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(Stroke. 2003;34:1170.)
© 2003 American Heart Association, Inc.

Original Contributions

Evaluating the Context-Dependent Effect of Family History of Stroke in a Genome Scan for Hypertension

Alanna C. Morrison, PhD; Andrew Brown, MD, MPH; Sharon L.R. Kardia, PhD; Stephen T. Turner, MD Eric Boerwinkle, PhD for the Genetic Epidemiology Network of Arteriopathy (GENOA) Study

From the Human Genetics Center, University of Texas, Houston Health Science Center, Houston (A.C.M., E.B.); Department of Medicine, University of Mississippi Medical Center, Jackson, Miss (A.B.); Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor (S.L.R.K.); Division of Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minn (S.T.T.); and Institute of Molecular Medicine, Houston, Tex (E.B.).

Correspondence to Alanna C. Morrison, PhD, Human Genetics Center, University of Texas, Houston Health Science Center, 1200 Herman Pressler, Ste 453 E, Houston, TX 77030. E-mail Alanna.C.Morrison{at}uth.tmc.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose— Hypertension is an important risk factor for stroke, and the 2 diseases may share susceptibility genes in common. We sought to identify genomic regions influencing susceptibility to both hypertension and stroke.

Subjects and Methods— Genome-wide linkage scans were performed in samples of 338 white and 265 black hypertensive sibships recruited by the Genetic Epidemiology Network of Arteriopathy Study of the NHLBI Family Blood Pressure Program (FBPP). The hypertensive sibships were stratified by positive (+FH) or negative (-FH) family history of stroke. Genome-wide scans were repeated in each stratum, and the results were compared within each ethnic group by a regression-based analysis of heterogeneity.

Results— In whites, the best evidence for linkage was found on chromosome 16 in the unstratified sample of hypertensive sibpairs (logarithm of odds [LOD]=1.85 at 71 cM). In blacks, the best evidence for linkage was found on chromosome 2 in the unstratified sample of hypertensive sibpairs (LOD=1.95 at 230 cM). Additional evidence for linkage (LOD 1.5) was observed among white hypertensive sibpairs with a -FH on chromosome 13 and among black hypertensive sibpairs with a +FH of stroke on chromosome 19.

Conclusions— Significant evidence for linkage heterogeneity among hypertensive sibpairs stratified by family history of stroke suggests the presence of genes influencing susceptibility to both hypertension and stroke on chromosomes 13 (whites) and 19 (blacks). Although no significant evidence of heterogeneity was observed on chromosome 16 in whites and chromosome 2 in blacks, these chromosomes do provide evidence of linkage to hypertension.

Key Words: hypertension • linkage (genetic) • stroke

	Introduction

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Individuals untreated or undertreated for hypertension are at significant increased risk of stroke.¹ Although genetic mutations have been identified for rare mendelian forms of hypertension² and stroke,^3,4 the genetic contribution to these diseases in the general population likely involves a large number of genes influencing multiple physiological systems. The established epidemiological relationship between hypertension and stroke^5,6 and results from animal model studies⁷ indicate that these diseases may share at least some genes in common. Identification of genes contributing to hypertension and stroke is complicated by the fact that the effect of any one gene may be only small to moderate in size. Overcoming this complication may be realized by the application of appropriate analytical strategies to samples of individuals of sufficient size and homogeneity.

Our objective was to first perform a genome-wide scan for hypertension in samples of white and black hypertensive sibpairs recruited by the Genetic Epidemiology Network of Arteriopathy (GENOA) of the NHLBI Family Blood Pressure Program (FBPP). Genome scans were then repeated in samples of hypertensive sibpairs stratified by family history of stroke information, and the results were compared. Significant evidence for linkage heterogeneity among hypertensive sibpairs stratified by family history of stroke suggests the presence of genes influencing susceptibility to both hypertension and stroke.

	Subjects and Methods

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Affected Sibpairs
Subjects in this study included 603 sibships comprised of 2 to 7 individuals (338 white and 265 black sibships) (Table 1). The sibships were recruited by the GENOA Study. GENOA is 1 of 4 multicenter networks comprising the Family Blood Pressure Program (FBPP), a large NHLBI study of the genetics of hypertension and its target organ complications. The 3 GENOA field centers, located in Jackson, Mississippi, Starr County, Texas, and Rochester, Minnesota, recruited blacks, Mexican Americans, and non-Hispanic whites, respectively. The field centers in Jackson and Rochester recruited sibships containing at least 2 individuals with hypertension diagnosed before age 60. The data analyzed here focus on these 2 ethnic groups. A standardized algorithm was used to define the blood pressure diagnostic category. Participants included in the present analyses met at least 1 of the following 2 criteria for the diagnosis of hypertension: prior diagnosis of hypertension by a physician and use of prescription antihypertensive medication reported at the study visit; or the second and third blood pressure measurements obtained at the study visit averaged 140 mm Hg for the systolic pressure or 90 mm Hg for the diastolic pressure. Exclusion criteria included hypertension onset at an age 60 years, secondary hypertension, alcoholism or drug abuse, insulin-dependent diabetes mellitus, active malignancy, or pregnancy or lactation. Selection bias occurs when there is a difference between the characteristics of the people selected for the study and the characteristics of those who are not. Although the impact of this bias on the study findings is not easily determined, prevalence-incidence bias may potentially exist in this study.

View this table: [in this window] [in a new window]   TABLE 1. Summary of Hypertensive Sibships

All available full biologic siblings of the index sibling pairs were invited to participate in interviews, physical examinations, and phlebotomy. A detailed description of the FBPP design and methods is published elsewhere.⁸ Individuals were measured for a number of demographic and clinical variables of interest, including information related to family history of stroke as determined by questionnaire. Kornegay et al⁹ have reported that there is a reasonable agreement between proband-reported family history of stroke and self-reported personal history of stroke in members of the proband’s family. Additionally, it has been shown that the accuracy of reporting is high for other common diseases, such as myocardial infarction,¹⁰ coronary heart disease, diabetes, hypertension, and asthma.¹¹ Positive family history was defined by proband-reported history of stroke or cerebral hemorrhage diagnosed by a physician for either biologic parent or at least 1 full biologic sibling. The proportion of hypertensive sibships with a positive family history of stroke was 0.49 in whites (n=165) and 0.40 in blacks (n=107).

Genotypes
An average of 411 microsatellite markers equally spaced approximately every 8.4 cM throughout the genome were genotyped by standard protocols. Marker incompatibilities, such as potential genotyping errors and misclassification of biological relationships, were tested using the program ASPEX¹² and PedCheck.¹³ Only full sibpairs were included in the linkage analyses reported here.

Linkage Analyses and Test of Heterogeneity
Multipoint linkage analyses were performed using MAPMAKER/SIBS.¹⁴ Genotypes at all marker loci were used to calculate multipoint identity by descent (IBD) probabilities every 1 cM using a hidden Markov model. Marker order and map locations were deduced from the Marshfield map.¹⁵ Maximum likelihood estimation¹⁶ was used to determine marker allele frequencies within each ethnic group. Linkage evidence is expressed in terms of multipoint LOD scores.

Genome scans were performed for the unstratified sample of hypertensive sibpairs in each ethnic group and were repeated in the groups stratified by family history of stroke information. On the basis of results of these analyses, regions were identified (LOD 1.5) indicating evidence of linkage in the hypertensive sibling pairs with a +FH, a -FH, or unstratified analyses. A region of increased evidence of linkage among one family history of stroke strata compared with the other suggests the presence of a locus that may be influencing susceptibility to both hypertension and stroke. A regression-based test of heterogeneity was applied to evaluate whether these results are due to chance or they represent evidence for linkage heterogeneity among hypertensive sibpairs with differing family history of stroke information. The regression-based test of heterogeneity was performed post hoc by first identifying all regions for which the maximum LOD score for a given peak was greater than 1.5, regardless of whether the peak resulted from a genome scan of the stratified or unstratified samples. At a location m, chosen to best represent the maximum evidence for linkage at a peak, the estimated proportion of alleles shared IBD (_mi) was calculated for a given sibpair i by the equation _mi=(2)_mi+(1)_mi/2, where (1)_mi and (2)_mi are the probabilities of sharing 1 or 2 alleles IBD, respectively. A regression model may be fit to test the null hypothesis that _mi=0.50. This analysis was extended to include a variable (X_i) that quantifies differential IBD sharing among sibpairs with differing exposure profiles (_mi=+ßX_i), such as positive (X_i=1) versus negative (X_i=0) family history of stroke.^17,18 The null hypothesis is that ß=0, indicating that there is no imbalance in IBD sharing across exposure profiles. If there is linkage and a positive family history of stroke is associated with increased evidence for linkage, then ß>0. The null hypothesis was evaluated by a Wald statistic. The regression-based test of heterogeneity assumes independence among sibpairs. Violation of this assumption by including the total sample of nonindependent sibpairs did not lead to any changes in the results (data not shown).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 2 contains basic descriptive statistics for select variables in each ethnic group. In addition to the proportion of men, means and standard deviations are reported for age, body mass index, systolic and diastolic blood pressure, and cholesterol levels. Mean age and systolic blood pressure were significantly greater among white individuals with positive family history of stroke as compared with those with a negative family history. The proportion of men was significantly greater among white individuals with a negative family history of stroke than those with a positive family history. Mean levels and proportions of the descriptive characteristics did not significantly differ between family history of stroke stratum in blacks.

View this table: [in this window] [in a new window]   TABLE 2. Descriptive Statistics

The results from the linkage analyses are reported as multipoint LOD score plots for chromosomes containing a peak LOD 1.5. Two chromosomes meeting this criteria were identified for whites (Figure 1), and an additional 2 chromosomes were identified in blacks (Figure 2).

View larger version (20K): [in this window] [in a new window]   Figure 1. Multipoint linkage results for whites. Significance of the regression-based test of heterogeneity is reported as a probability value.

View larger version (22K): [in this window] [in a new window]   Figure 2. Multipoint linkage results for blacks. Significance of the regression-based test of heterogeneity is reported as a probability value.

In whites, the best evidence for linkage was found on chromosome 16 in the unstratified sample of hypertensive sibpairs (Figure 1, LOD=1.85 at 71 cM and LOD=1.32 at 91 cM). Stratification by family history of stroke revealed that sibships with a +FH were associated with the linkage evidence at the first peak (LOD=1.58 at 71 cM), whereas sibships with a -FH appeared to explain the linkage evidence at the second peak (LOD=1.30 at 88 cM). To investigate these observations, the regression-based test of heterogeneity was performed at 71 and 91 cM. This test did not reveal a significant imbalance in IBD sharing between hypertensive sibpairs stratified by family history of stroke information (ß=0.02, P=0.39 at 71 cM; ß=-0.01, P=0.61 at 91 cM). Additional evidence for linkage was observed among white hypertensive sibpairs with a -FH on chromosome 13 (Figure 1, LOD=1.56 at 26 cM). The regression-based test of heterogeneity was evaluated at 26 cM, indicating a significant imbalance in IBD sharing among hypertensive sibpairs with a -FH compared with those with a +FH (ß=-0.07, P=0.004).

In blacks, the best evidence for linkage was found on chromosome 2 in the unstratified sample of hypertensive sibpairs (Figure 2, LOD=1.41 at 181 cM and LOD=1.95 at 230 cM). Visual inspection of the peak at 180 cM suggested that sibships with a -FH appeared to comprise the linkage information at that location. The regression-based test of heterogeneity evaluated at this location did not reveal an imbalance in IBD sharing among hypertensive sibpairs with a -FH compared with those with a +FH (ß=-0.01, P=0.52). No significant evidence of heterogeneity was detected when the test was evaluated for the second peak on chromosome 2 at 230 cM (ß=-0.02, P=0.34). Additional evidence for linkage was observed among black hypertensive sibpairs with a +FH on chromosome 19 (Figure 2, LOD=1.67 at 9 cM and LOD=1.76 at 30 cM). A significant difference in IBD sharing among hypertensive sibpairs with a +FH, compared with those with a -FH, was observed at 30 cM (ß=0.05, P=0.05).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Linkage analyses in sibpairs have proven successful for localizing susceptibility genes in complex disease.^19,20 Minimizing heterogeneity among sibpairs through the analysis of appropriate subgroups may increase success in the identification of suggestive genomic regions. We have attempted to define subgroups of individuals of sufficient size and homogeneity by stratification of hypertensive sibpairs based on a priori knowledge of family history of stroke information. Comparisons of unstratified and stratified analyses led to the identification of regions on chromosomes 13 and 16 in whites and on chromosomes 2 and 19 in blacks, demonstrating evidence for linkage (LOD 1.5). A regression-based test of heterogeneity was performed to evaluate whether the differences in evidence for linkage in these regions observed between the groups of hypertensive sibpairs stratified by family history of stroke information may be due to chance. The results suggest that the peak LOD scores determined in whites on chromosome 13 (26 cM) and in blacks on chromosome 19 (30 cM) represent evidence for heterogeneity among hypertensive sibpairs with differing family history of stroke information. These regions potentially contain genes influencing susceptibility to both hypertension and stroke.

The region on chromosome 13 identified in whites (Figure 1) overlaps with a region detected in a genome-wide scan for susceptibility genes influencing body mass index in 2 complementary samples of white subjects (LOD=3.2).²¹ An additional study in a dizygotic twin sample indicated evidence for linkage in a neighboring region for low-density lipoprotein levels, high-density lipoprotein levels, total cholesterol levels, and body mass index.²² It has been proposed that the gene acting in this region lowers cholesterol. Epidemiologic research from the Framingham Study spanning 5 decades has indicated that hypertension usually occurs in conjunction with other metabolically linked risk factors such as glucose intolerance, obesity, left ventricular hypertrophy, and dyslipidemia, including elevated total and LDL cholesterol levels, raised triglyceride levels, and reduced HDL cholesterol levels.²³ Clustering of these risk factors with hypertension significantly contributes to increased risk of coronary disease, stroke, peripheral artery disease, and heart failure. On the other hand, reduction in the number of risk factors present in a hypertensive individual may decrease the risk of vascular disease. Hence, it is possible that a gene located in the region identified on chromosome 13 decreases stroke risk by lowering cholesterol levels or influencing interindividual variation in body mass index in hypertensive individuals. White individuals with a negative family history of stroke were observed to have lower body mass index and cholesterol levels than subjects with a positive family history of stroke (Table 2); however, these differences were not statistically significant. Although the 5-hydroxy-tryptamine receptor gene (HTR2A) has been suggested as a candidate gene in this region,²¹ a search of available databases did not yield additional obvious candidate genes in this region, indicating the existence of a novel gene potentially influencing both hypertension and stroke risk.

Interesting candidate genes in the region identified on chromosome 19 among blacks with a +FH include the LDL receptor and the intracellular adhesion molecule-1 (ICAM-1). The role of the LDL receptor in lipid homeostasis includes delivery of lipids required for cellular function and regulating the concentration of cholesterol-rich lipoproteins in the circulation.²⁴ Recent studies also suggest that diseases such as hypertension and atherosclerosis exhibit vascular changes that are characteristic of an inflammatory response. These vascular alterations are associated with, and influenced by, change in the avidity and density of adhesion molecules,²⁵ such as ICAM-1. Hence, given their hypothesized role in atherosclerotic processes, both the LDL receptor and ICAM-1 deserve further attention as candidate genes mediating increased risk of stroke among hypertensive individuals.

This study was motivated by the idea that significant evidence for linkage heterogeneity between hypertensive sibpairs stratified by family history of stroke information would identify particular gene regions, influencing susceptibility to both hypertension and stroke. Regions were also identified for which evidence of linkage (LOD 1.5) existed in the analysis of the unstratified sample of hypertensive sibpairs but was decreased in the stratified analyses. Lack of significant heterogeneity between hypertensive sibpairs with differing family history of stroke information suggests that the observed decreased evidence for linkage in the stratified sample may simply be a consequence of the reduction in sample size. Nevertheless, the regions identified in the unstratified samples warrant further attention as hypertension candidate gene regions. Support for a hypertension candidate gene on chromosome 2 comes from recent studies^26,27 corroborating the evidence for linkage in the regions presented here (blacks, LOD=1.41 at 181 cM and LOD=1.95 at 230 cM). Also intriguing is the region on chromosome 16 identified in the unstratified sample of white hypertensive sibpairs. Although not consistently identified in genome-wide scans of linkage for hypertension or blood pressure, a search of the available databases for candidate genes in this region revealed a number of solute carrier proteins potentially involved in regulation of sodium and water homeostasis by the kidney.

In conclusion, these data reflect the utility of taking advantage of methods involving samples of individuals of sufficient size and homogeneity in the analysis of complex traits. Identification of genomic regions demonstrating differential linkage for a complex disease across strata of a related trait is a powerful method to better understand the underlying mechanisms of the disease and their relationships to the trait. Future analyses of complex diseases will benefit from the development and application of analytical methods that have the ability to systematically evaluate the contribution of genes operating in heterogeneous environments without unduly sacrificing sample size or power.

	Acknowledgments

 
This work was carried out through the support of the NHLBI and as part of the GENOA Study of the FBPP.

Received April 24, 2002; revision received October 29, 2002; accepted October 30, 2002.

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This Article Abstract Full Text (PDF) All Versions of this Article: 34/5/1170    most recent 01.STR.0000068780.47411.16v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morrison, A. C. Articles by Boerwinkle, E. Search for Related Content PubMed PubMed Citation Articles by Morrison, A. C. Articles by Boerwinkle, E. Related Collections Cerebrovascular disease/stroke Genetics of Stroke