A Whole-Genome Scan for Stroke or Myocardial Infarction
in Family Blood Pressure Program Families
Richard Sherva, PhD; Michael B. Miller, PhD; James S. Pankow, PhD; Steven C. Hunt, PhD;
Eric Boerwinkle, PhD; Thomas H. Mosley, PhD; Alan B. Weder, MD;
J. David Curb, MD; Amy Luke, MD; Alanna C. Morrison, PhD;
Myriam Fornage, PhD; Donna K. Arnett, PhD
Background and Purpose—Atherothrombotic diseases, including stroke and myocardial infarction, share a common
pathogenesis. Chromosomal regions have been linked to atherothrombotic diseases in family studies, and association
studies have identified candidate gene polymorphisms that affect the risk of stroke and/or myocardial infarction. Using
data from the Family Blood Pressure Program, we tested for chromosomal regions linked to the composite phenotype
of stroke or myocardial infarction in a large set of hypertensive families.
Methods—Nonparametric linkage analysis was implemented in MERLIN, which tests for excess allele-sharing among
affected siblings. Empirical distributions based on gene dropping simulations were constructed for each test statistic, and
the ⫺log10 of the associated probability values were compared.
Results—Analyses were based on 9607 individuals in 226 black, 395 Hispanic, and 207 white families; 106 families had
multiple affected individuals. Several regions showed linkage to stroke or myocardial infarction, most significantly in
Hispanics on chromosomes 2p21 (⫺log10 P⫽3.0) and 7q21.1 (⫺log10 P⫽2.8), 9q32 in blacks and Hispanics (⫺log10
P⫽3.0), 11p13 in blacks (⫺log10 P⫽2.1), and 12q24.33 in whites (⫺log10 P⫽3.0).
Conclusions—There is statistically significant evidence for loci affecting stroke or myocardial infarction on chromosomes
2, 9, and 12. (Stroke. 2008;39:1115-1120.)
Key Words: cerebrovascular accident 䡲 epidemiology 䡲 linkage (genetics) 䡲 LOD score 䡲 myocardial infarction
Downloaded from http://ahajournals.org by on March 24, 2022
S
troke and myocardial infarction (MI) are common manifestations of atherothrombotic disease and together are
the leading cause of death and disability in the United States.
There are approximately 865 000 new and recurrent MIs in
the United States each year and 750 000 new and recurrent
cases of stroke.1 Ischemic blockage accounts for approximately
80% of stroke events; approximately 10% are due to intracerebral hemorrhage; 10% result from subarachnoid hemorrhage.2
Ischemic stroke and MI are similar phenotypes despite
occurring in different locations. They share several pathophysiological mechanisms (eg, inflammation, atherosclerosis,
plaque rupture, thrombosis, ischemic blockage) and risk
factors (hypertension, smoking, dyslipidemia, no or high
alcohol consumption, inflammation, homocystinemia, hypercoagulable states, diabetes).3,4 Both phenotypes have a substantial familial component. Monozygotic twins are 1.6 times
more likely to be concordant for stroke than dizygotic twins;
several studies show a small, significant increase in stroke
risk in those with a family history of stroke.5 MIs are
2.48-fold more common in individuals with a sibling who has
had an MI compared with those without.6 The heritability of
arterial and venous thrombosis is estimated at 60% using
liability threshold models.7 Past genome scans for stroke and
MI have identified potential regions and genes of interest in
various populations.8 –15
Combining stroke and MI allows detection of genes common to the pathogenesis of both and may increase power for
detection of susceptibility loci. Therefore, we performed a
genome scan for stroke or MI in black, Hispanic, and white
families enrolled in the Family Blood Pressure Program
(FBPP), the largest sample of families with data available for
linkage analysis on stroke and MI. A combination of liability
threshold and affected sibpair (ASP) models was used to
detect linked regions.
Received April 4, 2007; final revision received July 2, 2007; accepted July 20, 2007.
From the Division of Epidemiology and Community Health (R.S., M.B.M., J.S.P.), University of Minnesota, Minneapolis, Minn; the Cardiovascular
Genetics Division (S.C.H.), University of Utah School of Medicine, Salt Lake City, Utah; the Human Genetics Center (E.B.) and the Institute of Molecular
Medicine (E.B.), University of Texas–Houston Health Science Center, Houston, Texas; the Department of Medicine (T.H.M.), University of Mississippi
Medical Center, Jackson, Miss; the Division of Hypertension (A.B.W.), University of Michigan School of Medicine, Ann Arbor, Mich; the Pacific Health
Research Institute (J.D.C.), Honolulu, Hawaii; the Department of Preventative Medicine and Epidemiology (A.L.), Loyola University Strich School of
Medicine, Maywood, Ill; the Human Genetics Center (A.C.M.), University of Texas at Houston, Houston, Texas; the Institute of Molecular Medicine for
the Prevention of Human Diseases (M.F.), University of Texas Health Science Center, Houston, Texas; and the Department of Epidemiology (D.K.A.),
University of Alabama Birmingham, Ala.
Correspondence to Donna K. Arnett, PhD, MSPH, RPHB 220E, 1530 3rd Avenue South, Birmingham AL 35294-0022. E-mail arnett@uab.edu
© 2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.107.490433
1115
1116
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April 2008
Table 1.
Descriptive Characteristics of the FBPP Sample by Race (Nⴝ9607)
Mean (SD or %)
Variable
Black
Hispanic
White
P*
Age, years
50.5 (13.4)
55.2 (11.9)
53.3 (13.5)
⬍0.0001
Body mass index, kg/m2
31.2 (7.4)
30.9 (6.2)
29.7 (6.2)
⬍0.0001
Systolic blood pressure, mm Hg
130 (22.6)
131 (22.5)
127 (20.5)
⬍0.0001
Diastolic blood pressure, mm Hg
73 (12.5)
71 (10.6)
72 (11.1)
⬍0.0001
199.8 (44.4)
205.2 (47.1)
204.4 (38.2)
⬍0.0001
Cholesterol, mg/dL
Drinks per week
2.9 (8.9)
8.9 (14.7)
3.4 (6.6)
⬍0.0001
Stroke, N
189 (4.6)
76 (4.6)
117 (3.0)
0.0002
MI, N
188 (4.6)
111 (6.8)
252 (6.5)
Diabetes, %
17.9
60.9
10.7
⬍0.0001
Current smoker, %
27.7
17.2
13.9
⬍0.0001
0.0005
*P values are for analysis of variance tests for overall differences in outcome variables by race.
Materials and Methods
Recruitment and Participants
FBPP data were obtained by pooling data from 4 National Heart
Lung and Blood Institute hypertension genetics studies, The Genetic
Epidemiology Network (GenNet), the Genetic Epidemiology Network of Atherosclerosis (GENOA), the Hypertension Genetic Epidemiology Network (HyperGEN), and Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe).
Recruitment and inclusion criteria varied across networks and are
published elsewhere.16 Informed consent was obtained from all
participants.
Downloaded from http://ahajournals.org by on March 24, 2022
Data Collection
All networks measured a standard set of 95 phenotypes. Stroke and
MI data were obtained through self-report based on the following
questions: “Have you ever been told by a doctor that you had a heart
attack?” and “Have you ever been told by a doctor that you had a
stroke or transient ischemic attack?” Diabetes status was also
assessed in this manner. Lifestyle factors such as smoking status,
alcohol use, and family structure were ascertained by interview.
Anthropomorphic data were recorded according to standardized
protocols.
Other Measurements
Systolic and diastolic blood pressures were measured using an
automated device with a consistent protocol across networks. Blood
pressure was measured 3 times on each participant and averaged for
analysis. Lipids were measured spectrophotometrically using enzymatic methods (Cobas Mira analyzer; Roche Diagnostics) in
GENOA, an enzymatic method in SAPPHIRe, the ProAct cholesterol system (Roche) in GenNet, and an enzymatic method (COBAS
FARA centrifugal analyzer; Roche Diagnostics) in HyperGEN.
Genotyping
Genotyping was done by the National Heart, Lung and Blood
Institute Mammalian Genotyping Service (Marshfield, Wis). Genotypes for 391 short tandem repeat polymorphisms were determined
by automated polymerase chain reaction and scanning
fluorescence detection.
Statistical Analysis
Race-specific and combined Kong-Cox logarithm of the odds (LOD)
scores17 were calculated using the nonparametric LOD feature in
MERLIN,18 which tests for excess allele sharing among an ASP.
LOD scores were calculated within racial groups and summed to
obtain whole-sample estimates. In MERLIN,18 empirical probability
values were also calculated for Kong-Cox LOD scores based on
gene-dropping simulations in which a single, fully informative
marker is repeatedly, randomly “dropped” from parents to offspring
in pedigrees with the same structure and affection status as the actual
families. A LOD score was computed for each simulation
(N⫽1 000 000), the set of which was considered as an empirical
distribution under the null hypothesis of no linkage between marker
and trait loci.
Results
The overall FBPP characterized 9607 individuals. There were
226 black, 395 Hispanic, and 207 white families; 880
individuals reported a history of stroke or MI and 83
individuals reported a history of both events. Table 1 shows
baseline characteristics.
For ASP linkage analysis, there were 828 individuals in
103 families with multiply affected individuals: 29 families
had a pair of MI-affected individuals and 10 families had a
pair affected for stroke; 30 families had a discordantly
affected pair (ie, one had a stroke, one had MI); 13 families
had one member of the relative pair with both events and the
other had one event. Of the 21 families with more than 2
affected members, 5 had all affected members concordant for
a history of MI and 2 for history of stroke. The remaining 14
families had various combinations of concordant and discordant affection status among relative pairs. Kong-Cox LOD
scores were computed for 32 black, 26 Hispanic, and 37
white families with an ASP. The Figure shows the Kong-Cox
LOD plots for each race group and in the combined sample.
Table 2 shows the ⫺log10 of the empirically determined
probability values greater than 2.0 and their chromosomal
locations.
Discussion
In the FBPP, we found 3 significant linkage regions for the
composite phenotype that are consistent with prior reports
(summarized in Table 3). Although our LOD scores in these
previously identified linkage regions do not achieve genomewide significance, nor were they our most significant results,
we show ⫺log10 probability values of 1.9, 1.9, and 1.0 at
2q36-q37.3, 2q21.1-22, and 14q32.2, respectively. The previous 2q36-q37.3 signal was for MI or coronary heart disease
in a small sample of Australian ASPs,8 whereas our signal
was mainly in blacks. Genes of interest in the vicinity include
Sherva et al
Whole-Genome Scan for Stroke or MI
1117
Downloaded from http://ahajournals.org by on March 24, 2022
Figure. Kong-Cox LOD plots for stroke or MI in affected sibpairs.
insulin receptor substrate-1, the high-density lipoprotein cholesterol-binding protein, and calpain 10. Similarly, our modest signal at 14q32.2 was driven mainly by black and
Hispanic families, whereas the original finding was in Ger-
man families.11 Our replication of linkage on 2q21.1-22 was
also observed in both black and Hispanic families, but not in
whites. The original finding was in Finnish families ascertained for premature coronary heart disease.9 This region
1118
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April 2008
Table 2. Chromosomal Regions With ⴚlog10 P Values of
Combined Race Kong-Cox LOD Scores Greater Than 2.0
Location (cM)
⫺Log10 Kong-Cox
P Value
1
243
2.2
2
64
3.0
2
186
2.2
4
20
2.2
7
94
2.8
9
99
3.0
2.4
Chromosome
9
140
11
45
2.1
12
166
3.0
20
97
2.1
Downloaded from http://ahajournals.org by on March 24, 2022
contains the gene thrombospondin type-1 domain-containing
protein 7B precursor. The protein’s function has not been
characterized, although thrombospondin type-1, in addition to
its role in platelet aggregation and coagulation, interacts with
platelet-derived growth factor to stimulate smooth muscle
cell proliferation19 and with platelet glycoprotein IV (CD36)
to inhibit angiogenesis.20 The latter findings are of particular
interest because CD36, discussed in more detail subsequently, lies directly under our chromosome 7 peak. If the
thrombospondin type-1 domain on this protein has similar
functions, it could conceivably affect atherogenesis, stroke,
and MI through multiple pathways.
In addition to the genes located in previously identified
regions, our novel linkage regions also contain interesting
candidates. One of these lies directly under the peak at 20 cM
on chromosome 4. HS3ST1 encodes the rate-limiting enzyme
heparan sulfate 3-O-sulfotransferase-1, which in turn controls
production of the anticoagulant heparan sulfate (HSact) in
endothelial cells. HajMohammadi et al created an HS3ST1
double knockout mouse strain; although their tissue HSact
levels were dramatically reduced, the knockout mice showed
a similar hemostatic profile as wild-type mice. The authors
suggest that deficiency in the activity of the human HS3ST1
gene product might exert an affect only when combined with
deficiencies for other HS3ST1 isozymes or other
anticoagulants/fibrinolytics.21
Probably the most promising candidate gene in a novel
linkage region is located directly under the 93 cM peak on
chromosome 7. CD36 is a receptor for thrombospondin
type-1, which affects the adhesion of platelets to collagen.22
Substantial research has been conducted on this gene, mostly
in the context of metabolic syndrome and cellular fatty acid
uptake. Griffin et al found an increase in macrophage CD36
transcripts under high glucose conditions in human vascular
lesion cells, suggesting this as a mechanism for accelerated
atherosclerosis in patients with diabetes.23 Also, CD36 is a
scavenger receptor specific to oxidized low-density lipoprotein.24 Animal models collectively show that CD36 deficiency underlies insulin resistance, defective fatty acid metabolism, and hypertriglyceridemia.25–27 Finally, the evidence
suggesting this gene may interact with a domain of a protein
located in another of our stroke/MI-linked regions may
warrant molecular study of both genes.
We found racial/ethnic differences in our findings, consistent with the observed variation in lifestyle and, perhaps,
genetic factors that underlie these phenotypes across these
groups. Stroke and MI rates vary by race/ethnicity. Blacks
and Hispanic Americans have higher stroke rates than whites,
although stroke rate differences for Hispanics are mostly
attributable to Mexican Americans having an increased incidence of intracerebral hemorrhage and subarachnoid hemorrhage.28 In contrast, MI rates are similar across the ethnic
groups.1 Although we adjusted for lifestyle and other risk
factors in our analysis, it is likely that these adjustments did
not fully capture the nongenetic sources of variation among
ethnic groups. Additionally, gene– environment interactions
could explain the race-specific findings.
The different recruitment and inclusion protocols that gave
rise to the samples in each ethnic group could also have
influenced the results. Although similar inclusion criteria
were used in black and white families, Hispanic families were
eligible only if they had 2 or more members with adult-onset
diabetes. This fact could also imply different genetic mech-
Table 3. Linkage Peaks From Previous Genome Scans for Atherothrombotic Disease End Points and
ⴚlog10 P Values at Corresponding Locations in the Current Study
Chromosomal
Location
LOD
Score
Phenotype
Population
2q36-q37.3
2.63
MI/CHD
53 Australian sibpairs7
⫺log10 P Value From Current
Study (⌬ location)
8
1.9 (15 cM)
2q21.1-22
3.0
Premature CHD
156 Finnish families
1.9 (5 cM)
5q12
4.4
Ischemic stroke
476 Icelandic patients and 438 relatives13
0.7
5q12
2.06
Ischemic stroke
56 Swedish families14
0.7
10q23
2.06
CHD
99 Indo-Mauritian families9
0.0
11
13q12-13
2.86
MI
14q32.2
3.9
MI
513 western European families10
Icelandic females
1.0
0.1
16p13
3.06
CHD
99 Indo-Mauritian families9
0.8
Xq23-26
2.46
Premature CHD
156 Finnish families8
NA
⌬ location indicates difference between location of previously reported LOD score and location of peak in the current study;
difference equals zero if not listed.
CHD indicates coronary heart disease; NA, not applicable.
Sherva et al
anisms caused stroke and MI in different ethnic groups and
may explain the differences in linkage results. As an example,
the signal in the region of the CD36 gene was observed only
in Hispanics, 60% of whom are diabetic.
We confirmed our results using a liability threshold model
implemented in SOLAR, calculated an empirical LOD score
using 10 000 simulations, and compared the agreement between the magnitudes of the adjusted liability threshold LOD
and Kong-Cox LOD scores. There was evidence for linkage
using the liability threshold model at all the locations identified using ASP models, and the genomewide correlation
between the ⫺log10 of the probability values for LOD scores
calculated in threshold and at the corresponding location in
ASP analysis was 0.44, suggesting that the findings reported
here have good agreement with another independent method
of linkage analysis.
Study Limitations
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Phenotypic measurement methods were not optimal in this
study. First, stroke and MI history data were obtained through
self-report and were not verified. Also, people with a history
of stroke or MI that resulted in failure to meet inclusion
criteria (including fatal stroke or MI) were not enrolled. In
addition, stroke subtypes were not differentiated. Knowing
that approximately 80% of all strokes are ischemic, any genes
unique to this subtype would likely be overrepresented.
Combining stroke and MI events may or may not be a
weakness of these analyses. Although much evidence exists
that stroke and MI are influenced by similar pathophysiological mechanisms, there may still be significant heterogeneity
in the genetic mechanisms that influence risk, and certain risk
factors have stronger effects on either stroke or MI. For
example, serum cholesterol appears to be a more important
MI risk factor,29 and its effect seems to be opposite on
ischemic and hemorrhagic stroke risk.30 The importance of
other risk factors also differs between stroke and MI. Pulse
pressure is a significant predictor of MI but not stroke,31
whereas overall blood pressure predicts stroke rate but not
pulse pressure-adjusted MI.32 LOD scores from multivariateadjusted liability threshold models were very similar to
unadjusted scores, indicating that small differences in the
effects of certain prognostic factors on stroke versus MI
would not significantly bias the results. In addition, the high
number of families with members affected by both types of
events supports the idea that stroke and MI share common
genetic factors.
Finally, ascertainment of these families may have reduced
our power to detect linkage but does not increase the chances
of observing false-positive LOD scores. Enrolling the most
high-risk participants may reduce the amount of genetic
heterogeneity available and provide a less distinct “reference”
group to which affected individuals can be compared. Linkage results are robust to these issues, however, because LOD
scores are based on the correlation between genetic similarity
and phenotypic similarity. Although these families are, by
definition, genetically similar, and due to ascertainment more
phenotypically similar, the “Mendelian coin toss” on which
identity-by-descent calculations are based assures that ascertainment will not cause type 1 error.
Whole-Genome Scan for Stroke or MI
1119
In conclusion, we presented results of a whole-genome
scan for stroke or MI conducted in a large, ethnically diverse
pool of families. We used 2 fundamentally different linkage
models to show statistically significant evidence for loci
affecting stroke or MI on chromosomes 2, 9, and 12.
Source of Funding
Support for this research provided by The National Heart Lung and
Blood Institute cardiovascular disease genetics training grant 5 T32
HL007972.
Disclosures
None.
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