Sixty-five common genetic variants and prediction of type 2 diabetes

UCLEB Consortium; Philippa J Talmud; Jackie A Cooper; Richard W Morris; Frank Dudbridge; Tina Shah; Jorgen Engmann; Caroline Dale; Jon White; Stela McLachlan; Delilah Zabaneh; Andrew Wong; Ken K Ong; Tom Gaunt; Michael V Holmes; Debbie A Lawlor; Marcus Richards; Rebecca Hardy; Diana Kuh; Nicholas Wareham; Claudia Langenberg; Yoav Ben-Shlomo; S Goya Wannamethee; Mark W J Strachan; Meena Kumari; John C Whittaker; Fotios Drenos; Mika Kivimaki; Aroon D Hingorani; Jacqueline F Price; Steve E Humphries

doi:10.2337/db14-1504

Sixty-five common genetic variants and prediction of type 2 diabetes

UCLEB Consortium, Philippa J Talmud, Jackie A Cooper, Richard W Morris, Frank Dudbridge, Tina Shah, Jorgen Engmann, Caroline Dale, Jon White, Stela McLachlan, Delilah Zabaneh, Andrew Wong, Ken K Ong, Tom Gaunt, Michael V Holmes, Debbie A Lawlor, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas WarehamClaudia Langenberg, Yoav Ben-Shlomo, S Goya Wannamethee, Mark W J Strachan, Meena Kumari, John C Whittaker, Fotios Drenos, Mika Kivimaki, Aroon D Hingorani, Jacqueline F Price, Steve E Humphries

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Abstract / Description of output

We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.

Original language	English
Pages (from-to)	1830-40
Number of pages	11
Journal	Diabetes
Volume	64
Issue number	5
Early online date	4 Dec 2014
DOIs	https://doi.org/10.2337/db14-1504
Publication status	Published - May 2015

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UCLEB Consortium, Talmud, P. J., Cooper, J. A., Morris, R. W., Dudbridge, F., Shah, T., Engmann, J., Dale, C., White, J., McLachlan, S., Zabaneh, D., Wong, A., Ong, K. K., Gaunt, T., Holmes, M. V., Lawlor, D. A., Richards, M., Hardy, R., Kuh, D., ... Humphries, S. E. (2015). Sixty-five common genetic variants and prediction of type 2 diabetes. Diabetes , 64(5), 1830-40. https://doi.org/10.2337/db14-1504

@article{d0592627ddbe4463be5a06072ab15db1,

title = "Sixty-five common genetic variants and prediction of type 2 diabetes",

abstract = "We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.",

author = "{UCLEB Consortium} and Talmud, {Philippa J} and Cooper, {Jackie A} and Morris, {Richard W} and Frank Dudbridge and Tina Shah and Jorgen Engmann and Caroline Dale and Jon White and Stela McLachlan and Delilah Zabaneh and Andrew Wong and Ong, {Ken K} and Tom Gaunt and Holmes, {Michael V} and Lawlor, {Debbie A} and Marcus Richards and Rebecca Hardy and Diana Kuh and Nicholas Wareham and Claudia Langenberg and Yoav Ben-Shlomo and Wannamethee, {S Goya} and Strachan, {Mark W J} and Meena Kumari and Whittaker, {John C} and Fotios Drenos and Mika Kivimaki and Hingorani, {Aroon D} and Price, {Jacqueline F} and Humphries, {Steve E}",

year = "2015",

month = may,

doi = "10.2337/db14-1504",

language = "English",

volume = "64",

pages = "1830--40",

journal = "Diabetes ",

issn = "0012-1797",

publisher = "AMER DIABETES ASSOC",

number = "5",

}

UCLEB Consortium, Talmud, PJ, Cooper, JA, Morris, RW, Dudbridge, F, Shah, T, Engmann, J, Dale, C, White, J, McLachlan, S, Zabaneh, D, Wong, A, Ong, KK, Gaunt, T, Holmes, MV, Lawlor, DA, Richards, M, Hardy, R, Kuh, D, Wareham, N, Langenberg, C, Ben-Shlomo, Y, Wannamethee, SG, Strachan, MWJ, Kumari, M, Whittaker, JC, Drenos, F, Kivimaki, M, Hingorani, AD, Price, JF & Humphries, SE 2015, 'Sixty-five common genetic variants and prediction of type 2 diabetes', Diabetes , vol. 64, no. 5, pp. 1830-40. https://doi.org/10.2337/db14-1504

TY - JOUR

T1 - Sixty-five common genetic variants and prediction of type 2 diabetes

AU - UCLEB Consortium

AU - Talmud, Philippa J

AU - Cooper, Jackie A

AU - Morris, Richard W

AU - Dudbridge, Frank

AU - Shah, Tina

AU - Engmann, Jorgen

AU - Dale, Caroline

AU - White, Jon

AU - McLachlan, Stela

AU - Zabaneh, Delilah

AU - Wong, Andrew

AU - Ong, Ken K

AU - Gaunt, Tom

AU - Holmes, Michael V

AU - Lawlor, Debbie A

AU - Richards, Marcus

AU - Hardy, Rebecca

AU - Kuh, Diana

AU - Wareham, Nicholas

AU - Langenberg, Claudia

AU - Ben-Shlomo, Yoav

AU - Wannamethee, S Goya

AU - Strachan, Mark W J

AU - Kumari, Meena

AU - Whittaker, John C

AU - Drenos, Fotios

AU - Kivimaki, Mika

AU - Hingorani, Aroon D

AU - Price, Jacqueline F

AU - Humphries, Steve E

PY - 2015/5

Y1 - 2015/5

N2 - We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.

AB - We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.

U2 - 10.2337/db14-1504

DO - 10.2337/db14-1504

M3 - Article

C2 - 25475436

SN - 0012-1797

VL - 64

SP - 1830

EP - 1840

JO - Diabetes

JF - Diabetes

IS - 5

ER -

Sixty-five common genetic variants and prediction of type 2 diabetes

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