The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland

Figures & data

Table 1. Baseline characteristics of participants.

	Normoglycemia		Diabetes
	N total	Median [IQR] or n	N total	Median[IQR] or n
N total	3,547	3.547	362	362
Age (years)	3,547	45.2 [36.7,55.0]	362	57.4 [48.1,67.6]
Males (%)	3,547	1,577 (44.5)	362	173 (47.8)
BMI (kg/m^2)	3515	25.5 [22.6,29.3]	350	28.2 [23.2,32.5]
Systolic blood pressure (mmHg)	3,523	124.0 [113.0,137.0]	360	136.5 [123.5,153.0]
Diastolic blood pressure (mmHg)	3,524	76.0 [69.0,84.0]	360	80.0 [71.0,88.5]
Hba1c (mmol/mol)	3,537	38.1 [35.5,41.0]	361	42.1 [38.8,46.4]
Blood glucose at 0 minutes (mmol/L)	3,547	5.6 [5.2,5.9]	362	7.1 [6.1,7.6]
Blood glucose at 120 minutes (mmol/L)	3,547	5.3 [4.3,6.5]	362	9.9 [6.4,13.6]
Total cholesterol mmol/l	3,547	5.8 [5.0,6.6]	361	6.0 [5.3,6.9]
LDL (mmol/l)	3,524	3.5 [2.9,4.3]	357	3.6 [2.9,4.4]
TG (mmol/l)	3,547	1.0 [0.8,1.4]	361	1.2 [0.8,1.8]
TBC1D4 (HO)	3,065	70 (2.3)	306	46 (15.0)
TBC1D4 (HT)	3.065	834 (27.2)	306	79 (25.8)
Inuit genetic admixture (%)	3,126	0.77 [0.61,0.91]	316	0.8 [0.64,0.97]
Smoking (%)	3,159	2,197 (70.5)	316	180 (57.0)
Albumin/creatinine ratio (mg/g)	3,241	7.0 [5.0,13.0]	322	14.0 [7.0,35.0]
Albuminuria yes/no (mg/g)	3,241	309 (9.5)	322	89 (27.6)
eGFR (ml/min/1.73 m^2)	3,526	93.8 [79.2,105.5]	360	88.8 [74.7,100.9]
Chronic kidney disease (eGFR<60 ml/min/1.73 m^2)	3,526	223 (6.3)	360	39 (10.8)

Data are median [interquartile range] and n (%). Diabetes is screen detected by OGTT criteria and self-reported..

Table 2. TBC1D4 genotype distribution among individuals with and without albuminuria and CKD.

Genotype distribution	Albuminuria			CKD
	N	Yes	No	N	Yes	No
TBC1D4 HO (% of total)	126 (3.7)	13 (3.4)	113 (3.7)	142 (3.7)	8 (3.1)	134 (3.7)
TBC1D4 HT (% of total)	893 (26.3)	105 (27.6)	788 (26.1)	1,060 (27.3)	60 (23.4)	1,000 (27.6)
TBC1D4 WT (% of total)	2,382 (70.0)	262 (69.0)	2,120 (70.2)	2,682 (69.0)	180 (73.5)	2,493 (68.7)
Total (%)	3,401 (100)	380 (11.2)	3,021 (88.8)	3,884 (100)	257 (6.6)	270 (93.4)

Data are n and (%) of total.

Table 3. Cross-sectional analysis of the effect of diabetes on albuminuria: stepwise logistic regression presented as odds ratios (ORs).

Outcome albuminuria	Crude OR	P value	Model 1 OR	P value	Model 2 OR	P value	Model 3 OR	P value
Diabetes vs. no diabetes	3.6 (2.76,4.75)	<0.001	2.34 (1.76,3.11)	<0.001	2.13 (1.55,2.93)	<0.001	2.37 (1.69,3.33)	<0.001
Male vs. female			0.88 (0.71,1.09)	0.25	0.81 (0.63,1.03)	0.09	0.83 (0.64,1.06)	0.14
Age (years)			1.05 (1.04,1.06)	<0.001	1.04 (1.03,1.05)	<0.001	1.04 (1.03,1.05)	<0.001
BMI (kg/m^2)					0.98 (0.95,1.00)	0.07	0.98 (0.95,1.01)	0.14
Systolic blood pressure (mmHg)					1.02 (1.01,1.03)	<0.001	1.02 (1.01,1.03)	<0.001
Diastolic blood pressure (mmHg)					1.00 (0.99,1.01)	0.83	1.00 (0.99,1.01)	0.76
LDL (mmol/l)					0.96 (0.86,1.07)	0.45	0.93 (0.83,1.05)	0.25
TG (mmol/l)					1.24 (1.03,1.50)	0.02	1.32 (1.09,1.60)	0.01
Smoking vs. no smoking					0.85 (0.66,1.11)	0.23	0.84 (0.64,1.10)	0.21
HO vs (HT+WT)							0.44 (0.22,0.90)	0.02
Inuit genetic admixture (per % point increase)							1.01 (1.00,1.01)	0.001

Data are odds ratio (OR) with confidence limits, and p values are considered significant below 5% (shown in bold). The crude model shows the effect of diabetes on CKD. Model 1: adjusted for age and sex. Model 2: model 1 + BMI, systolic and diastolic blood pressure, LDL cholesterol, TG and smoking. Model 3: model 2 + the TBC1D4 variant and Inuit genetic admixture.

Table 4. Cross sectional analysis of the effect of diabetes on CKD: stepwise logistic regression presented as odds ratios (ORs).

Outcome CKD	Crude OR	P value	Model 1 OR	P value	Model 2 OR	P value	Model 3 OR	P value
Diabetes vs. no diabetes	1.8 (1.3,2.6)	0.001	1.01 (0.69,1.5)	0.97	0.78 (0.51,1.19)	0.24	0.85 (0.55,1.32)	0.47
Male vs. female			1.07 (0.83,1,38)	0.62	1.03 (0.78,1.35)	0.84	1.01 (0.76,1.33)	0.95
Age (years)			1.06 (1.05,1.07)	<0.001	1.05 (1.04,1.06)	<0.001	1.05 (1.04,1.06)	<0.001
BMI (kg/m^2)					0.95 (0.92,0.98)	0.001	0.94 (0.92,0.97)	0.003
Systolic blood pressure (mmHg)					1.01 (1.00,1.02)	0.009	1.01 (1.00,1.02)	0.02
Diastolic blood pressure (mmHg)					1.00 (0.98,1.01)	0.74	1.00 (0.99,1.01)	0.94
LDL (mmol/l)					1.07 (0.95,1.21)	0.28	1.09 (0.96,1.23)	0.17
TG (mmol/l)					1.71 (1.40,2.08)	<0.001	1.62 (1.32,2.00)	<0.001
Smoking vs. no smoking					0.88 (0.65,1.19)	0.40	0.96 (0.70,1.30)	0.80
HO vs (HT+WT)							0.76 (0.34,1.71)	0.50
Inuit genetic admixture (per % point increase)							0.99 (0.99,1.0)	0.03

Data are odds ratio (OR) with confidence limits, and p values are considered significant below 5%. The crude model shows the effect of diabetes on CKD. Model 1: adjusted for age and sex. Model 2: model 1 + BMI, systolic and diastolic blood pressure, LDL cholesterol, TG and smoking. Model 3: model 2 + the TBC1D4 variant and genetic admixture.

Figure 1. The effect of diabetes on eGFR at follow-up adjusted for baseline eGFR using linear regression, expressed as a proportion change in follow-up eGFR. Model 1: adjusted for age and sex. Model 2: model 1 + BMI, systolic and diastolic blood pressure, LDL cholesterol, TG, smoking and years between baseline and follow-up. Model 3: model 2 + the TBC1D4 variant and admixture (from Table S2).

Figure 2. The effect of diabetes on ACR at follow-up adjusted for baseline ACR using linear regression, expressed as a proportion change in follow-up ACR. Model 1: adjusted for age and sex. Model 2: model 1 + BMI, systolic and diastolic blood pressure, LDL cholesterol, TG, smoking and years between baseline and follow-up. Model 3: model 2 + the TBC1D4 variant and admixture (from Table S1).