Beta2-Adrenergic Receptor Gene Variations Associated with
Stage-2 Hypertension in Northern Han Chinese

The Health Outcome

The health outcome of interest is stage-2 hypertension (systemic, essential). The definition of stage-2 hypertension used for the study conforms to the definitions by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (Chobanian AV, 2003): Normal (previously considered optimal) when systolic <120 mmHg and diastolic <80 mmHg; Prehypertension (new category) when systolic 120-139 mmHg or diastolic 80-89 mmHg; Stage 1 Hypertension when systolic 140-159 mmHg or diastolic 90-99 mmHg; Stage 2 Hypertension when systolic >160 mmHg or diastolic >100 mmHg (combines former stages 2 and 3).

Hypertension is highly prevalent, especially in developed nations, and is an important risk factor for cardiovascular and renal diseases. According to the NHANES III survey of the US population from 1988-91, the age-adjusted prevalence among non-Hispanic black, non-Hispanic white, and Mexican-Americans was 32.4%, 23.3%, and 22.6%, respectively. (Burt VL, 1995)

This paper studies hypertension in Han Chinese (the predominant ethnic group in China). As economic and social conditions in China continue to approach those of western nations, changes in prevalence of risk factors (e.g., obesity) are likely to increase the incidence of hypertension in China. The prevalence of hypertension among the Chinese population aged 35-74 has been estimated at 27% (Gu D, 2002). Incidence of hypertension increases with age. As life-expectancy in China lengthens as a result of improved living standards, prevalence of hypertension among the elderly and China's entire population will most likely increase.

Medical consequences of hypertension are numerous and serious, including ischemic heart diseases, congestive heart failure, cerebrovascular events, hypertensive nephrosclerosis, end-stage renal disease, and retinopathy.

The Finding

The study by Ge et. al. is a case-control study conducted by the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA) to investigate association of three polymorphisms (-47C/T, Arg16/Gly, and Gln27/Glu) of the beta2-adrenoreceptor (ADRB2; Kobilka BK,1987) with stage-2 hypertension among unrelated northern Han Chinese hypertensive (n=503) and normal control subjects (n=504). These polymorphisms have been subjects of previous investigations which yielded conflicting or inconclusive results (Kato N, 2001; Ranade K, 2001). Analysis of genotype frequencies showed no difference in frequency of the C allele, but significantly higher Arg/Gly, Gly/Gly and Gln/Gln genotypes among hypertensive subjects. Stepwise regression analyses indicated significant positive contribution by the Gly16 allele (OR=1.46, 95% C.I. of 1.11-1.93) and negative contribution by the Glu27 allele (OR=.42, 95% C.I. 28-.62). However, genotypes at Arg16/Gly and Gln27/Glu do not predict hypertension completely as body mass index (BMI), glucose, triglyceride, creatinine, and alcohol drinking were significant additional predictors in models which took into account the Arg16/Gly and Gln27/Glu genotypes. Case and control subjects were combined in an analysis of mean systolic blood pressure according to genotypes. The mean systolic blood pressures (SBP) of persons with the Gly/Gly, Gly/Arg, and Arg/Arg genotypes were 150.3, 149.45, and 143 mmHg, respectively (p=.025). This suggests that Gly16 confers risk for hypertension in both heterozygous and homozygous states; however, there was no evidence of gene dose effect in this limited study. The mean SBP of the combined group with Glu/Glu or Glu/Gln genotypes was 136.3 mHg, significantly lower than that of the Gln/Gln group; comparisons of diastolic blood pressures yielded similar contrast. Gln/Gln homozygosity was associated with hypertension but the effect of Gln16 in heterozygous state was unclear from the study because of the small number of subjects in the Glu/Glu category.

Neither parental genotype nor sequence data are available to provide direct information about haplotype frequencies. Haplotypes frequencies were estimated using allele frequencies and genotype information; however, some polymorphisms were not in Hardy Weinberg equilibrium, which could affect the validity of these estimates.

Public Health Implications

Hypertension is highly prevalent and has serious health consequences. Association of the ADRB2 Arg16/Gly and Gln27/Glu polymorphisms with hypertension has been investigated in multiple studies in a number of countries with various ethnic groups. Most of those studies were small and might not have had adequate power to detect an effect. A strength of this study is its large sample size and the findings merit further investigation, especially to understand functional implications of Arg16/Gly and Gln27/Glu variants. The limitations of the study are: (1) the outdated blood pressure cutoff used for the definition of the control group; (2) possible problems with genotyping as suggested by lack of Hardy Weinberg equilibrium (although the authors argue against this); (3) significant differences in covariates between cases and controls; and (4) the absence of direct haplotype data. Given the extent of discrepancies in the literature and shortcomings of the study itself, clinical validity of these polymorphic markers remains unproven.

References

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