From the Departments of Molecular Genetics, Biochemistry, and
Microbiology (K.L.O., C.A.K., Y.R.S., A.G.M.) and Internal Medicine, Division
of Nephrology (M.P.R., M.R.), University of Cincinnati Medical Center (Ohio);
and Cardiovascular Genetics Group, Division of Cardiology, University of Utah
School of Medicine, Salt Lake City (S.C.H.).
Correspondence to Anil G. Menon, Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, 231 Bethesda Ave, Cincinnati, OH 45267-0524. E-mail Anil.Menon{at}uc.edu
The cloning of the ob gene in 1994 was an important advance
in the study of obesity.5 Indeed,
ob/ob mice are severely obese due to mutations in the
ob gene that result in the lack of secretion of functional
leptin protein, the product of the ob
gene.5 In mice, this obese phenotype can
be corrected by administration of recombinant leptin
protein.6 7 Leptin is a 16-kD protein expressed
predominantly in adipose tissue and is thought to act as a satiety
signal in a feedback mechanism involving a target receptor in the
hypothalamus.5 The end result of this feedback
loop is the regulation of body fat stores. Unlike the ob/ob
mice, a deficiency of circulating leptin has not been identified in
obese humans and, in fact, OB mRNA levels from adipose
tissue as well as serum leptin levels are
elevated.8 9 10 11 These findings suggested that it
was possible for obesity in humans to be caused by mutations in the
OB gene if altered expression or functionally defective
leptin protein resulted from such
mutations.12 13 14 Interest in identifying the loci
that contribute significantly to human obesity and hypertension is
based on the significant impact of such findings on the design of
pharmacological intervention strategies for both hypertension and
obesity.
Because there is a higher prevalence of both
hypertension2 and obesity15
in African Americans, they represent an excellent population in
which to identify potential genetic factors that contribute to both
traits. In this study we report the results of sib pair linkage
analysis and mutational analysis of the coding portion
of the leptin gene in a population of hypertensive African Americans.
We report the extent of allele sharing at highly polymorphic
loci within and around the OB gene in African American sib
pairs, using either the phenotype of essential hypertension or
the phenotype of obesity as measured by BMI and the absence of
significant nucleotide sequence variation in the coding
region of the leptin gene in the DNA of these individuals.
Treated hypertensive subjects were included if they reported the onset
of hypertension before age 60 years and were undergoing continuous
treatment with antihypertensive medication for the previous 6 months.
In hypertensive subjects not on antihypertensive treatment, average
diastolic blood pressure was confirmed to be >90
mm Hg on a second visit a week later. All index patients met the
following criteria: no reported history of secondary hypertension,
serum potassium level >3.5 mEq/L unless on thiazide or loop
diuretics, serum creatinine <1.6 mg/dL for men and
<1.4 mg/L for women, alcohol intake <1.5 oz of ethanol per day, and
no use of steroids or estrogen before diagnosis of hypertension. In
index subjects with non–insulin-dependent diabetes mellitus, the
diagnosis of hypertension had to precede the diagnosis of diabetes
mellitus by at least 5 years.
In this study two different traits were analyzed for excess
allele sharing at the leptin locus. First, essential hypertension
was analyzed as a qualitative trait with the use of the
previously described inclusion criteria for hypertensive subjects
because actual blood pressures could not be reliably used since many
subjects were already on antihypertensive medications. Second, we
analyzed BMI as a quantitative trait. A subset of sibships was
analyzed separately that included only those sib pairs in which
both sibs had a BMI
Clinical characteristics of the study population are summarized in
Table 1
Analysis of Sib Pair Relationships
Genotyping
SSCP Analysis
Statistical Analysis
MIM Program
Using sibling pair linkage analysis with these same markers, we
detected weak evidence for genetic linkage between BMI (considered a
quantitative trait) and the leptin locus in this same group of African
Americans with hypertension (P=0.08 for D7S1875,
P=0.27 for OB-tet, P=0.03 for D7S504,
and P=0.19 for D7S635) (Table 2
Since the results became more consistent across markers when
analysis included only those subjects with a BMI
Detection of Variants
Experimental data in rodents have suggested that leptin, the serum
protein encoded by the ob gene, plays a central role in
regulating food intake and energy
expenditure,6 7 8 and inactivation of this gene is
observed to cause severe obesity in mice. To determine whether
polymorphic markers at the human OB gene were linked
either to essential hypertension or to obesity, we performed linkage
analysis in a hypertensive African American population.
Affected sib pair analysis did not show any evidence of linkage
to the trait of essential hypertension and showed only suggestive
linkage to the phenotype of obesity (defined as BMI >27.8
kg/m2 for men and BMI >27.3
kg/m2 for women).15
Although analysis was performed with four different markers,
including OB-tet, a marker within the 3' untranslated region
of the OB gene, linkage was detected with only one marker,
D7S504, which lies outside OB.
Part of the reason why the MIM results were not as significant as the
SIBPAL results is that only full siblings could be used in MIM. This
resulted in a loss of approximately one quarter of the total sib pairs
and a corresponding loss of power. However, the fact that the
multipoint analysis did not improve the overall significance
level and that the OB-tet marker, which is located within
the leptin gene, was not significant in this analysis
diminishes the likelihood that the suggestive linkage by individual
markers is real. Analysis of a larger population of sibships
will therefore be required to increase the power of this study. Further
patient recruitment is under way. Other groups have detected stronger
genetic linkage between severe obesity and the human OB
gene12 13 by using a higher BMI threshold (35
kg/m2) in the collection of sib pairs. Our study
was directed at essential hypertension and the more commonly seen form
of obesity (average BMI >27.3 kg/m2 for women
and >27.8 kg/m2 for
men),15 and our data suggest that OB
is not a major contributor to either trait in this population of
African Americans. Other studies suggest that genes other than
OB may play the major role in human obesity. Comuzzie et
al22 report the identification of a distinct
locus on human chromosome 2 that confers susceptibility to obesity in
white populations.22 As in our study of African
Americans, Comuzzie et al found no evidence of linkage to obesity with
markers on chromosome 7 in the region containing the leptin
(OB) gene in Mexican Americans.
Although the sib pair method of analysis did not detect
linkage, our study does not exclude the possibility that the
OB gene is linked to BMI in the African American population.
Complex disorders such as obesity may require very large numbers of sib
pairs (reviewed by Schork23) to provide adequate
power to detect linkage and power calculations on our population well
below the 80% threshold generally used in such studies. Further
complications could include the problem of "admixture" in the
African American population. Therefore, our findings can only be
considered preliminary at this point.
To address the possibility that our sib pair analyses may have
lacked the power to detect linkage between OB and
hypertension and the inherent difficulties that are posed by genetic
admixture in the study population, we performed mutational
analysis of the human OB gene using DNA from
individuals in this population. SSCP analysis of the 167
African American subjects in our study did not reveal any significant
alterations in the coding region of the human OB gene. A
single polymorphism was detected in exon 2, ATT(Ile) to
GTT(Val), a conservative alteration in amino acids not
expected to significantly alter the function of the protein. This
variant was not present in the corresponding sibling or in any
other individual analyzed and is therefore more likely to be a
neutral sequence variation than a mutant that alters leptin function.
This absence of mutations is consistent with recent reports in
other human populations22 23 24 25 26 and strengthens the
absence of linkage in this study. Although we cannot exclude the
possibility that alterations in the promoter or regulatory regions of
this gene are affected in these individuals, our data and the data from
other reports indicate that the leptin locus is not significantly
linked to BMI and that polymorphic variants in the coding region of
the leptin gene are not seen in individuals with high BMI.
Received October 21, 1997;
first decision November 10, 1997;
accepted January 13, 1998.
2.
Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts
RH. Weight and blood pressure: findings in hypertension screening of 1
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PM. The relation of adiposity to blood pressure and development of
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Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT,
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Magosin SA, Bauer TL, Rasato EL, Colberg J, Caro JF. Evidence against
either a premature stop codon or the absence of obese gene
mRNA in human obesity. J Clin Invest. 1995;95:2986–2988.
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JF. Serum immunoreactive-leptin concentrations in normal-weight and
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Extreme obesity may be linked to markers flanking the human
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13.
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Carey A, Harris T, Jury C, Cardon LR, Basdevant A, Demenais F,
Guy-Grand B, North M, Froguel P. Indication for linkage of the human
OB gene region with extreme obesity. Diabetes. 1996;45:687–690.[Abstract]
14.
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Concannon P. Identification of microsatellite markers near the human
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15.
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obesity in the United States. Ann Intern Med. 1985;103:983–988.
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T, Nakagowa Y, Hamuda Y, Ueda H, Miki T, Ogihara T. A novel
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Scientific Contributions
Genetic Markers at the Leptin (OB) Locus Are Not Significantly Linked to Hypertension in African Americans
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—Increased body mass index
(BMI) has been correlated with increased blood pressure in human
populations. To examine the role of the leptin gene (OB)
in essential hypertension in African Americans, we performed affected
sib pair analysis on a set of 103 hypertensive African American
sibships using four highly polymorphic markers at the human leptin
locus. No evidence of linkage was detected between these markers and
the phenotype of essential hypertension either in these
sibships or in a severely obese subset of 46 sibships in which each
sibling had a BMI 
85th percentile for the US population. Using BMI
rather than hypertension as a quantitative trait, we found significant
linkage for the marker D7S504 (P=0.029) but not for the
other markers. Significance strengthened in the overweight subset of
sibships for this marker (P=0.001), and there was a
trend of lower P values for the other three markers.
However, multipoint analysis with the use of all four markers
simultaneously to estimate linkage between BMI and the
leptin locus did not demonstrate a statistically significant
relationship. Analysis of the coding region of the leptin gene
(exons 2 and 3) by single-strand conformational polymorphism
revealed a rare Ile-Val polymorphism at amino acid 45 but revealed
no other alterations. These results suggest that the OB
gene is not a major contributor to the phenotype of essential
hypertension in African Americans, although a minor contribution to the
phenotype of extreme obesity in this group cannot be ruled
out.
Key Words: obesity • hypertension, essential • leptin • body mass index
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Essential
hypertension and obesity both result from multiple environmental and
genetic determinants. These disorders are closely linked in
epidemiological studies,1 with high BMI strongly
correlated with increased blood pressure2 3 and
lean individuals with elevated blood pressure showing a predisposition
to becoming obese.3 While environmental
determinants certainly account for some of this epidemiological
linkage, shared genetic determinants may also contribute to the
association between hypertension and obesity. For example, monozygotic
twins have a higher concordance rate for the joint occurrence of
hypertension and obesity (31%) than dizygotic twins (15%), and
multivariate genetic modeling using this twin data
suggests a common latent factor that is, in part, likely to be
genetically determined.4
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
The population base consisted of 103 hypertensive sibships
(consisting of 24 half sibships and 79 full sibships) that came from 73
families and included 167 individuals. The number of sib pairs
analyzed for each marker used in the analysis is shown
in Table 2
. Subjects were recruited from the Hypertension Clinics of
the University of Cincinnati and the Veterans Administration Hospital,
as well as from the community at large. The study was approved by the
Institutional Review Board of the University of Cincinnati. All
subjects underwent a brief clinical evaluation and provided a blood
sample for plasma electrolytes and DNA isolation. Subjects were seated
for 5 minutes, after which blood pressure readings were done in
triplicate with the use of a mercury manometer with the appropriate
cuff size based on the upper midarm circumference. Korotkoff phase V
was used to define the diastolic pressure. Height was
self-reported, but weight was measured with street clothing.
View this table:
[in a new window]
Table 2. Affected Sibling Pair Linkage Analysis
Between Markers Near the Leptin Locus and Hypertension or BMI in
African Americans 85th percentile for the US population (27.8
kg/m2 for men and 27.3
kg/m2 for women).15
Although the terms obesity and overweight are often used
interchangeably, obesity implies excess body fat, which is not always
correlated with being overweight. It should be emphasized that in this
study BMI rather than excess fat was measured. . The range of BMIs in the entire
group was 18.1 to 56.8 kg/m2, with the BMI <27
in 26 subjects, 27 but <37 in 99 subjects, and 37 in 42
subjects.
View this table:
[in a new window]
Table 1. Clinical Characteristics of Hypertensive African
American Siblings
Establishment of full or half sibling relationships was based on
questionnaires to the study subjects as well as PCR genotyping of DNA
from these subjects with the use of 17 unlinked highly polymorphic
markers. These markers were CD4, D16S408, D16S420, AGT, AE3, D7S504,
D14S59, D6S282, D1S188, D14S81, D1S162, D10S179, LA4, SPN, RPN, NHE5,
and D15S126. The identity-by-descent assumptions of full sibships
sharing 50% of their genomes and half sibships sharing 25% of their
genomes were transformed to identity-by-state expectations with the use
of the Weeks and Lange equation.16 We determined
95% confidence intervals for each sibship using genotype
information to calculate variance with (N-1) degrees of freedom, where
N is the number of markers. The average observed number of alleles
shared for these markers was calculated and compared with the 95%
confidence intervals calculated for full and half sibships. Only
sibships falling within the 95% confidence interval for a full sibling
pair or a half sibling pair were included in the analysis.
Subjects were genotyped at four closely linked short
tandem repeat polymorphisms: one in the 3' UTR of the OB
gene (OB-tet),17 one telomeric to the
OB locus (D7S1875), and two centromeric to the OB
locus (D7S635 and D7S504).18 These markers are
known to be within a 1-cM segment of chromosome 7 based on the
high-density genetic map of this chromosome available through the
Whitehead/Massachusetts Institute of Technology Center for Genome
Research. Primers for OB-tet were designed on the basis of
the published genomic sequence.19 Primers for
markers D7S1875, D7S635, and D7S504 were obtained from Research
Genetics Inc and end-labeled with 32P with the
use of standard protocols. PCR was performed in accordance with the
manufacturers' suggested conditions in a PTC 100 thermal cycler from
MJ Research Inc. PCR products were resolved on 6% denaturing
polyacrylamide gels and autoradiographed with the use of Kodak
XAR film, and alleles were sized relative to markers of known
size.
SSCP analysis was performed on exons 2 and 3, which
represent the entire protein-coding region of the OB
gene. Exon 3 is a large exon and was therefore divided between two sets
of primers. Each 15-µL SSCP PCR reaction contained 100 ng of human
genomic DNA template, a primer concentration of 0.25 pmol/µL, and 0.1
µL [
-32P]dATP. PCR products were
denatured and then resolved on nondenaturing MDE gels that were
subsequently vacuum dried and autoradiographed. Abnormal conformers
were cut out from gels, eluted in double-deionized water, and
reamplified. Both strands were sequenced without subcloning with the
use of an automated ABI 377 sequencer.
The most recent update of the sib pair linkage program SIBPAL
version 2.7 (1996) of the program package Statistical Analysis
for Genetic Epidemiology was used to calculate
linkage. SIBPAL performs a linear regression between the estimated
proportion of alleles a sib pair shares identical by descent at a
locus and the square of the sib pair trait difference. (For a
qualitative trait, the trait difference is 0 for sibs who share the
same trait and 1 for sibs who do not share the same trait.) When
parental data are missing, as in our study, this program uses the
phenoset for all possible genotypes. Allele frequencies
were calculated with the use of the genotype of one member from
each family. The logarithm of BMI was used because of the positive skew
in the distribution of BMIs to facilitate data handling. The inclusion
of the covariates age and gender in the BMI analysis did not
significantly change results (data not shown).
The multipoint IBD (identity by descent) method
(MIM)20 21 was also used to estimate linkage
between BMI as a quantitative trait and the OB locus.
Assumed distances of 0.3 cM between D7S1875 and OB-tet, 0.3
cM between OB-tet and D7S504, and 0.3 cM between D7S504 and
D7S635 were used in the analysis since all four markers are
known to be within a 1-cM segment of chromosome 7 based on the
high-density genetic map of this chromosome available through the
Whitehead/Massachusetts Institute of Technology Center for Genome
Research. Since this program only handles full siblings, the half
siblings were not included in this analysis. The log of BMI was
standardized to a mean of 0 and SD of 1. This method estimates the
proportion of genetic variance for BMI that is attributable to the
OB gene region encompassed by these four markers. This
method also requires either an estimate of the proportion of total
variance in BMI that is due to additive genes or the use of multiple
estimates spanning a reasonable range of proportions. Most studies have
estimated that the additive genetic variance for BMI ranges from 20%
to 40%. Therefore, we tested for linkage assuming 10%, 20%, 30%,
and 50% total genetic variance. The null hypothesis is that the
proportion of additive genetic variance due to the marker loci is 0.
Deviation from this hypothesis was tested with the use of a
2 test with 1 df. P
values from this test are shown in Table 4.
View this table:
[in a new window]
Table 4. Multipoint (MIM) Analysis
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Affected Sib Pair Analysis
In this study two different traits, one qualitative and one
quantitative, were analyzed for genetic linkage determined by
excess allele sharing at the leptin locus. The first was
hypertension as a qualitative trait; actual blood pressure could not be
used because most subjects were already on antihypertensive treatment.
The second was obesity, measured by BMI, as a quantitative trait.
Subjects were genotyped at four closely linked short tandem
repeat polymorphisms: D7S1875, D7S635, D7S504, and
OB-tet, which is actually part of the OB gene.
These markers were chosen because of their highly polymorphic
nature, with heterozygosity scores of 0.894, 0.854, 0.797, and 0.853,
respectively. Sib pair linkage was first used to calculate linkage with
hypertension. Table 2
shows results of
the analysis with four different polymorphic markers at the
leptin locus. Linkage was not detected between the phenotype of
essential hypertension (considered a qualitative trait) and the leptin
locus in African Americans. Marker D7S504 showed the greatest excess
sharing of alleles for full sibs (0.525) but also showed less than
expected sharing for the half sibs (0.197). OB-tet had
nonsignificant excess sharing for the half sibs but no excess for the
full sibs. Therefore, there was no consistent evidence for any
trend toward linkage. The results did not change when the sib pairs
being analyzed were limited to those whose BMI was 85th
percentile (Table 3). Therefore, our
analysis suggests that the human leptin locus does not play a
major role in the etiology of essential hypertension in African
Americans, although it does not formally exclude a minor role for this
locus in hypertension.
View this table:
[in a new window]
Table 3. Affected Sibling Pair Linkage Analysis
Between Markers Near the Leptin Locus and Hypertension or BMI in
African Americans With BMI 85th Percentile for the US Population). The evidence for this
linkage was slightly stronger when the analysis was restricted
to a subset of 46 sibships in which each sibling had a BMI 85th
percentile for the US population (P=0.08 for D7S1875,
P=0.08 for OB-tet, P=0.001 for D7S504,
and P=0.06 for D7S635) (Table 3). 85th
percentile, it was important to perform a multipoint analysis
of the data. This method estimates the proportion of genetic variance
for BMI that is attributed to the OB gene region encompassed
by these markers. The program MIM (University of Utah, Salt Lake City)
was used to perform this analysis on each marker individually
and on all markers simultaneously. As can be seen in Table 4, the MIM results for each individual
marker were not significant for any estimate of total additive
variance. The multipoint analysis did not show significance and
resulted in little increase of information above that contained by the
marker D7S1875 alone.
SSCP analysis was used to detect mutations in the human
OB gene in the population. The OB gene is encoded
by three exons. Exon 1, only 29 bp in size, is not part of the
protein-coding region and was therefore excluded from the
analysis. The entire coding sequence of the OB gene,
represented by exons 2 and 3, was amplified through PCR
with the use of three sets of primers. One conformational variant was
found in exon 2, and sequencing revealed an ATT(Ile) to
GTT(Val) transition. This polymorphism was not
present in the corresponding sibling or in any other individual
analyzed. No other variants were detected in the coding
sequence of the OB gene.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Essential hypertension and obesity are both thought to be caused
by multiple environmental and genetic determinants. These two traits
are closely linked in epidemiological studies, and essential
hypertension is estimated to be up to three times more prevalent among
the obese.15 This correlation suggests that
essential hypertension and obesity may share genetic determinants in
some individuals.
Selected Abbreviations and Acronyms
BMI
=
body mass index
MIM
=
multipoint IBD (identity by descent) method
PCR
=
polymerase chain reaction
SSCP
=
single-strand conformational polymorphism
Acknowledgments
This study was supported in part by grants from the National
Institutes of Health Program of Excellence and Markey Foundation (to
A.G.M.), Dialysis Centers Inc (to M.P.R. and M.R.), and the National
Institute of Diabetes and Digestive and Kidney Diseases (to S.C.H). We
wish to thank Drs Gary Shull and Pierre Meneton for discussions and
helpful comments on the manuscript and to acknowledge the excellent
technical assistance of Terri Lewis, Kristen Braig, and Martin Heur.
Some of the results in this article were obtained by using the program
package SAGE, which is supported by a US Public Health Service resource
grant (1 P41RR03655) from the Division of Research Resources.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Kaufman JS, Durazo-Arvizu RA, Rotimi CN, McGee DL,
Cooper RS, for the Investigators of the International Collaborative
Study on Hypertension in Blacks. Obesity and hypertension prevalence in
populations of African origin. Epidemiology. 1996;7:398–405.[Medline]
[Order article via Infotrieve]
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