Incidence of HNF1A and GCK MODY Variants in a South African Population

Figures & data

Table 1 Characteristics of the Study Population According to Gender

	Total -N1643	Males - N407	Females - N1236	p-value
	Mean±SD	Mean±SD	Mean±SD
Hyperglycaemia, Yes, N (%)	549 (33.4)	105 (25.8)	444 (35.9)	0.0068*
Diabetes, Yes, N (%)	310 (18.9)	61 (15.0)	249 (20.1)	0.0539
Pre-DM, Yes, N (%)	239 (14.5)	44 (10.8)	195 (15.8)	0.0313*
Age (years)	49.2±15.3	47.0±15.6	50.0±15.1	0.0008*
BMI	29.3±8.1	24.7±6.6	30.8±8.0	<0.0001*
WaistC (cm)	92.9±17.3	86.2±16.8	95.1±16.9	<0.0001*
HipC (cm)	104.6±16.6	94.5±12.5	107.9±16.4	<0.0001*
WHR	0.89±0.09	0.91±0.09	0.88±0.09	<0.0001*
SBP (mmHg)	127.2±23.9	126.6±24.3	127.5±23.7	0.5441
DBP (mmHg)	81.9±13.8	80.9±15.3	82.2±13.2	0.0851
FBG (mmol/L)	5.74±2.76	5.39±2.18	5.85±2.92	0.0029*
Post-2hr BG (mmol/L)	6.61±2.93	5.75±2.99	6.90±2.85	<0.0001*
HbA1c (%)	6.19±1.53	5.92±1.25	6.28±1.61	0.0001*
Fasting BI (mIU/L)	9.5±11.8	7.6±9.7	10.2±12.3	0.0001*
Post-2hr BI (mIU/L)	55.5±53.6	33.7±38.3	63.1±56.1	<0.0001*
Glucose/Insulin ratio	1.00±0.88	1.32±1.07	0.90±0.79	<0.0001*
Triglycerides-S (mmol/L)	1.47±1.07	1.55±1.57	1.44±0.85	0.0886
LDL Cholesterol (mmol/L)	3.23±1.03	2.95±0.97	3.32±1.03	<0.0001*
HDL Cholesterol (mmol/L)	1.32±0.36	1.25±0.37	1.35±0.36	<0.0001*
Cholesterol (mmol/L)	5.17±1.17	4.83±1.12	5.29±1.17	<0.0001*
Cholesterol/HDL ratio	4.11±1.20	4.07±1.33	4.13±1.15	0.4149
CRP (mg/L)	8.5±15.7	8.1±17.2	8.6±15.2	0.6328
Cotinine (ng/mL)	141.7±160.7	157.6±153.1	136.4±162.8	0.0231*
Gamma GT-S (IU/L)	46.2±70.6	54.1±97.1	43.6±59.2	0.0097

Note: *Chi-square.

Abbreviations: WaistC, waist circumference; HipC, hip circumference; WHR, waist-to-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HbA1c, glycated haemoglobin; BI, blood insulin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; Gamma GT, gamma glutamyl transferase; BMI, body mass index; Chol, cholesterol.

Table 2 Genotype Distributions and Minor Allele Frequencies

HNF1A, rs1169288, p.I27L	N=1623	HNF1A, rs115080759, p.L389V	N=1640	HNF1A, rs137853245, p.A276D	N=1642
A/A, N (%)	969 (59.7)	T/T, N (%)	1628 (99.3)	C/C, N (%)	1642 (100)
A/C, N (%)	557 (34.3)	T/G, N (%)	12 (0.7)	C/A, N (%)	0
C/C, N (%)	97 (5.9)	G/G, N (%)	0	A/A, N (%)	0
C, N (%)	751/3246 (23.1%)	G, N (%)	12/3280 (0.4%)	G, N (%)	0
HWE (p-value)	0.1576	HWE (p-value)	0.8818	HWE (p-value)	N/A
HNF1A, rs142318174, p.G52A	N=1638	HNF1A, rs140491072, p.Y322C	N=1641	GCK, rs4607517	N=1361
G/G, N (%)	1638 (100)	A/A	1641 (100)	G/G, N (%)	1321 (97.1)
G/C, N (%)	0	A/G, N (%)	0	A/G, N (%)	28 (2.1)
C/C, N (%)	0	G/G, N (%)	0	A/A, N (%)	12 (0.9)
C, N (%)	0	G, N (%)	0	A, N (%)	52/2722 (1.9)
HWE (p-value)	N/A	HWE (p-value)	NA	HWE (p-value)	<0.0001

Abbreviation: HWE, Hardy–Weinberg equilibrium.

Table 3 Participant Characteristics Compared Across HNF1A rs1169288 SNP Alleles

HNF1A, rs1169288 (p.I27L)	Variant
	AA (N=969)	CA (N=557)	CC (N=97)	Gender	SNP	Gender* SNP
	Mean±SD	Mean±SD	Mean±SD	p-value	p -value	p -value
Hyperglycaemia, Yes, N (%)	317 (32.7)	187 (33.6)	38 (39.2)	N/A	N/A	0.4345*
Diabetes, Yes, N (%)	177 (18.3)	108 (19.4)	22 (22.7)	N/A	N/A	Combined 0.7593
Pre-DM, Yes, N (%)	140 (14.4)	79 (14.2)	16 (16.5)
Age (years)	48.8±15.2	50.1±15.4	48.6±15.3	0.3736	0.2434	0.1626
BMI	29.5±8.4	29.0±7.7	30.1±8.1	<0.0001	0.3227	0.6479
WaistC (cm)	92.8±17.2	92.9±17.5	94.6±17.4	<0.0001	0.6016	0.3640
HipC (cm)	104.6±16.6	104.5±16.5	106.3±16.6	<0.0001	0.6133	0.6557
WHR	0.89±0.10	0.89±0.09	0.89±0.08	<0.0001	0.9717	0.2683
SBP (mmHg)	126.8±23.0	128.2±25.2	126.7±23.0	0.7523	0.5068	0.7031
DBP (mmHg)	81.8±13.6	82.3±14.3	82.2±13.0	0.6781	0.7869	0.1978
FBG (mmol/L)	5.70±2.67	5.77±2.86	5.79±2.34	0.0181	0.8532	0.3610
Post-2hr BG (mmol/L)	6.60±3.00	6.60±2.84	6.72±2.65	0.0002	0.9331	0.3948
HbA1c (%)	6.18±1.54	6.19±1.54	6.23±1.39	0.0055	0.9511	0.5368
Fasting BI (mIU/L)	9.9±13.7	8.9±8.2	10.2±7.9	0.0211	0.2719	0.9720
Post-2hr BI (mIU/L)	55.8±55.4	54.8±52.4	57.5±44.2	<0.0001	0.8964	0.3691
Glucose/Insulin ratio	0.99±0.81	1.03±1.00	0.86±0.64	<0.0001	0.2316	0.7501
Triglycerides (mmol/L)	1.43±0.96	1.51±1.17	1.58±1.57	0.0003	0.1936	0.0041*
LDL Chol (mmol/L)	3.19±1.02	3.30±1.07	3.28±0.93	0.0095	0.1607	0.2502
HDL Chol (mmol/L)	1.33±0.38	1.32±0.35	1.28±0.29	0.0090	0.3706	0.4872
Chol (mmol/L)	5.14±1.16	5.24±1.22	5.23±1.11	0.0047	0.2266	0.1811
Chol/HDL ratio	4.09±1.25	4.15±1.10	4.20±1.22	0.8099	0.4792	0.7782
CRP (mg/L)	9.47±17.43	7.33±13.64	5.62±6.36	0.7075	0.0068	0.1964
Cotinine (ng/mL)	140.7±159.5	146.1±164.2	125.9±156.8	0.3616	0.5134	0.7389
Gamma GT-S (IU/L)	46.6±67.3	46.4±75.3	45.0±81.9	0.0019	0.9782	0.1113

Note: *Denotes significance (p < 0.05).

Abbreviations: WaistC, waist circumference; HipC, hip circumference; WHR, waist-to-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HbA1c, glycated haemoglobin; BI, blood insulin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; Gamma GT, gamma glutamyl transferase; BMI, body mass index; Chol, cholesterol.

Table 4 Generalized Linear Regression Models Showing Phenotypes Associated with HNF1A rs1169288

HNF1A rs1169288 (C)	Dominant		Recessive		Additive
	Effect Size (95% CI)	p-value	Effect Size (95% CI)	p-value	Effect Size (95% CI)	p-value
Age (years)	0.001 (−0.001;0.003)	0.427	0.000 (−0.002; 0.001)	0.365	0.001 (−0.001; 0.003)	0.764
Gender (Female)	−0.047 (−0.113; 0.019)	0.165	0.003 (−0.029; 0.034)	0.868	−0.047 (−0.113; 0.019)	0.285
WaistC (cm)	0.000 (−0.002; 0.002)	0.752	0.000 (−0.001; 0.001)	0.882	0.000 (−0.002; 0.002)	0.841
SBP (mmHg)	−0.001 (−0.002; 0.001)	0.559	0.000 (−0.001; 0.001)	0.692	−0.001 (−0.002; 0.001)	0.529
DBP (mmHg)	0.002 (−0.001; 0.005)	0.310	0.001 (−0.001; 0.002)	0.354	0.002 (−0.001; 0.005)	0.236
FBG (mmol/L)	−0.012 (−0.05; 0.025)	0.521	−0.001 (−0.018; 0.017)	0.951	−0.012 (−0.05; 0.025)	0.584
Post-2hr BG (mmol/L)	0.008 (−0.007; 0.023)	0.277	0.005 (−0.002; 0.012)	0.178	0.008 (−0.007; 0.023)	0.160
HbA1c (%)	−0.032 (−0.089; 0.024)	0.265	−0.013 (−0.04; 0.014)	0.348	−0.032 (−0.089; 0.024)	0.204
Fasting BI (mIU/L)	−0.001 (−0.003; 0.002)	0.670	0.000 (−0.001; 0.001)	0.811	−0.001 (−0.003; 0.002)	0.798
Post-2hr BI (mIU/L)	0.000 (−0.001; 0.000)	0.605	0.000 (0.000; 0.000)	0.384	0.000 (−0.001; 0.000)	0.449
Triglycerides (mmol/L)	−0.016 (−0.051; 0.019)	0.378	0.000 (−0.016; 0.017)	0.990	−0.016 (−0.051; 0.019)	0.475
LDL Chol (mmol/L)	0.036 (0.006; 0.066)	0.019*	0.009 (−0.006; 0.023)	0.233	0.036 (0.006; 0.066)	0.017*
HDL Chol (mmol/L)	−0.059 (−0.141; 0.023)	0.157	−0.026 (−0.064; 0.013)	0.189	−0.059 (−0.141; 0.023)	0.097*
CRP (mg/L)	−0.002 (−0.004; 0.000)	0.040*	−0.001 (−0.002; 0.000)	0.068	−0.002 (−0.004; 0.000)	0.017*
Gamma GT-S (IU/L)	0.000 (−0.001; 0.000)	0.611	0.000 (0.000; 0.000)	0.803	0.000 (−0.001; 0.000)	0.610

Note: *Denotes significance (p < 0.05).

Abbreviations: WaistC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HbA1c, glycated haemoglobin; BI, blood insulin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; Gamma GT, gamma glutamyl transferase.

Table 5 Participant Characteristics Compared Across HNF1A rs115080759 SNP Alleles

HNF1A, rs115080759	Variant
	TT (N=1628)	GT (N=12)	GG (N=0)	Gender	SNP	Gender*SNP
	Mean±SD	Mean±SD	Mean±SD	p -value	p -value	p -value
Hyperglycaemia, Yes, N (%)	543 (33.4)	5 (41.7)	0	N/A	N/A	0.5430
Diabetes, Yes, N (%)	305 (18.7)	4 (33.3)	0	N/A	N/A	Combined 0.4078
Pre-DM, Yes, N (%)	238 (14.6)	1 (8.3)	0
Age (years)	49.2±15.3	49.0±13.9	N/A	0.8061	0.9609	0.8061
BMI	29.3±8.1	31.1±6.9	N/A	0.0287	0.4520	0.8760
WaistC (cm)	92.8±17.3	97.4±16.3	N/A	0.0421	0.3676	0.4897
HipC (cm)	104.5±16.6	108.6±13.4	N/A	0.0129	0.3962	0.7844
WHR	0.89±0.09	0.90±0.08	N/A	0.9765	0.8036	0.4571
SBP (mmHg)	127.2±23.9	126.9±22.0	N/A	0.8026	0.9619	0.7319
DBP (mmHg)	81.9±13.8	84.3±9.5	N/A	0.4625	0.5512	0.3169
FBG (mmol/L)	5.72±2.74	7.92±4.99	N/A	0.0339	0.0061	0.0098*
Post-2hr BG (mmol/L)	6.62±2.93	5.47±0.85	N/A	0.5317	0.2705	0.8996
HbA1c (%)	6.18±1.52	7.30±2.73	N/A	0.0615	0.0116	0.0127*
Fasting BI (mIU/L)	9.6±11.8	7.8±3.6	N/A	0.6059	0.6073	0.9581
Post-2hr BI (mIU/L)	55.5±53.7	52.7±39.5	N/A	0.4714	0.8822	0.7352
Glucose/Insulin ratio	1.00±0.87	1.56±1.76	N/A	0.0004	0.0284	0.0213*
Triglycerides (mmol/L)	1.47±1.08	1.24±0.53	N/A	0.6385	0.4518	0.4686
LDL Chol (mmol/L)	3.23±1.03	3.33±1.00	N/A	0.4978	0.7311	0.7849
HDL Chol (mmol/L)	1.32±0.36	1.27±0.40	N/A	0.4065	0.5868	0.8687
Chol (mmol/L)	5.18±1.17	5.17±1.27	N/A	0.4942	1.0000	0.7262
Chol/HDL ratio	4.11±1.20	4.27±1.08	N/A	0.8717	0.6423	0.7716
CRP (mg/L)	8.5±15.8	6.0±7.3	N/A	0.6849	0.5902	0.7371
Cotinine (ng/mL)	142.3±160.9	57.1±90.7	N/A	0.3096	0.0797	0.4891
Gamma GT-S (IU/L)	46.2±70.7	49.1±68.2	N/A	0.7800	0.8897	0.5058

Note: *Denotes significance (p < 0.05).

Abbreviations: WaistC, waist circumference; HipC, hip circumference; WHR, waist-to-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HbA1c, glycated haemoglobin; BI, blood insulin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; Gamma GT, gamma glutamyl transferase; BMI, body mass index; Chol, cholesterol.

Table 6 Participant Characteristics Compared Across GCK rs4607517 SNP Alleles

GCK, rs4607517	Variant
	GG (N=1321)	AG (N=28)	AA (N=12)	Gender	SNP	Gender*SNP
	Mean±SD	Mean±SD	Mean±SD	p -value	p -value	p -value
Hyperglycaemia, Yes, N (%)	453 (34.3)	9 (32.1)	2 (16.7)	N/A	N/A	0.4290
Diabetes, Yes, N (%)	251 (19.0)	7 (25.0)	2 (16.7)	N/A	N/A	Combined 0.3847
Pre-DM, Yes, N (%)	202 (15.3)	2 (7.1)	0
Age (years)	49.6±15.1	51.7±18.0	44.5±17.3	0.2449	0.7154	0.4318
BMI	29.3±8.1	30.9±9.0	29.2±9.3	0.2072	0.2976	0.0547
WaistC (cm)	93.0±17.4	95.0±15.5	91.1±18.4	0.0698	0.7338	0.9835
HipC (cm)	104.6±16.6	109.0±17.9	103.3±17.0	0.0013	0.3439	0.7761
WHR	0.89±0.09	0.87±0.07	0.88±0.06	0.1440	0.7944	0.7682
SBP (mmHg)	127.6±24.1	127.4±19.6	118.1±23.4	0.6729	0.6029	0.9138
DBP (mmHg)	82.1±13.8	81.6±13.7	76.9±17.3	0.3357	0.5378	0.5283
FBG (mmol/L)	5.75±2.73	5.58±1.58	6.77±6.82	0.1775	0.9047	0.6773
Post-2hr BG (mmol/L)	6.63±2.97	7.45±4.24	5.85±0.95	0.0723	0.5255	0.5543
HbA1c (%)	6.19±1.54	6.16±1.16	6.41±2.15	0.1256	0.9379	0.5609
Fasting BI (mIU/L)	9.5±12.5	10.6±13.8	9.6±6.3	0.8858	0.6692	0.5690
Post-2hr BI (mIU/L)	55.6±54.7	50.7±51.3	96.0±73.6	0.0420	0.2150	0.9815
Glucose/Insulin ratio	1.00±0.86	1.01±0.60	1.35±2.24	0.6457	0.9258	0.0765
Triglycerides (mmol/L)	1.46±1.07	1.59±0.87	1.57±0.92	0.8446	0.9652	0.5702
LDL Chol (mmol/L)	3.25±1.03	3.12±0.82	3.53±0.75	0.5195	0.5698	0.5491
HDL Chol (mmol/L)	1.32±0.37	1.30±0.33	1.33±0.36	0.0236	0.5923	0.3737
Chol (mmol/L)	5.19±1.18	5.10±0.94	5.74±0.85	0.9507	0.1095	0.2551
Chol/HDL ratio	4.12±1.17	4.16±1.27	4.16±0.90	0.5446	0.7093	0.4373
CRP (mg/L)	8.7±15.8	4.7±7.2	6.2±8.4	0.5067	0.2660	0.7580
Cotinine (ng/mL)	141.5±161.9	123.3±165.0	170.1±186.8	0.8643	0.8863	0.7621
Gamma GT-S (IU/L)	46.2±71.7	44.3±42.4	26.3±11.7	0.9285	0.6219	0.4450

Abbreviations: WaistC, waist circumference; HipC, hip circumference; WHR, waist-to-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HbA1c, glycated haemoglobin; BI, blood insulin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; Gamma GT, gamma glutamyl transferase; BMI, body mass index; Chol, cholesterol.

Table 7 Generalized Linear Regression Models Showing Phenotypes Associated with GCK rs4607517

GCK rs4607517 (A)	Dominant		Recessive		Additive
	Effect Size (95% CI)	p-value	Effect Size (95% CI)	p-value	Effect Size (95% CI)		p-value
Age (years)	0.000(−0.001;0.001)	0.923	0.000 (−0.001; 0.000)	0.582	0.000 (−0.001; 0.001)		0.882
Gender (Female)	−0.002 (−0.027; 0.023)	0.872	0.001 (−0.012; 0.015)	0.837	−0.001 (−0.035; 0.033)		0.971
WaistC (cm)	0.000 (−0.001; 0.001)	0.685	0.000 (−0.001; 0.000)	0.528	0.000 (−0.001; 0.001)		0.963
SBP (mmHg)	0.000 (−0.001; 0.001)	0.621	0.000 (0.000; 0.000)	0.589	0.000 (−0.001; 0.001)		0.565
DBP (mmHg)	0.000 (−0.001; 0.001)	0.845	0.000 (−0.001; 0.001)	0.940	0.000 (−0.002; 0.001)		0.862
FBG (mmol/L)	−0.007 (−0.021; 0.007)	0.335	−0.002 (−0.01; 0.005)	0.594	−0.009 (−0.028; 0.010)		0.359
Post-2hr BG (mmol/L)	0.000 (−0.005; 0.006)	0.877	−0.002 (−0.005; 0.002)	0.334	−0.001 (−0.009; 0.007)		0.787
HbA1c (%)	0.015 (−0.006; 0.035)	0.165	0.005 (−0.007; 0.016)	0.425	0.019 (−0.009; 0.048)		0.183
Fasting BI (mIU/L)	0.000 (−0.001; 0.001)	0.667	0.000 (−0.001; 0.000)	0.485	0.000(−0.001; 0.001)		0.970
Post-2hr BI (mIU/L)	0.000 (0.000; 0.000)	0.917	0.000 (0.000; 0.000)	0.049*	0.000 (0.000; 0.000)		0.481
Triglycerides (mmol/L)	0.023 (0.010; 0.036)	0.001*	0.016 (0.008; 0.023)	<0.001*	0.039 (0.020; 0.057)		<0.001*
LDL Chol (mmol/L)	−0.007 (−0.019; 0.004)	0.199	−0.001 (−0.007; 0.005)	0.760	−0.008 (−0.024; 0.007)		0.288
HDL Chol (mmol/L)	0.003 (−0.027; 0.034)	0.825	0.005 (−0.012; 0.021)	0.565	0.008 (−0.033; 0.050)		0.696
CRP (mg/L)	0.000 (−0.001; 0.000)	0.211	0.000 (0.000; 0.000)	0.868	0.000 (−0.001; 0.000)		0.395
Gamma GT-S (IU/L)	0.000 (0.000; 0.000)	0.301	0.000 (0.000; 0.000)	0.257	0.000 (0.000; 0.000)		0.228

Note: *Denotes significance (p < 0.05).

Abbreviations: WaistC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HbA1c, glycated haemoglobin; BI, blood insulin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; CRP, C-reactive protein; Gamma GT, gamma glutamyl transferase.