(Hypertension. 2000;36:14.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Role of Tumor Necrosis Factor-
Gene Locus in Obesity and Obesity-Associated Hypertension in French Canadians
From the Centre de Recherche, Centre Hospitalier de l’Université de Montreal (CHUM) (Z.P., B.D., J.T., P.L., P.H.), Montreal, Canada; Hospital Complex of Sagamie (D.G.), Chicoutimi, Canada; and Medical College of Wisconsin (T.A.K., A.W.C.), Milwaukee, Wis.
Correspondence to Dr Pavel Hamet, Centre de Recherche, CHUM-Hôtel-Dieu, Laboratory of Molecular Medicine, 3850 St Urbain St, Montréal, Québec H2W 1T8, Canada. E-mail hamet{at}ere.umontreal.ca
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Abstract |
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Abstract—Obesity represents a serious risk factor for the development of cardiovascular diseases, including hypertension. Segregation studies suggest that obesity and obesity-associated hypertension may share some genetic determinants. The results of the present candidate gene investigation suggest that in hypertensive pedigrees of French-Canadian origin, one such determinant is the tumor necrosis factor (TNF)-
gene locus. Gender-pooled quantitative
sib-pair analysis demonstrated a significant effect of the gene
locus on 3 global and 7 regional measures of obesity
(P=0.05 to 0.0004). Gender-separate quantitative
sib-pair analyses showed that the impact of the locus on
obesity is most significant in the abdominal region in men and in the
thigh region in women. Furthermore, the haplotype relative-risk test
demonstrated a significant association between the TNF- gene locus
and both obesity (P=0.006) and obesity-associated
hypertension (P=0.02). These effects were most
significant in individuals with nonmorbid obesity. In conclusion, the
results of linkage and association analyses suggest that in
hypertensive pedigrees of French-Canadian origin, the TNF- gene
locus contributes to the determination of obesity and
obesity-associated hypertension. In addition, the data indicate that
gender modifies the effect of the locus on the regional distribution of
body fat.
Key Words: tumor necrosis factor • hypertension, obesity • obesity • genes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Obesity is a leading risk factor for the development of essential hypertension. It has been estimated in the Framingham Heart Study that for each 4.5 kg of weight gain, there is an accompanying increase of 4 mm Hg in systolic blood pressure in both men and women.1 Several mechanisms have been implicated in the pathogenesis of obesity-associated hypertension, including insulin resistance, salt sensitivity, and activation of the sympathetic nervous system.2
The pathogenesis of both obesity and hypertension is complex,
characterized by the involvement of several genes and environmental
factors.3 4 Genetic analyses suggest that some of
the genes that determine obesity may also contribute to the development
of obesity-associated hypertension.5 6 One such gene may
be that coding for tumor necrosis factor (TNF)-.
TNF- is a proinflammatory cytokine that, in addition to its
role in the immune response and cancer, is involved in the development
and phenotypic expression of obesity. It has been suggested that
TNF- functions as an adipostatic factor that is induced by
increasing obesity to limit its further progression.7 This
hypothesis is based on a large body of research that demonstrates
TNF- expression is heightened in obesity8 9 and that
TNF- exerts antiadipogenic effects. Thus, the exposure of adipose
tissue and cells to TNF- in vitro dramatically suppresses the gene
expression of key enzymes involved in fatty acid uptake and
lipogenesis.10 11 12 In addition, TNF- inhibits
differentiation11 and stimulates apoptosis of
adipocytes.13
In obesity, some of these antiadipogenic effects may be mediated by
TNF-–induced insulin resistance. The complete absence of TNF- or
of both of its receptors results in a significant improvement in
insulin sensitivity in mice with dietary, hypothalamic, or genetic
obesity.14 15 In obese humans, elevated TNF- expression
in adipose and muscle tissues is positively correlated with the level
of fasting hyperinsulinemia.9 16
The role of TNF- has not been studied in hypertension as extensively
as in obesity and insulin resistance. It has been demonstrated that
TNF- increases the production of
endothelin-117 18 and
angiotensinogen.19 20 In addition, as
described, TNF- has been related to the development of
obesity-associated insulin resistance, which is one of the proposed
mechanisms of obesity-associated hypertension.2 The goal
of the present study was to investigate whether the TNF- gene
locus is involved in the determination of obesity and
obesity-associated hypertension in hypertensive pedigrees of
French-Canadian origin.
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Methods |
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Fifty pedigrees of French descent were selected from a genetically isolated population of the Chicoutimi/Lac St Jean region in the Canadian province of Quebec.21 The pedigrees were ascertained through "hypertension-affected" sib pairs. "Affected" status was defined by the presence of (1) early-onset essential hypertension (onset at the age of
55 years) and (2)
dyslipidemia (total cholesterol of 
5.2
mmol/L, HDL cholesterol of 0.9 mmol/L, or both). In
addition, affected status was characterized by the absence
of (1) secondary hypertension, (2) diastolic blood
pressure of >110 mm Hg while on blood pressure–lowering
medication, (3) gross obesity (body mass index [BMI] of >35
kg/m2), (4) diabetes mellitus (fasting blood
glucose of >6 mmol/L or the use of insulin or oral hypoglycemic
agents), (5) renal dysfunction (serum creatinine of
>180 mmol/L), (6) liver disease, (7) malignancy, (8) pregnancy,
and (9) substance abuse, including alcohol. Furthermore, to ensure
genetic homogeneity, only sib pairs with both parents of Catholic
French-Canadian origin were selected. Once an affected sib pair was
identified, other family members, including siblings, parents,
children, and aunts and uncles, were also included. This collection
included a total of 262 individuals. The study was approved by the
local ethics committee, and the subjects gave their informed
consent. In these individuals, 3 global and 11 regional measures of obesity were collected through standardized procedures. The global measures included BMI, total body fat (TBF) derived from skinfold measurements,22 and TBF determined with bioimpedance (RJL Systems, Inc). The regional measures included 6 trunk and extremity circumferences and 5 skinfold measurements. Descriptive statistics on obesity-related phenotypes are presented in Table 1.
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The TNF- gene locus was investigated with the use of three
polymorphisms: (1) an NcoI polymorphism located in
the promoter region of the TNF- gene at position -308 (index of
heterozygosity 0.18),23 (2) an NcoI
polymorphism located 
3 kb upstream of the gene (index of
heterozygosity 0.40),23 and (3) a
CA-dinucleotide repeat polymorphism located 6.6 kb
upstream of the gene (index of heterozygosity 0.88).24
Quantitative sib-pair analysis was conducted with use of the SIBPAL computer program (Version 2.8, S.A.G.E. package; Department of Epidemiology and Biostatistics, Case Western Reserve University). This nonparametric linkage analysis is based on regression of the squared trait difference on the proportion of marker alleles shared between 2 siblings. One-tailed Student’s t test is used to test the significance of the regression. Before linkage analyses, all variables were adjusted for significant covariates, such as age, gender, and height, by means of linear regression. The allele frequencies of DNA markers were estimated in the total sample of individuals (n=262). To control for possible bias, we used the more conservative unweighted option for sib-pair analysis. Given the fact that a candidate gene approach was used here, we chose P<0.05 as our initial criterion for linkage.
The power to detect linkage with quantitative sib-pair analysis
is concentrated in sib pairs either concordant or discordant for high
or low values of the trait, or both.25 Therefore, only
individuals with either "low" (22 kg/m2) or
"high" (27 kg/m2) BMI were selected for
quantitative sib-pair analyses (Figure 1). These individuals created a total of
152 sib pairs, including 102 sib pairs concordant for high BMI, 8 sib
pairs concordant for low BMI, and 42 sib pairs discordant for low and
high BMI. BMI values of 22 and 27 kg/m2 were
chosen because it has been demonstrated that individuals with BMI of
22 kg/m2 rarely have metabolic
conditions, such as insulin resistance,26 and that
Canadian adults with BMI of 27 kg/m2 have
nearly twice the prevalence of hypertension as those with BMI of <27
kg/m2.27
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Association analysis was performed with use of the TRANSMIT
program (Version 2.3; D. Clayton, MRC Biostatistics Unit). This program
tests for associations between a genetic marker and disease by
examining the transmission of multipoint haplotypes from parents to
affected offspring. The 
2 statistic is used to
compare multipoint haplotype frequencies observed in affected offspring
with those expected under mendelian transmission. The TRANSMIT program
can also be used when parental genotypes are unknown; in this
case, data from unaffected siblings are used.
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Results |
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Quantitative sib-pair analysis (SIBPAL) demonstrated significant effects of the TNF-
gene locus on all global and most
regional measures of obesity (Figure 2).
With respect to global measures of obesity, the most significant result
was observed for BMI (t=-2.74, P=0.004)
and less significant data were obtained for TBF derived from skinfold
measurements (t=-1.79, P=0.04) and TBF
determined through bioimpedance (t=-1.63,
P=0.05) (Figure 2). In regard to the regional obesity
measures, the TNF- gene locus demonstrated the most significant
impact on thigh circumferences (t=-3.10 to -3.47,
P=0.001 to 0.0004). Upper arm, waist, and hip circumferences
were also linked to the locus but less significantly. Among skinfold
measurements, thigh skinfold was the only one that reached statistical
significance (t=-2.55, P=0.007) (Figure 2).
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To confine this obesity-related effect of the locus closer to the
TNF- gene, an association-based analysis (TRANSMIT) was
conducted. This analysis demonstrated that marker haplotype
frequencies observed in affected offspring (BMI 27
kg/m2) differ significantly from those expected
under mendelian transmission (2=10.45, 3
df, P=0.02). Taken together, the results of both
linkage and association analyses suggest that the TNF- gene
locus is involved in the determination of obesity in hypertensive
pedigrees of French-Canadian origin.
Among individuals with BMI of 27 kg/m2 (n=110),
88% had early-onset hypertension, whereas among the individuals with
BMI of 22 kg/m2 (n=30), 38% were affected
(2=18.03, 1 df,
P=0.00002). The difference in the prevalence of hypertension
between the 2 groups indicated a close relationship between obesity and
early-onset hypertension in our data set.
To explore the possibility that the TNF- gene locus is involved in
the development of obesity-associated hypertension, association
analysis (TRANSMIT) was conducted. This analysis showed
that haplotype frequencies observed in affected offspring (BMI of 27
kg/m2 and hypertension diagnosed at the age of
55 years) do not significantly differ from those expected under
mendelian transmission (2=6.25, 3
df, P=0.1), suggesting that the TNF- gene
locus is not involved in the pathogenesis of obesity-associated
hypertension. However, on the basis of the known actions and the
presumed role of TNF- in obesity and hypertension, the TNF- gene
is not likely to be involved in the development of hypertension in
subjects with severe obesity. Therefore, we carried out association
analysis, with affected status being assigned to hypertensive
individuals with nonmorbid obesity (BMI 27 to 35
kg/m2). This analysis revealed a
significant association between the TNF- gene locus and
obesity-associated hypertension (2=9.6, 3
df, P=0.02) (Table 2). Furthermore, the selection of only
individuals with nonmorbid obesity (BMI 27 to 35
kg/m2) as affected offspring also increased the
significance of the association between the locus and obesity
(2=12.6, 3 df, P=0.006)
(Table 2). In this analysis, the haplotype 1.2.10 was
significantly associated with obesity (2=4.57,
1 df, P=0.03). These results suggest that the
TNF- gene locus is a significant determinant of both obesity and
obesity-associated hypertension and that this effect is limited mainly
to individuals with nonmorbid obesity.
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Furthermore, descriptive statistics on obesity-related
phenotypes demonstrate that men and women differ in most
measures of regional body fat distribution (Table 1). The
average values of all skinfold measurements were found to be higher in
women than in men, with the most significant difference being observed
in the thigh skinfold (P=3.0x10-16).
In contrast, most of the circumference measures were greater in men
than in women. Among them, the most significant difference was noticed
in waist circumference (P=0.0003) and the waist/hip ratio
(P=8.6x10-15). To further explore
the issue of gender, we performed gender-separate quantitative sib-pair
analyses. They showed that in male sib pairs, the TNF- gene
locus exerts the most significant effects on waist circumference
(t=-1.58, P= 0.06), the waist/hip ratio
(t=-1.77, P=0.04), and suprailiac skinfold
(t=-2.87, P=0.004). In contrast, in female sib
pairs, the locus has the most significant impact on upper thigh
circumference (t=-3.02, P=0.002), middle thigh
circumference (t=-3.00, P=0.002), and thigh
skinfold (t=-2.39, P=0.01) (Figure 3). Thus, the TNF- gene locus appears
to most significantly influence the accumulation of fat in the
abdominal region in men and in the thigh region in women.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of the present linkage and association analysis suggest that in hypertensive pedigrees of French-Canadian origin, the TNF-
gene locus is involved in the
pathogenesis of obesity and obesity-associated hypertension. Although
these results do not provide direct evidence for the involvement of the
TNF- gene, in consideration of the known actions of TNF-, this
gene represents the best candidate within the chromosomal
region.
The effect of the TNF- gene locus on human obesity alone has been
reported previously. A significant relationship between the gene locus
and various global measures of adiposity was observed in populations as
diverse as Pima Indians and European whites.28 29 30 These
studies were performed in families or groups of unrelated individuals
with obesity, non–insulin-dependent diabetes mellitus, or
ischemic heart disease. The results of the current
investigation extend the previous observations in that they demonstrate
the effect of the locus in pedigrees with hypertension.
A role of the TNF- gene locus in obesity-associated hypertension has
not been previously demonstrated. However, it has been observed in an
isolated Native Canadian population that a positive correlation exists
between serum TNF- concentration and both systolic blood
pressure and insulin resistance in subjects with a wide range of
adiposity.31 Furthermore, TNF- has been implicated in
the development of endothelial dysfunction. In vascular
smooth muscle cells, TNF- was shown to stimulate the
production of a potent vasoconstrictor,
endothelin-1.18 Consistent with this in vitro
finding, significant positive correlations were found between serum
TNF- and serum endothelin-1 levels in patients with android
obesity.17 Moreover, in spontaneously hypertensive rats
(SHR), several studies have reported that TNF- synthesis and
secretion in response to lipopolysaccharide stimulation are
increased in comparison with normotensive controls.32 This
effect was most marked in adipose tissue and was associated with
increased angiotensinogen gene expression.20
In addition, the body temperature response to
lipopolysaccharide differs between SHR and its normotensive
control,33 and it has been demonstrated that this response
is, at least in part, determined by the TNF- gene
locus.34 Finally, the TNF- gene locus as a part of the
RT1 complex has been suggested in some,35 36 but not
all,37 38 studies to contribute to the pathogenesis of
hypertension in SHR and New Zealand genetically hypertensive rats.
In the present study, the effect of the TNF- gene locus on both
obesity and obesity-associated hypertension was found to be most
significant in nonmorbidly obese individuals. This finding is
consistent with the proposed actions of TNF- in obesity.
Enhanced activity of the cytokine due to the development of
obesity is, on one hand, predicted to contribute to the development of
hypertension but is, on the other hand, expected to limit the
progression of obesity.7
Gender-separate linkage analyses indicate that the TNF- gene
locus influences regional accumulation of fat, most significantly in
the abdominal region in men and in the thigh region in women. Such a
gender-specific effect of the TNF- gene could be the result of a
gender difference in the regional expression of either the gene itself
or any other element involved in the cascade of events that lead from
activation of the gene to its action in the target tissue. At
present, the only element in the TNF- cascade that is known to
have gender-specific regional effects is lipoprotein lipase
(LPL).39 This enzyme normally promotes lipid accumulation
in adipose cells. A significant proportion of the antiadipogenic
effects of TNF- are mediated through the inhibition of
LPL.10 Arner et al39 showed that both the
mRNA level and the enzyme activity of LPL are higher in abdominal than
in thigh adipose cells in men and vice versa in women. Notably, these
gender-specific regional differences of LPL closely parallel those of
the TNF- gene effect on body fat accumulation observed in the
present study, suggesting a possibility that LPL may be involved in
determination of the gender-specific regional effects of the TNF-
gene.
In conclusion, the results of linkage and association analyses
suggest that in hypertensive pedigrees of French-Canadian origin, the
TNF- gene locus contributes to the pathogenesis of obesity and
obesity-associated hypertension. Furthermore, the results also indicate
that the locus influences regional body fat distribution differently in
men and women.
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Acknowledgments |
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This work was supported by the Medical Research Council of Canada (grant MT-14654) and the National Institutes of Health (US Public Health Service grant 5-P50-HL-54998-02). We thank Drs Alan Deng and Jean-Louis Chiasson for their helpful comments on the manuscript, Ginette Dignard for her secretarial help, and Ovid Da Silva for his editorial assistance. We thank Manon Bernard, Danielle DeGuise, Nicole Baribault, and Jacinthe Tremblay for their work on phenotype collection.
Received November 3, 1999; first decision December 29, 1999; accepted February 18, 2000.
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E. H. Serne, R. T. de Jongh, E. C. Eringa, R. G. IJzerman, and C. D.A. Stehouwer Microvascular Dysfunction: A Potential Pathophysiological Role in the Metabolic Syndrome Hypertension, July 1, 2007; 50(1): 204 - 211. [Full Text] [PDF]
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H. Izawa, Y. Yamada, T. Okada, M. Tanaka, H. Hirayama, and M. Yokota Prediction of Genetic Risk for Hypertension Hypertension, May 1, 2003; 41(5): 1035 - 1040. [Abstract] [Full Text] [PDF]
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Z. Pausova, L. Sedova, J. Berube, P. Hamet, J. Tremblay, M. Dumont, D. Gaudet, M. Pravenec, V. Kren, and J. Kunes Segment of Rat Chromosome 20 Regulates Diet-Induced Augmentations in Adiposity, Glucose Intolerance, and Blood Pressure Hypertension, May 1, 2003; 41(5): 1047 - 1055. [Abstract] [Full Text] [PDF]
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J. M. Fernandez-Real, M. Broch, C. Richart, J. Vendrell, A. Lopez-Bermejo, and W. Ricart CD14 Monocyte Receptor, Involved in the Inflammatory Cascade, and Insulin Sensitivity J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1780 - 1784. [Abstract] [Full Text] [PDF]
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T. A. Kotchen, U. Broeckel, C. E. Grim, P. Hamet, H. Jacob, M. L. Kaldunski, J. M. Kotchen, N. J. Schork, P. J. Tonellato, and A. W. Cowley Jr Identification of Hypertension-Related QTLs in African American Sib Pairs Hypertension, November 1, 2002; 40(5): 634 - 639. [Abstract] [Full Text] [PDF]
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G. Villuendas, J. L. San Millan, J. Sancho, and H. F. Escobar-Morreale The -597 G->A and -174 G->C Polymorphisms in the Promoter of the IL-6 Gene Are Associated with Hyperandrogenism J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1134 - 1141. [Abstract] [Full Text] [PDF]
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Z. Pausova, F. Gossard, D. Gaudet, J. Tremblay, T. A. Kotchen, A. W. Cowley, and P. Hamet Heritability Estimates of Obesity Measures in Siblings With and Without Hypertension Hypertension, July 1, 2001; 38(1): 41 - 47. [Abstract] [Full Text] [PDF]
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