Table 2 Effect of gain-of-function OPRD1 variants on metabolic homeostasis in RaDiO and the AMP T2D knowledge portal

Study	Trait	n	%, mean ± SD or median [IQR] of the trait in carriers	%, mean [± SD] or median [IQR] of the trait in non-carriers	OR [CI]	Π or β ± SE	P
RaDiO	Hyperglycemia	6745	50%	47%	0.89 [0.15–4.7]	–	0.89
AMP-All	Type 2 diabetes	34,812	67%	57%	1.7 [1.3–2.2]	–	6.1 × 10⁻⁵
AMP-Africans	Type 2 diabetes	4966	69%	54%	2.0 [1.5–2.6]	–	3.6 × 10⁻⁶
RaDiO	BMI (kg m^-²)	6971	25 [24–27]	26 [23–29]	–	0.040 ± 0.22	0.86
AMP-All	BMI (kg m^-²)	17,073	–	–	–	−0.027 ± 0.0093	0.0038
AMP-Africans	BMI (kg m^-²)	1988	–	–	–	−0.011 ± 0.013	0.41
RaDiO	HDL* (mmol l⁻¹)	6008	1.8 ± 0.39	1.5 ± 0.45	–	0.33 ± 0.17	0.049
AMP-All	HDL* (mmol l⁻¹)	7427	–	–	–	0.048 ± 0.046	0.30
AMP-Africans	HDL* (mmol l⁻¹)	492	–	–	–	0.095 ± 0.049	0.055
RaDiO	TG* (mmol l⁻¹)	6051	0.55 [0.54–0.92]	1.1 [0.76–1.6]	–	−0.37 ± 0.18	0.046
AMP-All	TG* (mmol l⁻¹)	7974	–	–	–	−0.13 ± 0.054	0.018
AMP-Africans	TG* (mmol l⁻¹)	492	–	–	–	−0.11 ± 0.060	0.069
RaDiO	LDL* (mmol l⁻¹)	–	–	–	–	-	-
AMP-All	LDL* (mmol l⁻¹)	5288	–	–	–	−0.37 ± 0.12	0.0026
AMP-Africans	LDL* (mmol l⁻¹)	489	–	–	–	−0.48 ± 0.16	0.0026
RaDiO	SBP** (mmHg)	5257	120 ± 17	130 ± 15	–	−1.3 ± 8.3	0.88
AMP-All	SBP** (mmHg)	6551	–	–	–	−0.91 ± 2.3	0.70
AMP-Africans	SBP** (mmHg)	493	–	–	–	−0.79 ± 3.3	0.81
RaDiO	DBP** (mmHg)	4693	70 ± 11	78 ± 9.4	–	−2.3 ± 5.7	0.69
AMP-All	DBP** (mmHg)	6552	–	–	–	2.6 ± 1.4	0.066
AMP-Africans	DBP** (mmHg)	493	–	–	–	2.5 ± 2.0	0.22

In the RaDiO study, gain-of-function variants included the six rare variants encoding p.P24S, p.A32G, p.I183V, p.K250R, p.T361N, and p.P366L which increased the activity of DOP in response to two DOP agonists. In the AMP T2D knowledge portal, the gain-of-function encoding p.I52V increased the activity of DOP in response to two DOP agonists and was common in Africans. Association analyses were performed using the MiST method (two-tailed) adjusted for age, sex, BMI, and ancestry (for the analyses of hyperglycemia, type 2 diabetes, HDL, TG, SBP, and DBP) or for age, sex and ancestry (for the analyses of overweight/obesity and BMI). *To avoid possible biases due to treatment, these traits were only assessed in participants without type 2 diabetes in the AMP T2D knowledge portal or in participants who were not on lipid-lowering agents in the RaDiO study. **To avoid possible biases due to treatment, these traits were only assessed in participants without type 2 diabetes in the AMP T2D knowledge portal or in participants who were not under blood pressure lowering medications in the RaDiO study. β mean effect, BMI body mass index, CI confidence interval, DBP diastolic blood pressure, HDL high-density lipoprotein, LDL low-density lipoprotein, OR odds ratio, π mean effect, SBP systolic blood pressure, SE standard error, TG triglycerides.

Search