Combining genetic markers and clinical risk factors improves the risk assessment of impaired glucose metabolism

Figures & data

Table I. Polymorphisms analyzed in the present study.

			Allele frequencies		Genotype frequencies (n)
Genes	Description	Polymorphisms	Major	Minor
Insulin sensitivity
GYS1	Glycogen synthase 1	rs8103451 A>C (A1>A2)	A: 0.94	C: 0.06	A/A: 427	A/C: 57	C/C: 1
IRS1	Insulin receptor substrate 1	rsl801278 A>C (Gly972Arg)	A: 0.93	C: 0.07	A/A: 422	A/C: 60	C/C: 3
IGF2BP2	Insulin-like growth factors 2 mRNA binding protein 2	rs4402960 C>A	C: 0.72	A: 0.28	C/C: 259	C/A: 181	A/A: 45
PPARG	Peroxisome proliferator-activated receptor γ	rsl801282 C>G (Prol2Ala)	C: 0.89	G: 0.11	C/C: 390	C/G: 86	G/G: 9
PPARGC1A	PPARG co-activator 1	rs8192678 G>A (Gly482Ser)	G: 0.64	A: 0.36	G/G: 186	G/A: 251	A/A: 48
PPARA	Peroxisome proliferator-activated receptor α	rsl800206 C>G (Leul62Val)	C: 0.93	G: 0.07	C/C: 421	C/G: 57	G/G: 7
Lipolysis/lipid metabolism
ADRB2	β2 adrenergic receptor	rsl042714 C>G (Gln27Glu) rs 1042713 G>A (Glyl6Arg)	C: 0.59 G: 0.65	G: 0.41 A: 0.35	C/C: 174 G/G: 209	C/G: 225 G/A: 216	G/G: 86 A/A: 60
ADRB3	β3 adrenergic receptor	rs4994 T>C (Trp64Arg)	T: 0.91	C: 0.09	T/T: 402	T/C: 80	C/C: 3
FABP2	Fatty acid -binding protein 2	rsl799883 G>A (Ala54Thr)	G: 0.72	A: 0.28	G/G: 246	G/A: 197	A/A: 42
LIPC	Hepatic lipase	rsl800588 (−514 C>T)	C: 0.80	T: 0.20	C/C: 307	C/T: 158	T/T: 20
Adipokines
ADIPOQ	Adiponectin	rs2241766 (+45T>G)	T: 0.88	G: 0.12	T/T: 375	T/G: 99	G/G: 11
		rsl501299 (+276 G>T)	G: 0.71	T: 0.29	G/G: 252	G/T: 188	T/T: 45
IL6	Interleukin 6	rsl800795 (−174 G>C)	G: 0.57	C: 0.43	G/G: 159	G/C: 236	C/C: 90
TNFA	Tumor necrosis factor a	rs 1800629 (−308 G>A)	G: 0.85	A: 0.15	G/G: 352	G/A: 123	A/A: 10
Pancreatic function (β-cell)
ABCC8	Sulfonylurea receptor 1	rsl799854 (exon 16–30T)	C: 0.57	T: 0.43	C/C: 161	C/T: 228	T/T: 96
		rsl801261 C>T (Thr759Thr)	C: 0.96	T: 0.04	C/C: 444	C/T: 40	T/T: 1
CDKAL1	CDK5 regulatory subunit associated protein 1-like 1	rs7756992A>G	A: 0.76	G: 0.24	A/A: 278	A/G: 177	G/G: 30
		rsl0946403 A>G	A: 0.84	G: 0.16	A/A: 342	A/G: 131	G/G: 12
CDKN2A/2B	Cyclin-dependent kinase inhibitor 2A/2B	rs3731211T>A	T: 0.72	A: 0.28	T/T: 250	T/A: 198	A/A: 37
		rs3731201 A>G	A: 0.84	G: 0.16	A/A: 346	A/G: 122	G/G: 17
		rs495490 A>G	A: 0.93	G: 0.07	A/A: 420	A/G: 64	G/G: 1
		rs564398 A>G	A: 0.62	G: 0.38	A/A: 196	A/G: 211	G/G: 78
		rsl0811661 A>G	A: 0.77	G: 0.23	A/A: 293	A/G: 162	G/G: 30
HHEX/IDE	Hematopoietically expressed homeobox/nsulin-degrading enzyme	rsllll875 G>A	G: 0.61	A: 0.39	G/G: 181	G/A: 227	A/A: 77
		rs7923837 G>A	G: 0.63	A: 0.37	G/G: 190	G/A: 231	A/A: 64
HNF1B	Hepatocyte nuclear factor 1 β	rs4430796 G>A	G: 0.54	A: 0.46	G/G: 139	G/A: 246	A/A: 100
HNF4A	Hepatocyte nuclear factor 4 α	rsl885088 G>A	G: 0.77	A: 0.23	G/G: 288	G/A: 167	A/A: 30
		rs745975 C>T	C: 0.76	T: 0.24	C/C: 278	C/T: 179	T/T: 28
KCNJ11	Potassium inwardly rectifying channel, subfamily J, member 11	rs5215 A>G	A: 0.58	G: 0.42	A/A: 164	A/G: 234	G/G: 87
		rs2285676 A>G	A: 0.65	G: 0.35	A/A: 207	A/G: 216	G/G: 62
		rsl 1024273 C>A	C: 0.72	A: 0.28	C/C: 251	C/A: 192	A/A: 42
OPRM1	Opioid receptor mu 1	rsl799971 T>C	T: 0.78	C: 0.22	T/T: 301	T/C: 159	C/C: 25
SLC30A8	Solute carrier family 30 (zinc transporter), member 8	rs 13266634 G>A	G: 0.68	A: 0.32	G/G: 223	G/A: 217	A/A: 45
TCF7L2	Transcription factor 7-like 2	rs7903146 G>A	G: 0.74	A: 0.26	G/G: 265	G/A: 184	A/A: 36
		rs7901695 T>C	T: 0.68	C: 0.32	T/T: 226	T/C: 216	C/C: 43
UCP2	Uncoupling protein 2	rs660339 A>C (Ala55Val)	A: 0.62	C: 0.38	A/A: 190	A/C: 225	C/C: 70
WFS1	Wolfram syndrome 1	rsl0010131 G>A	G: 0.62	A: 0.38	G/G: 174	G/A: 257	A/A: 54

Risk alleles are shown in bold.

Figure 1. Comparison of areas under the receiving-operating characteristic (ROC) curves. Area under the ROC curve for the full model (gray): 0.85 (95% CI 0.81–0.89). Area under the ROC curve for the reduced model (black): 0.81 (95% CI 0.76–0.85). P-value for the difference between the areas under the ROC curves of the two models: 0.004. (From DeLong et al. (33).)

Table II. Characteristics of the participants.

	Normal glucose tolerant	IFG/IGT/T2DM	P-value
n = 485	386	99
Sex M = 215/F = 270	171/215	44/55	0.98^a
Age (years)	37.36 (17.6–68.1)	49.19 (17.9–78.1)	<0.0001
Body mass index (kg/m^2)	26.09 (17.33–52.97)	31.76 (19.12–64.94)	<0.0001
Smoking yes/no (%)	24%/76%	17%/83%	0.17^a
Systolic blood pressure (mmHg)	114.3 (84–180)	128.0 (96–200)	<0.0001
Diastolic blood pressure (mmHg)	70.36 (48–112)	77.66 (51–103)	<0.0001
Fasting glucose levels (mmol/L)	5.03 (3.6–6.0)	5.92 (4.35–13.0)	<0.0001
2-h glucose levels (mmol/L)	5.58 (2.7–7.7)	9.37 (4.5–19.7)	<0.0001

Data are means (min-max). P-values are for differences between normal glucose tolerant and IFG/IGT/T2DM.

IFG = impaired fasting glucose; IGT = impaired glucose tolerant; T2DM = diabetic.

^aFrom a chi-square test.

Table III. Results of logistic regression analyses predicting undiagnosed IFG/IGT/T2DM.

	Full model			Reduced model
Independent variable	OR	P-value	95% CI	OR	P-value	95% CI
Sex (women vs men)	1.16	0.60	0.68–2.00	1.12	0.67	0.67–1.86
Age (years)	1.31	<0.0001	1.18–1.47	1.28	<0.001	1.15–1.42
Body mass index (kg/m^2)	1.19	<0.0001	1.11–1.28	1.19	<0.0001	1.12–1.28
Smoking status (smokers vs nonsmokers)	1.46	0.28	0.73–2.89	1.30	0.43	0.66–2.47
Systolic blood pressure (mmHg)	1.02	0.38	0.98–1.07	1.02	0.38	0.98–1.07
Diastolic blood pressure (mmHg)	1.07	0.08	0.99–1.16	1.05	0.18	0.98–1.13
UCP2 Ala55Val (Ala/Ala versus Val/Val)	1.17	0.35	0.48–3.00
UCP2 Ala55Val (Ala/Val versus Val/Val)	2.48	0.005	1.08–6.16
ADIPOQ +276 G>T (T/+ versus G/G)	2.29	0.004	0.25–0.76
IGF2BP2 rs4402960 C>A (A/+ versus C/C)	2.49	0.002	1.43^.43
CDKN2A/2B rsl0811661 G>A (A/+ versus G/G)	5.83	0.03	1.47–39.79
CDKN2A/2B rs3731201 A>G (G/+ versus A/A)	1.96	0.02	0.29–0.91
CDKN2A/2B rs49540 A>G (G/+ versus A/A)	2.53	0.02	0.18–0.87
Model R^2	0.386			0.287
Likelihood ratio test (LRT)
-2 Log L Full model	354.253
-2 Log L Reduced model	393.234
LRT chi-square (7 df)	38.98
P-value	<0.00001

The OR for age was calculated for a 5-year increment in age, while for body mass index it was calculated for a 2 kg/m² increment.

OR = odds ratio; CI = confidence interval; IFG/IGT/T2DM = impaired fasting glucose/impaired glucose tolerance/type 2 diabetes.

Table VI. Overview of type 2 diabetes predictive models including genetic and/or clinical risk factors.^a (P-values are for comparison between AUC for clinical characteristics and for genetic variants plus clinical characteristics.)

Studies	Number of subjects	Genetic variants (n)	AUC for genetic variants	AUC for clinical characteristics	AUC for genetic variants and clinical characteristics	P-value
Weedon et al. (9)	6,077	3	0.58	NR	NR	NR
Lyssenko et al. (10)	2,293	2	NR	0.68^c	0.68	NR
Vaxillaire et al. (12)	3,877	3	0.56	0.82^d	0.84	NR
Lu & Elston (43)	Simulation based on (9)	3^b	0.58	NR	NR	NR
	Simulation based on (9)	7	NR	NR^e	0.66	NR
	Simulation based on (9)	12	NR	NR^e	0.67	NR
Cauchi et al. (39)	6,890	15	NR	NR^d	0.86	NR
van Hoek et al. (23)	6,544	18	0.60	0.66^d	0.68	<0.0001
Lango et al. (20)	4,907	18	0.60	0.78^d	0.80	2.88 X 10^−12
Lyssenko et al. (MPP) (21)	18,831	16	0.63	0.70^f	0.72	<0.0001
	18,831	16	0.63	0.74^g	0.75	0.0001
Meigs et al. (22)	2,377	18	NR	0.53^h	0.58	0.01
	2,377	18	NR	0.60^j	0.62	NS
	2,377	18	NR	0.90^i	0.90	NS
Miyake et al. (24)	4,686	11	0.63	0.68^d	0.72	NR
Ruchat et al.	485	6	NR	0.81^k	0.85	0.004

^aValues are the areas under the ROC curves, which represent the capacity of the model to discriminate between cases and controls. A value of 0.5 indicates no discrimination, while a value of 1 indicates perfect discrimination. ^bSame predictive genetic model as Weedon et al. (9). Clinical characteristics: ^cFasting glucose and BMI; ^dAge, sex, BMI; ^eDiet, physical activity, cigarette smoking and alcohol consumption; ^fAge, sex, family history, BMI; ^gAge, sex, family history, BMI, blood pressure, triglycerides, fasting glucose; ^hSex; ⁱSex, family history; ^jAge, sex, family history, BMI, blood pressure, HDL cholesterol, triglyceride, fasting glucose; ^kAge, sex, BMI, smoking status, blood pressure.NR = not reported; MPP = Malmö Preventive Project.

P-values are for comparison between AUC for clinical characteristics and for genetic variants plus clinical characterstics.