Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol

Figures & data

Table 1 Demographic and Clinical Profile of the Bisoprolol Pharmacokinetics Cohort

Demographics
Age (years, Mean ±SD)	64±12
Sex (% Female)	25.1
Weight (Kg, Mean ±SD)	83±16
BMI (Kg/m^2, Mean ±SD)	29±6
Medical History
Hypertension (%)	53.3
Hyperlipidemia (%)	50.5
Diabetes (%)	18.8
Chronic renal failure (%)	5.4
Current smokers (%)	25.9
NYHA classification
I (N)	381
II (N)	204
III or IV (N)	49
IV (N)	5
Medications
Aspirin (%)	94.0
P2Y12 inhibitors (%)	83.9
Statins (%)	96.0
ACE inhibitors (%)	74.1
ARB (%)	8.3
Aldosterone antagonists (%)	3.2
Warfarin (%)	4.4
Calcium channel antagonists (%)	10.3
Potassium channel activators (%)	10.4
Diuretics (%)	20.4

Abbreviations: NYHA, New York Heart Association; ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blockers.

Table 2 Pharmacokinetic Population Parameters of the Final Model

Parameter	Estimate	SE	p-value
Tlag_pop	3.17	0.149	-
ka_pop	2.31	FIXED	-
V_pop	218.00	FIXED	-
Cl_pop	13.1	0.382	-
beta_Cl_tAGE	−0.68	0.12	1.32x 10^−8
beta_Cl_tWT	0.68	0.11	8.96x 10^−10
beta_Cl_DIURETIC	−0.157	0.047	0.000882
beta_Cl_SMOKING	0.173	0.048	0.000335
beta_Cl_SEX	−0.122	0.047	0.00971
omega_Tlag	0.309	0.038	-
omega_ka	2.38	0.23	-
omega_V	0.193	0.03	-
omega_Cl	0.402	0.015	-
a	0.24	FIXED	-
b	0.05	FIXED	-

Abbreviations: Tlag, lag time before absorption; ka, absorption constant rate; V, volume of distribution; Cl, clearance, WT, body weight.

Table 3 SNPs That Reached Genome-Wide Significance (p value < 5×10⁻⁸) for Bisoprolol Clearance in PhACS Patients

Variation	Chr	Position (Build 37)	Ref. Allele	Variant Allele	Variant Allele Frequency	Beta	P value	Info Score
rs11029955	11	27,354,487	G	T	0.32	2.22	7.17E-09	0.997
rs7935021	11	27,373,436	C	T	0.31	−2.18	1.12E-08	1.000
rs61887779	11	27,364,260	G	A	0.28	2.28	1.17E-08	0.992
rs1871254	11	27,369,906	T	C	0.28	2.27	1.20E-08	0.996
rs2291022	11	27,370,588	T	C	0.28	2.27	1.21E-08	0.996
rs116702638	2	100,915,330	G	T	0.01	12.54	2.54E-08	0.568

Note: Positive beta values indicate increase in clearance rate associated with the variant allele.

Abbreviations: Chr, chomosome; Ref, reference.

Figure 1 Manhattan plot of bisoprolol clearance in patients with acute coronary syndrome. The red line represents the genome-wide significance p value threshold (5x10⁻⁸) and blue lines represents the nominal significance threshold (1x10⁻⁵).

Figure 2 Regional association plot for bisoprolol clearance at the CCDC34 locus (A), LONRF2 (B), CYP2D6 (C), and CYP3A (D). The colours reflect linkage disequilibrium (r²) for the signals with the lowest p values.

Table 4 Associations Between Office and 24-Hour Ambulatory Changes in Heart Rate and the Identified Bisoprolol GWAS-Significant SNPs in GENRES Patients

			24h Ambulatory Measurements		Office Measurements
SNP	Variant Allele	VAF Allele Frequency	Beta	P value	Beta	P value
rs11029955	T	0.32	−1.8	9.3x10^−5	−1.1	0.049
rs116702638	T	0.02	0.6	0.670	0.9	0.590

Notes: A negative beta value indicates a larger decrease in heart rate associated with the coded allele. The magnitude of beta indicates the magnitude of HR change per one copy of the coded allele. 206 individuals were analysed for 24h ambulatory measurements and 216 for office measurements.

Abbreviations: VAF, variant allele frequency. SNP: single nucleotide polymorphism.