Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis: Ten-Year Follow-Up of the GLACIER Study

Frida Renström; Dmitry Shungin; Ingegerd Johansson; the MAGIC Investigators; Jose C. Florez; Göran Hallmans; Frank B. Hu; Paul W. Franks

doi:10.2337/db10-0933

Genetics

Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis

Ten-Year Follow-Up of the GLACIER Study

Frida Renström¹,²,
Dmitry Shungin¹,³,
Ingegerd Johansson³,
the MAGIC Investigators⁴,*,
Jose C. Florez⁵,
Göran Hallmans⁶,
Frank B. Hu² and
Paul W. Franks¹,²,⁷

¹Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden;
²Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts;
³Department of Odontology, Umeå University Hospital, Umeå, Sweden;
⁴Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, U.K.;
⁵Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
⁶Department of Public Health and Clinical Medicine, Section for Nutritional Research, Umeå University Hospital, Umeå, Sweden;
⁷Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.

Corresponding author: Paul W. Franks, paul.franks{at}med.lu.se.

Diabetes 2011 Jan; 60(1): 345-354. https://doi.org/10.2337/db10-0933

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FIG. 1.
Association between the weighted genetic risk score and change in fasting glucose concentrations during 10 years of follow-up. The weighted genetic risk score (wGRS) was constructed as described in the research design and methods section. Data are mean (95% CI). Δ glucose levels (follow-up minus baseline) per quintile of the wGRS are adjusted for baseline age, sex, baseline fasting glucose, fasting time at baseline and follow-up, and follow-up time (N = 4,059).

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TABLE 1
Participant characteristics for the GLACIER Study cohort (n = 16,330)
Variable Mean or n^* SD or %^*
Sex (male/female)^* 6,526/9,872 40/60
Age (years) 52.3 8.8
BMI (kg/m²) 25.9 4.1
Fasting glucose (mmol/l) 5.4 0.6
2-h glucose (mmol/l)^† 6.7 1.5
NFG vs. IFG^* 10,766/5,564 66/34
*Values are n and proportion (%).
†2-h glucose concentrations available for 15,828 participants. NFG, normal fasting glucose.

TABLE 2

Characteristics for GLACIER Study participants in whom baseline and 10-year follow-up exams were performed (n = 4,059)

Variable	Baseline		Follow-up
Variable	Mean or n	SD or %	Mean or n	SD or %
Sex (male/female)^*	1,479/2,580	36/64	—	—
Age (years)	45.2	6.7	55.2	6.7
Family history of T2D^*^†	697/3,321/41	17/82/1	925/2,980/154	23/73/4
BMI (kg/m²)^‡	25.1	3.7	26.2	4.0
Fasting glucose (mmol/l)^‡	5.3	0.6	5.5	0.7
2-h glucose (mmol/l)^‡^§	6.5	1.3	7.1	1.7
Systolic blood pressure (mmHg)^‡	124	16	130	18
Diastolic blood pressure (mmHg)^‡	78	10	78	10
Triglycerides (mmol/l)^‡^¶	1.3	0.8	1.4	0.9
NFG vs. IFG^*^#	3,087/964	76/24	2,073/1,953	51/49

*Values are n and proportion (%).
†Yes/no/missing information.
‡A paired samples t test was used to compare mean values at baseline and follow-up, all of which (except DBP) increased significantly (P < 0.0001). Follow-up duration averaged 9.9 ± 0.3 years and ranged from 6 to 13 years.
§2-h glucose available for 4,059 participants at follow-up.
¶Triglycerides available in 3,352 and 4,020 participants at baseline and follow-up, respectively.
#The number of individuals with IFG increased significantly at follow-up compared with baseline (P < 0.0001). Frequencies were compared between baseline and follow-up using the Mantel-Haenszel χ² test (1 degree of freedom). T2D, type 2 diabetes; NFG, normal fasting glucose.

TABLE 3

Baseline associations between each SNP and fasting and 2-h glucose concentrations (n = 16,330)

SNP	Nearest gene (s)	Effect allele (other)	Effect allele frequency	Fasting glucose (mmol/l)		2-h glucose (mmol/l)
SNP	Nearest gene (s)	Effect allele (other)	Effect allele frequency	Effect (SE)^*	P^*	Effect (SE)^*	P^*	Effect (SE)^†	P^†
rs10830963	MTNR1B	G(C)	0.28	0.091 (0.008)	2.7 × 10⁻³¹	0.013 (0.019)	0.49	−0.042 (0.018)	0.02
rs560887	G6PC2	C(T)	0.71	0.063 (0.008)	1.9 × 10⁻¹⁶	0.013 (0.018)	0.47	−0.025 (0.018)	0.16
rs4607517	GCK	A(G)	0.15	0.054 (0.010)	3.1 × 10⁻⁸	0.083 (0.023)	3.9 × 10⁻⁴	0.050 (0.023)	0.03
rs11605924	CRY2	A(C)	0.50	0.033 (0.007)	1.5 × 10⁻⁶	0.062 (0.017)	2.0 × 10⁻⁴	0.042 (0.016)	9.1 × 10⁻³
rs2191349	DGKB-TMEM195	T(G)	0.51	0.029 (0.007)	2.7 × 10⁻⁵	0.007 (0.017)	0.69	−0.009 (0.016)	0.56
rs13266634	SLC30A8	C(T)	0.70	0.029 (0.008)	1.4 × 10⁻⁴	0.044 (0.018)	0.02	0.027 (0.017)	0.12
rs780094	GCKR	C(T)	0.71	0.025 (0.008)	1.1 × 10⁻³	−0.024 (0.018)	0.20	−0.039 (0.018)	0.03
rs7903146	TCF7L2	T(C)	0.20	0.028 (0.009)	1.2 × 10⁻³	0.084 (0.021)	6.9 × 10⁻⁵	0.066 (0.020)	1.2 × 10⁻³
rs10885122	ADRA2A	G(T)	0.89	0.035 (0.011)	1.5 × 10⁻³	−0.004 (0.026)	0.89	−0.024 (0.026)	0.36
rs174550	FADS1	T(C)	0.66	0.019 (0.007)	9.7 × 10⁻³	0.035 (0.017)	0.04	0.024 (0.017)	0.15
rs11920090	SLC2A2	T(A)	0.86	0.026 (0.010)	9.7 × 10⁻³	0.057 (0.024)	0.02	0.040 (0.023)	0.09
rs340874	PROX1	C(T)	0.53	0.016 (0.007)	0.02	0.016 (0.017)	0.33	0.006 (0.016)	0.69
rs7944584	MADD	A(T)	0.76	0.014 (0.008)	0.10	0.011 (0.020)	0.57	0.003 (0.019)	0.86
rs7034200	GLIS3	A(C)	0.43	0.009 (0.007)	0.18	0.003 (0.017)	0.88	−0.004 (0.016)	0.80
rs11708067	ADCY5	A(G)	0.79	0.010 (0.009)	0.24	0.087 (0.021)	2.4 × 10⁻⁵	0.080 (0.020)	5.7 × 10⁻⁵
rs11071657	C2CD4B	A(G)	0.60	0.007 (0.007)	0.35	−0.035 (0.017)	0.04	−0.041 (0.016)	0.01

SNPs are ranked by P value for the association with fasting glucose concentrations. Multiple testing was corrected for using the Holm procedure (29). All genotypes are located on the plus strand and coded according to HapMap CEU (phase II + III), release 27, National Center for Biotechnology Information build 36. Two-hour glucose concentrations were measured by a 75-g oral glucose tolerance test in accordance with the World Health Organization guidelines (21).
*Adjusted for age, sex, and fasting time.
†Adjusted for age, sex, fasting time, and fasting glucose concentrations.

TABLE 4

The ability of each SNP to predict changes in fasting and 2-h glucose concentrations over a 10-year follow-up period (n = 4,059)

SNP	Nearest gene (s)	Effect allele (frequency)	Change in fasting glucose (mmol/l)			Change in 2-h glucose (mmol/l)
SNP	Nearest gene (s)	Effect allele (frequency)	Effect (SE)^*	P^*	Corrected P^*	Effect (SE)^†	P^†	Corrected P^†	Effect^‡ (SE)^‡	P^‡	Corrected P^‡
rs4607517	GCK	A (0.15)	0.057 (0.022)	0.010	0.17	0.015 (0.048)	0.750	0.99	−0.029 (0.046)	0.528	0.99
rs10885122	ADRA2A	G (0.89)	0.062 (0.026)	0.017	0.27	0.042 (0.055)	0.451	0.99	−0.004 (0.052)	0.945	0.99
rs2191349	DGKB-TMEM195	T (0.51)	0.037 (0.016)	0.020	0.31	−0.007 (0.034)	0.849	0.99	−0.030 (0.033)	0.362	0.99
rs560887	G6PC2	C (0.71)	0.038 (0.017)	0.031	0.43	0.001 (0.038)	0.970	0.99	−0.027 (0.036)	0.454	0.99
rs10830963	MTNR1B	G (0.28)	0.034 (0.018)	0.059	0.77	−0.092 (0.039)	0.018	0.29	−0.131 (0.037)	4.0 × 10⁻⁴	6.5 × 10⁻³
rs780094	GCKR	C (0.71)	−0.030 (0.018)	0.088	0.99	−0.065 (0.038)	0.085	0.99	−0.052 (0.036)	0.144	0.99
rs7903146	TCF7L2	T (0.20)	0.028 (0.020)	0.159	0.99	0.044 (0.043)	0.307	0.99	0.027 (0.041)	0.515	0.99
rs11071657	C2CD4B	A (0.60)	0.021 (0.016)	0.193	0.99	−0.028 (0.036)	0.426	0.99	−0.046 (0.034)	0.174	0.99
rs11708067	ADCY5	A (0.79)	0.014 (0.020)	0.488	0.99	0.100 (0.043)	0.020	0.30	0.092 (0.040)	0.023	0.34
rs11920090	SLC2A2	T (0.86)	0.016 (0.024)	0.501	0.99	0.006 (0.051)	0.906	0.99	−0.002 (0.050)	0.959	0.99
rs11605924	CRY2	A (0.50)	0.011 (0.016)	0.503	0.99	−0.026 (0.034)	0.453	0.99	−0.032 (0.033)	0.322	0.99
rs340874	PROX1	C (0.53)	0.010 (0.016)	0.534	0.99	−0.037 (0.034)	0.278	0.99	−0.057 (0.032)	0.078	0.99
rs174550	FADS1	T (0.66)	−0.007 (0.017)	0.668	0.99	−0.006 (0.037)	0.873	0.99	0.002 (0.035)	0.947	0.99
rs7944584	MADD	A (0.76)	0.007 (0.019)	0.723	0.99	−0.072 (0.042)	0.085	0.99	−0.081 (0.040)	0.043	0.60
rs13266634	SLC30A8	C (0.70)	0.006 (0.017)	0.731	0.99	0.040 (0.037)	0.278	0.99	0.024 (0.035)	0.494	0.99
rs7034200	GLIS3	A (0.43)	0.005 (0.016)	0.757	0.99	−0.002 (0.035)	0.948	0.99	−0.003 (0.033)	0.926	0.99

SNPs are ranked by P value of the per-allele effect on change in fasting glucose concentrations. Multiple testing was corrected for using the Holm procedure (29). All genotypes are located on the plus strand and are coded according to HapMap CEU (phase II + III), release 27, National Center for Biotechnology Information build 36. Two-hour glucose concentrations were measured by an oral glucose tolerance test in accordance with the World Health Organization guidelines (21).
*Adjusted for baseline age, sex, fasting glycemia, fasting times at baseline and follow-up, and follow-up time.
‡Adjusted for baseline age, sex, 2-h glucose concentrations, fasting times at baseline and follow-up, and follow-up time.
†Adjusted for baseline age, sex, 2-h glucose concentrations, fasting times at baseline and follow-up, follow-up time and fasting glucose concentrations at baseline and follow-up.

TABLE 5

Cross-sectional and longitudinal associations between each SNP and IFG

SNP	Nearest gene(s)	Effect allele (freq.)	Cross-sectional^§		Longitudinal^†
SNP	Nearest gene(s)	Effect allele (freq.)	OR	95% CI	OR	95% CI
rs10830963	MTNR1B	G (0.28)	1.31	(1.24–1.38)^*	1.17	(1.05–1.30)^*
rs560887	G6PC2	C (0.71)	1.21	(1.15–1.28)^*	1.13	(1.02–1.25)^*
rs4607517	GCK	A (0.15)	1.19	(1.11–1.27)^*	1.13	(0.99–1.29)
rs10885122	ADRA2A	G (0.89)	1.13	(1.05–1.22)^*	1.16	(0.99–1.35)
rs2191349	DGKB-TMEM195	T (0.51)	1.11	(1.05–1.16)^*	1.09	(0.99–1.20)
rs7903146	TCF7L2	T (0.20)	1.11	(1.05–1.18)^*	1.08	(0.96–1.22)
rs13266634	SLC30A8	T (0.70)	1.10	(1.05–1.16)^*	1.05	(0.95–1.17)
rs11605924	CRY2	A (0.50)	1.09	(1.04–1.14)^*	1.09	(0.99–1.20)
rs780094	GCKR	C (0.72)	1.08	(1.02–1.13)^*	0.92	(0.83–1.02)
rs11920090	SLC2A2	T (0.86)	1.06	(0.99–1.13)	1.11	(0.96–1.28)
rs7034200	GLIS3	A (0.43)	1.05	(1.00–1.10)^*	1.02	(0.93–1.12)
rs11708067	ADCY5	A (0.80)	1.05	(0.99–1.12)	0.99	(0.87–1.11)
rs340874	PROX1	C (0.53)	1.04	(0.99–1.09)	1.12	(1.02–1.24)^*
rs174550	FADS1	T (0.66)	1.04	(0.98–1.09)	1.08	(0.97–1.19)
rs7944584	MADD	A (0.76)	1.04	(0.98–1.10)	1.00	(0.89–1.12)
rs11071657	C2CD4B	A (0.60)	1.01	(0.96–1.06)	1.02	(0.92–1.13)

Main effects are expressed as odds ratios (ORs) (IFG vs. normal glucose regulation) per copy of the effect allele at each locus ranked by effect size on baseline association with IFG.
§Models adjusted for age, sex, and fasting time (n = 16,330).
†Models adjusted for age and sex, fasting times at baseline and follow-up, follow-up time, and baseline IFG (n = 4,059).
*P < 0.05.