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Human Molecular Genetics Pages 1379-1383  

Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation
Introduction
Results
Discussion
Materials And Methods
Acknowledgements
References

Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation

Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation

Julia Krushkal1, Momiao Xiong2, Robert Ferrell3, Charles F. Sing4, Stephen T. Turner5 and Eric Boerwinkle1,2,*

1Institute of Molecular Medicine and 2Human Genetics Center, The University of Texas-Houston Health Science Center, Houston, TX 77225, USA, 3Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA, 4Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA and 5Division of Hypertension and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA

Received March 12, 1998; Revised and Accepted June 12, 1998

Elevated blood pressure is an important risk factor for renal-, cerebro- and cardiovascular diseases. We used an efficient discordant sib-pair ascertainment scheme to investigate the impact of the distal end of the long arm of human chromosome 5 (chromosomal region 5q31.1-qter) containing genes for the [alpha]1B and [beta]2 adrenergic receptors and the dopamine receptor type 1A on variation of systolic blood pressure in young Caucasians. We measured eight highly polymorphic markers spanning this positional candidate gene-rich region in 427 individuals from 55 three-generation pedigrees containing 69 discordant sibling pairs, and calculated multipoint identity by descent (MIBD) probabilities. The results of genetic linkage and association tests indicate that the region between markers D5S2093 and D5S462 is significantly linked to one or more polymorphic genes influencing interindividual variation in systolic blood pressure levels. Since the [alpha]1B adrenergic receptor and dopamine receptor type 1A genes are located close to these markers, these data suggest that genetic variation in one or both of these G protein-coupled receptors, which participate in the control of vascular tone, plays an important role in influencing interindividual variation in systolic blood pressure levels.

INTRODUCTION

Increased blood pressure of unknown etiology, or essential hypertension, is a common and important risk factor for stroke, congestive heart failure, coronary heart disease, peripheral arterial disease and end-stage renal disease (1-4), and is caused by complex interactions among numerous genetic and environmental factors (5-8). Although several genes have been identified which are responsible for rare syndromic forms of hypertension (8), the genes responsible for interindividual blood pressure variation and the risk to essential hypertension in the population at large are largely unknown.

The long arm of human chromosome 5 (chromosomal region 5q31.1-qter) is gene rich (9) and contains a cluster of genes hypothesized to be involved in blood pressure regulation. These genes encode the [beta]2 and [alpha]1B adrenergic receptors (genes ADRB2 and ADRA1B, respectively) and the dopamine receptor type 1A (gene DRD1A). These receptors belong to the superfamily of G protein-coupled receptors (10,11). Activation of dopamine receptor type 1A causes vasodilation, diuresis, natriureses and blood pressure decline (12,13). Stimulation of [alpha]1B adrenergic receptors results in vasoconstriction and blood pressure elevation (14,15). [beta]2 Adrenergic receptor agonists, in contrast, result in vasodilation and have a hypotensive effect (16).

In order to determine the impact of variation in the chromosomal region containing genes encoding these receptors on human blood pressure variation, we performed genetic linkage and transmission-disequilibrium analyses using a discordant sib-pair design which samples one sibling from the upper tail and one sibling from the lower tail of the continuous systolic blood pressure distribution. Risch and Zhang (17) used analytical methods to show that the discordant sibling sampling strategy is an efficient and powerful design, and that as few as 50 discordant sibling pairs provide adequate power to localize genes influencing interindividual variation in a quantitative trait. We describe here the first application of this design to elucidate an important role for the distal end of the long arm of chromosome 5 containing the adrenergic and dopamine receptor genes in influencing human systolic blood pressure variation in young Caucasians.

RESULTS

The results of the multipoint genetic linkage analyses of the distal portion of the long arm of chromosome 5 provide significant evidence for a gene or genes affecting systolic blood pressure variation in young Caucasians (Fig. 1). Therefore, we infer that the chromosome interval between markers D5S2093 and D5S462 includes one or more genes involved in interindividual systolic blood pressure variation. This region contains gene coding for the [alpha]1B adrenergic receptor. The gene coding for the dopamine receptor type 1A is also located close to this region. The highest level of significance (the lowest P-value) was observed 1 cM proximal to marker D5S1471 (P = 0.0163, t = -2.18), and is 24 cM away from the first marker D5S1480. Each position between 19 and 31 cM distal to D5S1480 had a P-value <0.05 (values below the dashed line). The consistency of these results across a broad region underscores their genuine nature (20).


Figure 1. t-values of Risch-Zhang's test for linkage using discordant sibling pairs. Order and distances for the marker loci were taken from the chromosome 5 sex-averaged linkage map of the Center for Medical Genetics at the Marshfield Medical Research Foundation (http://www.marshmed.org/genetics/ ). The plotted line indicates the values of the t statistic for the deviation of multipoint identity by descent sharing from that expected under the null hypothesis of no linkage to a gene affecting systolic blood pressure variation. The number of degrees of freedom is 68. The horizontal dashed line corresponds to a significance level (P-value) of 0.05 (= -1.6676). Location intervals for the candidate genes are shown by the bold horizontal lines on top of the figure. Location of the candidate genes is shown according to the Chromosome 5q-Specific Radiation Hybrid Map (Human Genome Research Center, University of California, Irvine, CA; http://chrom5.hsis.uci.edu/mapimags.html ) and (9,18) for ADRA1B; the Integrated Map of Chromosome 5 (The Whitehead Institute for Biomedical Research/MIT Center for Genome Research, Cambridge, MA; http://www-genome.wi.mit.edu/cgi-bin/contig/phys_map ) and (9,18) for ADRB2; the Human Gene Map (http://www.ncbi.nlm.nih.gov/SCIENCE96/ ) (19) for DRD1A.

Table 1. Transmission-disequilibrium test for the 5q chromosomal region containing the ADRB2, ADRA1B and DRD1A genes
Marker PDTDT tDTDT dfDTDT
D5S1480 0.6166 -0.2975 81
D5S636 0.0495 1.6854 44
D5S820 0.0793 1.4215 91
D5S2093 0.0131 2.2592 96
D5S1471 0.5407 -0.1025 87
D5S1456 0.2810 0.5821 93
D5S462 0.2181 0.7816 103
D5S211 0.0238 2.0055 99
PDTDT, significance levels computed from a transmission-disequilibrium test for discordant sibling pairs, tDTDT, with dfDTDT degrees of freedom.

Table 1 shows the results of the two-point transmission-disequilibrium test (TDT), which simultaneously investigates both linkage and association between the marker and putative blood pressure-controlling loci. The markers D5S636, D5S2093 and D5S211 showed significant transmission disequilibrium with a systolic blood pressure-controlling locus. The most significant results (P = 0.0131, t = 2.26) were observed for marker D5S2093, which defines the border of the most significant region identified from our linkage analysis. Therefore, from the data shown in Table 1 and Figure 1, this genome region shows both significant linkage and association with systolic blood pressure levels.

DISCUSSION

We have carried out the first discordant sibling pair linkage and association analyses to investigate the impact of the distal end of the long arm of human chromosome 5 containing the genes for the [alpha]1B and [beta]2 adrenergic receptors, and the dopamine receptor type 1A on variation of systolic blood pressure in young Caucasians from Rochester, MN. The results suggest that the region spanning the markers D5S2093-D5S462 is significantly linked to one or more genes controlling systolic blood pressure. This region contains the ADRA1B gene. Another gene mapped close to this region is the DRD1A gene, which is located between markers D5S462 and D5S211. The latter marker shows a significant association with systolic blood pressure variation (P = 0.0238, t = 2.01). We conclude that variation in one, both or other genes in this region influences interindividual variation in systolic blood pressure in young individuals from the Caucasian population in Rochester.

The [alpha]1B adrenergic receptor and the dopamine receptor type 1A are involved in molecular interactions regulating blood pressure, through inositol phosphate hydrolysis for the [alpha]1B adrenergic receptor and activation of adenylyl cyclase for the dopamine receptor type 1A (10,11,21). Mice lacking functional dopamine 1A receptors have an impaired regulation of renal sodium transport and develop essential hypertension (22). In addition, activation of this receptor has been applied to treatment of essential hypertension (12,13). The ADRA1B gene maps to a broad interval that includes markers D5S2093, D5S1471 and D5S1456. Both markers D5S1471 and D5S1456 are significantly linked to systolic blood pressure variation in this study, while marker D5S2093 shows significant association with systolic blood pressure levels. The [alpha]1B adrenergic receptor is involved in blood pressure regulation and the control of vascular tone through its participation in smooth muscle contraction in response to catecholamine stimulation (15,23).

ADRB2 is located between markers D5S1480 and D5S636, which did not show significant linkage with systolic blood pressure differences. However, marker D5S636 has shown some degree of association with systolic blood pressure variation (P = 0.0495, t = 1.69). Several recent analyses (24-26) have suggested association and linkage of the ADRB2 gene with blood pressure variation. It is possible that ADRB2 has little or no effect on blood pressure variation in the young Caucasians of Rochester, but it may make a significant contribution to blood pressure variation in the predominantly African-American samples used in the other studies (24-26). Each of these studies, however, used only a single biallelic marker within ADRB2. Our analyses utilized highly polymorphic markers, multipoint linkage methods and a TDT along the region spanning the DRD1A, ADRA1B and ADRB2 genes. Therefore, previous studies may have detected an effect, not of the ADRB2 gene itself, but of a closely linked gene, such as the ADRA1B or DRD1A gene. In addition to the ADRA1B and DRD1A genes, a large number of expressed sequence tags (ESTs) have been mapped to the genetic region between markers D5S2093 and D5S462, and also proximal to D5S2093 and distal to D5S462 (27-29). Therefore, a number of potential new positional candidate genes for human systolic blood pressure control may be identified from these ESTs in combination with the data presented here.

We obtained information localizing a gene affecting interindividual variation in systolic blood pressure levels to the distal portion of chromosome 5 from two complementary sources: linkage and association. The difference between the results of our linkage and association studies at some points may be explained by several factors. First, the linkage analysis utilized information from all available alleles from multiple markers simultaneously, while the TDT focused on transmission of each allele at individual marker loci. Second, markers D5S1471 and D5S1456 may be closely linked to one or more genes affecting systolic blood pressure levels, but there may be a lack of linkage disequilibrium between each of these markers and the blood pressure-related genes. Replication of these linkage and association findings to verify the results presented here will lead to further efforts to identify the responsible gene or genes and to characterize mutations influencing interindividual variation in blood pressure in the population at large.

MATERIALS AND METHODS

This analysis represents the first application of the discordant sibling pair design for linkage analyses of a quantitative trait in humans. For this method to have practical utility, investigators should already have available a large sample of pedigree data to construct the discordant sibling pairs. The Rochester Family Heart Study has collected detailed cardiovascular disease risk factor data on 3974 members of 583 multigeneration pedigrees from Rochester, MN. Families were ascertained without regard to health status if two or more of their children were enrolled in the primary and/or secondary schools of Rochester (30). For each individual, systolic blood pressure levels were measured three times at least 2 min apart using a random zero sphygmomanometer. The average of the three readings was used for the analyses reported here.

We identified 55 pedigrees having one or more full siblings above the gender- and age-specific 80th percentile and one or more full siblings below the gender- and age-specific 20th percentile of the systolic blood pressure distribution. These 55 pedigrees contained 69 discordant full sibling pairs. Trait characteristics of these siblings are described in Table 2. The two discordant groups of siblings were not significantly different for average age, weight, height and body mass index (BMI), and for gender prevalence. Not surprisingly, they showed statistically significant differences for mean systolic blood pressure levels. Mean diastolic blood pressure levels were also significantly different between the two groups of siblings. Since the two groups of siblings were selected based on their adjusted systolic blood pressure levels, the genetic linkage studies were limited to interindividual systolic blood pressure variation.

Table 2. Characteristics of the discordant siblings
  Lower 20% Upper 20%
No. of individuals 59 65
Males (%) 32 (54.24) 31 (47.69)
Females (%) 27 (45.76) 34 (52.31)
SBP (mmHg)* 92.23 ± 8.27 116.85 ± 7.79
DBP (mmHg)* 53.32 ± 12.71 63.10 ± 12.08
Age (years) 15.93 ± 5.20 16.54 ± 5.09
Weight (kg) 58.76 ± 21.07 56.57 ± 16.98
Height (cm) 163.04 ± 17.76 162.18 ± 16.93
BMI (kg/m2) 21.39 ± 4.66 20.91 ± 3.45
Values shown are means ± standard deviation. SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index (weight/height2).
*Statistically significant difference between the two groups of siblings (P < 0.05).
Differences between the two groups of siblings were tested by a contingency [chi]2 test for gender, and by the non-parameteric Wilcoxon's paired-sample test for the other traits.

All 427 individuals in the 55 pedigrees containing discordant sibling pairs were genotyped for eight highly polymorphic marker loci: D5S1480 (observed heterozygosity 76.9% with nine alleles present in the sample), D5S636 (81.9%, 12 alleles), D5S820 (79.9%, eight alleles), D5S2093 (67.7%, seven alleles), D5S1471 (72.1%, seven alleles), D5S1456 (77.3%, six alleles), D5S462 (67.2%, six alleles) and D5S211 (75.0%, eight alleles) on the distal end of the long arm of chromosome 5 using standard methods and an ABI 377 automatic sequencer (Forest City, CA). This chromosomal region in humans contains important candidate genes for blood pressure regulation, ADRAB2, ADRA1B and DRD1A (Fig. 1). Lanes were tracked and bands were identified and sized independently by two laboratory personnel.

Genotypes from all 427 individuals in the 55 three-generation pedigrees were used to calculate the multipoint identity by descent (MIBD) probabilities, but the analysis of systolic blood pressure levels was restricted to the 69 discordant sibling pairs. MIBD probabilities were calculated every 1 cM using a hidden Markov model (HMM) method (31). We used multipoint rather than multiple two-point analyses, because the former increases the power of the linkage test (32). Genetic distances among markers used in the MIBD computations are shown in Figure 1, and were provided by the chromosome 5 sex-averaged linkage map of the Center for Medical Genetics at the Marshfield Medical Research Foundation (Marshfield, WI). The average spacing between adjacent pair of markers used in our study was 5.1 cM. To assess genetic linkage, we used the t-statistic of Risch and Zhang (17,33) that compares identity by descent (IBD) sharing among discordant siblings with that expected under the null hypothesis of no linkage. Significance levels were determined from a one-sided Student's t distribution with 68 degrees of freedom. The one-sided test rather than a two-sided test was used in order to detect chromosomal regions exhibiting linkage to systolic blood pressure levels. In such regions, IBD sharing among discordant siblings should be significantly less than 0.5.

A TDT was used to assess whether transmission of alleles from parents to the discordant siblings was significantly different from that expected at random. TDT is a family-based linkage disequilibrium test that can be used as a test for linkage in the presence of association or a test for association in the presence of linkage, or both (34-39). Moreover, TDT is a valid test for linkage and association even in the presence of population subdivision and admixture (40).

Below we briefly introduce a TDT statistic suitable for quantitative trait linkage analyses using discordant sib-pairs (M.M. Xiong, J. Krushkal and E. Boerwinkle, unpublished data). Consider a marker with two alleles M and m. Let Ymk be the systolic blood pressure value of a sibling in the upper tail of the distribution having inherited allele m from the kth parent. Zmk is defined similarly for a sibling in the lower tail. Similarly, let Ymk be the systolic blood pressure value of a sibling in the upper tail having inherited allele M from the kth parent, and Zmk the systolic blood pressure value of a sibling in a lower tail. Then, the discordant transmission disequilibrium test statistic, DTDT, is defined as:

where Y[bar]M, Y[bar]m, Z[bar]M and Z[bar]m are the mean values of YM, Ym, ZMand Zm respectively, nYm is the number of parents transmitting the m allele to a child in the upper tail of the distribution, nZm is the number of parents transmitting the m allele to a child in the lower tail, nYM and nZM are similar values for the M allele, and S2 is

Under the null hypothesis of no linkage, DTDT has a t distribution with nyM + nym + nzM + nzm - 4 degrees of freedom. Since the chromosomal region was selected a priori on the basis of the presence of a number of candidate genes, we used nominal P-values (P < 0.05) to detect genetic effects in both the linkage and association studies.

ACKNOWLEDGEMENTS

The authors thank Kim Lawson, Terry Bertin and Phuong Mai for their technical assistance. This study was supported by NIH grants R01 HL51021-04 and U10 HL54481-03 from the National Heart, Lung and Blood Institute. It was carried out as part of the GENOA Network of the NHLBI Family Blood Pressure Program. J.K. is supported in part by a Minnie L. Maffett Fellowship from the Minnie L. Maffett Fellowship Fund.

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*To whom correspondence should be addressed. Tel: +1 713 500 9816; Fax: +1 713 500 0900; Email: eboerwin@gsbs.gs.uth.tmc.edu

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