Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder

Abstract

Adrenergic receptor beta(2) (ADRB2) is a primary target for epinephrine. It plays a critical role in mediating physiological and psychological responses to environmental stressors. Thus, functional genetic variants of ADRB2 will be associated with a complex array of psychological and physiological phenotypes. These genetic variants should also interact with environmental factors such as physical or emotional stress to produce a phenotype vulnerable to pathological states. In this study, we determined whether common genetic variants of ADRB2 contribute to the development of a common chronic pain condition that is associated with increased levels of psychological distress and low blood pressure, factors which are strongly influenced by the adrenergic system. We genotyped 202 female subjects and examined the relationships between three major ADRB2 haplotypes and psychological factors, resting blood pressure, and the risk of developing a chronic musculoskeletal pain condition-Temporomandibular Joint Disorder (TMD). We propose that the first haplotype codes for lower levels of ADRB2 expression, the second haplotype codes for higher ADRB2 expression, and the third haplotype codes for higher receptor expression and rapid agonist-induced internalization. Individuals who carried one haplotype coding for high and one coding for low ADRB2 expression displayed the highest positive psychological traits, had higher levels of resting arterial pressure, and were about 10 times less likely to develop TMD. Thus, our data suggest that either positive or negative imbalances in ADRB2 function increase the vulnerability to chronic pain conditions such as TMD through different etiological pathways that imply the need for tailored treatment options.

(c) 2006 Wiley-Liss, Inc.

Figures

Figure 1

(a) Schematic diagram of ADRB2 genomic organization, SNP positions and distribution percentages. The human ADRB2 is an intronless gene that spans ∼5,500 kb on chromosome 5q31-32. ADRB2 transcript codes for two independent peptides showed as break blocks: β2 adrenergic receptor protein and β2 adrenergic receptors upstream protein (BUP) that inhibits receptor translation (Parola and Kobilka, 1994). (b) Estimated frequencies of the ADRB2 haplotypes. The sequence of alleles in each haplotype reflects the order of occurrence from 5′ to 3′ in the ADRB2 gene locus (SNPs: G-7127A, rs11958940, rs1432622, rs1432623, rs2400707, rs1042713, rs1042714 and rs1042717, respectively).

Figure 2. Psychological scores and resting arterial blood pressure categorized by six major ADRB2 diplotypes

The major effects of six major ADRB2 diplotypes are presented. The following diplotypes are shown: homozygotes for H1 (1,1), homozygotes for H2 (2,2), homozygotes for H3 (3,3), heterozygotes H1-H2 (1,2), H1-H3 (1,3), and H2-H3 (2,3). Each value represents the mean of each variable with associated SEM. Greater positive values for PILL, BSI and Trait Anxiety scores reflect more negative psychological characteristics. The greater values for measured obtained from the POMS scale reflect more positive psychological characteristics: composed. PILL, STAI and POMS scores were measured in relative unites, blood pressure was measured in mm of mercury (mmHg), BSI depression and somatization presented as percent of subjects that show trait (subjects, scored at 30 and corresponded to individuals that answered all questions negatively, were treated as a group that showed no signs of depression or somatization). ***P < 0.01, **P < 0.05 and *P < 0.1 different from the indicated groups.

Figure 3. The effect of ADRB2 haplotypes on psychological scores and resting arterial blood pressure

The major effects of the number of copies of haplotype 1 (A), haplotype 2 (B) or haplotype 3 (C) are presented. The following haplotype dose-effects are shown: no corresponding haplotype (0), one copy (1) or two copies (2) of the corresponding haplotype. Each value represents the mean of each variable with associated SEM. Greater positive values for PILL, BSI and Trait Anxiety scores reflect more negative psychological characteristics. The greater values for measures obtained from the POMS scale reflect more positive psychological characteristics: composed. PILL, STAI and POMS scores were measured in relative unites, blood pressure was measured in mm of mercury (mmHg), BSI depression and somatization presented as percent of subjects that show trait (subjects, scored at 30 and corresponded to individuals that answered all questions negatively, were treated as a group that showed no sings of depression or somatization). ***P

Figure 4. Proposed functional variants of ADRB2 corresponding to the three major haplotypes

Putative haplotype-specific expression of ADRB2 on the postsynaptic membrane of CNS neurons at (A) resting state and (B) following stimulation with an agonist. In the periphery, epinephrine is released from adrenal glands and binds peripheral ADRB2, for example, smooth muscle.