Journal of Human Hypertension (2000] 14 95-97
© 2000 Macmillan Publishers Ltd All nghts reserved 09509240/00 $15 00 www nature com/jhh
ORIGINAL ARTICLE
Association of the α-adducin
polymorphism with blood pressure and
risk of myocardial infarction
BM Psaty1, C Doggen2, HL Vos3, JP Vandenbroucke2 and FR Rosendaal2·3
1 Cardiovascular Health Research Unit, the Departments of Medicine, Epidemiology, Health Services,
University of Washington, Seattle, WA USA; 2Department of Clinical Epidemiology and the ^Department
of Haematology, Leiden University Medical Center, Leiden, The Netherlands
Genetic Variation in adducin, a protein associated with the inner leaflet of the plasma membrane, may be in part responsible for salt-sensitive hypertension. In the Netherlands, 560 men who survived a myocardial infarc-tion and 646 men who had undergone an orthopaedic Intervention participated in a case-control study. In men in this study, the α-adducin polymorphism was not associated with the risk of myocardial infarction either among those with or among those without a clinical
his-tory of hypertension. In a cross-sectional analysis of blood pressure data from the controls, the a-adducin polymorphism was associated neither with self-reported hypertension (OR = 0.78, 95% Cl = 0.51-1.19) nor with mean levels of systolic or diastolic blood pressure. Additional studies in other populations are needed to assess the contribution of α-adducin to high blood pressure and cardiovascular risk.
Journal of Human Hypertension (2000) 14, 95-97
Keywords: myocardial infarction; genetics, α-adducin, blood pressure
Introduction
Genetic Variation in adducin, a protein associated with the inner leaflet of the plasma membrane, may be in part responsible for salt-sensitive hyperten-sion.1 The Gly460 —»Trp polymorphism of an
a-adducin subunit is associated with hypertension in French and Italian populations.2 Blood pressure
responses to acute salt-sensitivity tests and to chronic diuretic therapy were more pronounced in heterozygotes than in wild-type homozygotes.2 In a
Japanese population, however, the α-adducin poly-morphism was not associated with hypertension3
even though the phenotype of salt-sensitivity has been associated with an increased risk of cardio-vascular events among Japanese patients with essen-tial hypertension.4 Using data from a large Dutch
case-control study of myocardial infarction,^ we examined the associations of the α-adducin poly-morphism with level of blood pressure and risk of myocardial infarction.
Subjects and methods
The methods have been described in detail.5 Briefly,
cases were men aged less than 70 years and hospital-ised with first myocardial infarction in Leiden, The Netherlands, between January 1990 and January
Correspondence Dr Bruce M Psaty, Cardiovascular Health Research Umt, Suite No 1360, 1730 Mmor Avenue, Seattle, WA 98101, USA
Received 6 September 1999, accepted 13 September 1999
1996. Controls were men who had received prophy-lactic anticoagulants briefly after an orthopaedic Intervention between January 1990 and May 1996. The controls were frequency matched to the cases within 10-year age groups. Controls were excluded if they had had a previous myocardial infarction. Subjects (case and controls) were excluded if they had renal disease, severe neuropsychiatric prob-lems, or a life expectancy of less than l year. Response rates among eligible subjects were 84.3% for cases and 77% for controls.
All subjects completed a risk-factor questionnaire concerning cardiovascular risk factors such äs
smok-ing, alcohol intake, medical history of hypertension, and the use of selected medications. Blood pressure was measured in a standardised fashion with the person seated after 10 min rest during the visit when the fasting blood sample was obtained. Using published Information,2 genetic analysis for the a-adducin polymorphism was performed with a poly-merase chain reaction (PCR) using a mutagenic primer that introduced a BstXI site in the product of the Trp-containing allele. The PCR-product of both alleles contained an additional invariant BstXI-site that was used äs a positive control for the restriction enzyme digestion.
Statistical analysis involved the use of odds ratios, and analysis of variance was used for the blood pressure levels.
Results
under-fl)
α-Adducin polymorphism and blood pressure BM Psaty et algone an orthopaedic Intervention participated in this case-control study. The mean age of the case (56.2 years) did not differ from that of the controls (57.3 years). As expected, traditional risk factors such äs smoking were associated with the risk of
myocardial infarction in this population.5 Self-reported hypertension was also associated with the risk of myocardial infarction (odds ratio (OR) = 1.84, 95% CI = 1.42-2.42).
Among 646 controls, 34.4% were heterozygous and 5.9% were homozygous for the Trp460, variant allele. In the analysis of the case-control data, sub-jects without hypertension and with the wild-type alleles for α-adducin served äs the reference group (Table 1). The α-adducin polymorphism was not
associated with the risk of myocardial infarction either among those with or among those without hypertension. Among subjects without hyperten-sion, the presence of one or two variant alleles had trivial effects on the risk of myocardial infarction (OR = 0.94 for both groups). For subjects with self-reported hypertension and the wild-type alleles for α-adducin, compared with non-hypertensives with the wild-type (the reference group), the risk of myo-cardial infarction was 1.59 (95% CI = 1.12-2.26). Among subjects with self-reported hypertension, the presence of one or two variant alleles increased the risk of myocardial infarction slightly from 1.59 for the wild-type to 2.17 for heterozygotes and 2.09 for homozygotes; but the differences between these odds ratios and 1.59 were not statistically signifi-cant. In the stratum of subjects with hypertension, the presence of either one or two variant alleles com-pared with the wild-type was only weakly associa-ted with the risk of myocardial infarction (OR=1.36; 95% 01 = 0.83-2.24).
In a cross-sectional analysis of data from the con-trols, the α-adducin polymorphism was not associa-ted with self-reporassocia-ted hypertension (OR= 0.78, 95% CI = 0.51-1.19). While self-reported hypertension was strongly associated with mean levels of systolic and diastolic blood pressure (P < 0.001; Table 1), the α-adducin polymorphism was not associated with levels of systolic or diastolic blood pressure (P>0.1). Excluding subjects on antihypertensive drug treatment and adjusting for age and calendar year had trivial effects on the results. There was no interaction between diuretic drug treatment and genotype on blood pressure level.
Discussion
In this study from the Netherlands, the prevalence of Trp460 variant allele of α-adducin was higher than in French and Italian populations (23.5% heterozygotes and 3.3% homozygotes among the controls2). Previously associated with salt
sensi-tivity, the adducin polymorphism was not associa-ted with the risk of myocardial infarction in this study; and among controls, despite reasonable sam-ple sizes, the adducin variant was not associated with either self-reported hypertension or with level of blood pressure.
In French and Italian populations, the Trp460 allele has been associated with both the occurrence of hypertension and the response to diuretic ther-apy.2 Several recent studies have suggested that the
α-adducin polymorphism affects renal sodium handling in hypertension.13'7 Despite these
persuas-ive physiologic links, several other studies, like this one, have failed to find an association between the variant allele of α-adducin and hypertension in Anglo-Australians8 and in Japanese patients.3·51·10
The α-adducin polymorphism may be in linkage dis-equilibrium with other mutations that are respon-sible for salt sensitivity or the risk of hypertension. Issues related to control selection, case-fatality rates, and the possibility of unmeasured or unknown confounding factors remain potential alternative explanations for findings, including null findings, from case-control studies.
The α-adducin polymorphism is common; and if it affects either the incidence of hypertension or the response to diuretic therapy, this Information would be important from the point of view of public health. Additional studies in other populations are needed to assess the contribution of the α-adducin polymor-phism to high blood pressure and cardiovascular risk.
Acknowledgements
The research reported in this article was supported in part by grants HL40628, HL43201, HL60739 from the National Heart, Lung, and Blood Institute, AG09556 from the National Institute on Aging, from the Netherlands Heart Foundation (92.345), and from the NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek, The Hague, The
Table l Association of α-adducin polymorphism with case-control Status and blood pressure arnong conlrols
Hypertension α-adducin Gases Controls OR (95% CI) Controls
SBP DBF No Yes Wild-type Heterozygous Homozygous Wild-type Heterozygous Homozygous 243 138 22 90 54 13 313 190 30 73 32 8 1.00 0.94 0.94 1.59 2.17 2.09 reference 0.71-1.23 0.53-1.68 1.12-2.26 1.36-3.47 0.85-5.13 137.5 139.8 136.9 157.6 158.6 160.0 86.6 86.6 88.1 96.2 97.8 98.1
«-Adducin polymorphism and blood pressure BM Psaty ei sl
Netherlands). Dr Psaty is a Merck/SER Clinical Epi-demiology Fellow (co-sponsored by the Merck Co. Foundation, Rahway, NJ, and the Society for Epide-miologie Research, Baltimore, MD).
References
1 Bianchi G et al. Two point mutaüons within the addu-cin genes are involved in blood pressure Variation. Proc Natl Acad Sei USA 1994; 91: 3999-4003. 2 Cusi D et al. Polymorphism of alpha-adducin and salt
sensitivity in patients with essential hypertension. Lancet 1997; 349: 1353-1357.
3 Ishikawa K ei al. No association between alpha-addu-cin 460 polymorphism and essential hypertension in a )apanese population. Am J Hypertens 1998; 11: 502-506.
4 Morimoto A ei al. Sodium sensitivity and cardiovascu-lar events in patients with essential hypertension. Lancet 1997; 350: 1734-1737.
5 Doggen CJM, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with Factor V Leiden or Prothrombin 20210A. Circulation 1998; 97: 1037-1041.
6 Manunta P et al. Adducin polymorphism affects renal proximal tubule reabsorption in hypertension. Hyper-tension 1999; 33: 694-697.
7 Manunta P et al. Alpha-adducin polymorphism and renal sodium handling in essential hypertensive patients. Kidney Int 1998; 53: 1471-1478.
8 Wang WY, Adams DJ, Glenn CL, Morris BJ. The Gly460Trp variant of alpha-adducin is not associated with hypertension in white Anglo-Australians. Arn J Hypertens 1999; 12: 632-636.
9 Kato N et al. Lack of association between the alpha-adducin locus and essential hypertension in the Japanese population. Hypertension 1998; 31: 730-733. 10 Tamaki S et al. Polymorphism of alpha-adducin in Japanese patients with essential hypertension. Hyper-tens Res 1998; 21: 29-32.
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