypertension in first degree relatives

 
Figure 2Go shows individual TSH values in healthy normotensive subjects according to family history of hypertension. Healthy volunteers with a family history of hypertension had significantly higher serum TSH levels than healthy subjects without a family history of hypertension (P = 0.011; Fig. 2Go). A family history of hypertension remained a significant predictor of serum TSH concentrations even after adjusting for age, gender, race, and FTI (P = 0.025). Family history explained approximately 20% of the variability in serum TSH, whereas FTI explained only approximately 3%.



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  		FIG. 2. Serum TSH concentrations in healthy volunteers with and without hypertension family history. Mean serum TSH was significantly higher (P = 0.011) in healthy subjects with a positive family history of hypertension (2.2 ± 1.2 mIU/liter) compared with those without such a history (1.3 ± 0.7 mIU/liter). The box represents the interquartile range. Whiskers are 5th and 95th percentiles. Lines through the box represent the mean (dashed line) and median (solid line) TSH values.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrated that high-normal TSH values aggregate in hypertensive multiple sibling families. These results were robust, because they were replicated using two analytical approaches. The established criteria from several previous reports were used to define the high-normal TSH group (15, 32, 33). The present study also found that a family history of hypertension influenced serum TSH levels. Healthy euthyroid individuals with a family history of hypertension had significantly higher TSH concentrations than those without such a family history independently of other baseline characteristics. These findings support the hypothesis that genetic variants exist that affect both the serum TSH concentration and the presence of hypertension.

Genetic determinants of essential hypertension remain poorly understood in large part because of its heterogeneity (18, 19, 20, 21). Within the heterogeneous population of hypertensive patients, however, more genetically homogeneous subgroups can be identified (18, 19, 35). Once a more homogeneous subgroup is identified, defined by a common physiological or phenotypic trait, this intermediate phenotype can be used to focus genetic investigation.

Thyroid hormone has multiple effects on cardiovascular function (1). Cardiac expression of several genes is influenced by thyroid hormone (1). Both T3 and T4 have vasodilatory actions (2, 3). Type 2 iodothyronine deiodinase is expressed in human coronary artery and aortic smooth muscle cells (36), suggesting a role for intracellular T3 availability in maintaining vascular tone. Thyroid hormone deficiency leads to increased systemic vascular resistance and hypertension (4, 5, 6, 7, 8, 9). In euthyroid subjects, variation in serum thyroid hormone concentration was associated with impaired vasodilation (15), hypertension (16, 17), and other cardiovascular abnormalities (10, 11, 12, 13, 14).

Among genetic factors influencing thyroid function are polymorphisms in TSH receptor and type 2 iodothyronine deiodinase genes (37). These and other hypothalamic-pituitary-thyroid pathway genes have received little attention in investigating genetic determinants of essential hypertension. There is evidence, however, to suggest that these genes are involved in blood pressure regulation. In SHR, blood pressure elevation is at least partially TRH mediated (22, 23, 24, 25). SHR also have high-normal TSH concentrations compared with controls (24, 26, 27, 38), whereas T4 concentrations are not significantly different. An antisense inhibition of TRH decreased both blood pressure and serum TSH levels in SHR (24), suggesting that TRH participates in both blood pressure and TSH regulation. It is unclear whether the subtle TSH changes have physiological consequences or simply mark the TRH-mediated hypertension in this animal model.

Findings in the SHR prompted an association study in humans, which determined that a promoter region single nucleotide polymorphism of the TRH receptor gene was associated with hypertension in two populations (28). Other investigators have observed subtle differences in thyroid function in euthyroid hypertensive individuals compared with normotensive controls (16, 17). The findings of the present study combined with these previous reports support the hypothesis of the existence of genetic variants influencing both blood pressure and serum TSH. Mechanisms of their influence on blood pressure and serum TSH may differ, and circulating TSH and/or T4 variations may not be physiologically significant, but, rather, represent a phenotypic marker associated with these genetic variants. Alternatively, changes in circulating and/or tissue thyroid hormone concentrations may be one of the mechanisms underlying the association of thyroid pathway-related genes with hypertension.

An alternative explanation to our findings is the clustering of autoimmune thyroid disease in hypertensive multiple sibling families and in families of normotensive individuals with positive hypertension family history leading to higher TSH values. However, autoimmune thyroid disease is not known to aggregate specifically in hypertensive families. Furthermore, serum FTI in both hypertensive and normotensive subjects explained only a very small fraction of the variance in TSH. Additionally, there was no association of serum TSH with age or gender among our subjects as would be expected if underlying autoimmune thyroid disease was responsible for higher TSH concentrations (39, 40). Although the possibility that clustering of autoimmune thyroid disease contributed to the familial aggregation of high-normal TSH cannot be completely ruled out, it is unlikely to explain the overall results.

The present findings should be interpreted in the context of the study design. These results suggest, but do not prove, the existence of genetic influences on both blood pressure regulation and serum TSH. Genetic investigation combined with gene functional characterization are required to conclusively prove this hypothesis.

In summary, this study found that high-normal TSH values aggregate in hypertensive families, and hypertension family history influence serum TSH levels in healthy individuals. These data suggest that genetic variants exist that affect both blood pressure regulation and serum TSH levels, and that high-normal TSH in hypertensive individuals may be a phenotypic marker for these genetic variants. Most likely candidates include genes in the hypothalamic-pituitary-thyroid pathway. Additional investigation to characterize the roles of these genes in essential hypertension is warranted.


   Acknowledgments
 
We gratefully acknowledge the assistance of the dietary, nursing, administrative, and laboratory staffs of the three clinical research centers.


   Footnotes
 
This work was supported by the following grants: National Institutes of Health Grants HL-47651, HL-59424, and DK-63214; Specialized Center of Research in Hypertension from the National Heart, Lung, and Blood Institute (HL-55000); and National Center for Research Resources (General Clinical Research Centers) in Boston (M01-RR-02635) and Salt Lake City (M01-RR-00064). O.G. was supported in part by National Institutes of Health Training Grant T32-HL-007609.

Current address for O.G.: GlaxoSmithKline Pharmaceuticals, 1250 South College Road, Upper Providence, Pennsylvania 19426.

First Published Online August 9, 2005

Abbreviations: BMI, Body mass index; CV, coefficient of variation; DBP, diastolic blood pressure; FTI, free T4 index; SBP, systolic blood pressure; SHR, spontaneously hypertensive rat; THBR, thyroid hormone binding ratio.

Received February 22, 2005.

Accepted July 29, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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