title: Use of net reclassification improvement (NRI) method confirms the utility of combined genetic risk score to predict type 2 diabetes.
abstract: BACKGROUND
  Recent genome-wide association studies (GWAS) identified more than 70 novel loci for type 2 diabetes (T2D), some of which have been widely replicated in Asian populations. In this study, we investigated their individual and combined effects on T2D in a Chinese population.
  
  
  METHODS
  We selected 14 single nucleotide polymorphisms (SNPs) in T2D genes relating to beta-cell function validated in Asian populations and genotyped them in 5882 Chinese T2D patients and 2569 healthy controls. A combined genetic score (CGS) was calculated by summing up the number of risk alleles or weighted by the effect size for each SNP under an additive genetic model. We tested for associations by either logistic or linear regression analysis for T2D and quantitative traits, respectively. The contribution of the CGS for predicting T2D risk was evaluated by receiver operating characteristic (ROC) analysis and net reclassification improvement (NRI).
  
  
  RESULTS
  We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10(-18)<P<8.5×10(-3)), as well as nominal associations of NOTCH2, JAZF1, KCNJ11 and HNF1B (0.05<P<0.1) with T2D risk, which yielded odds ratios ranging from 1.07 to 2.09. The 8 significant SNPs exhibited joint effect on increasing T2D risk, fasting plasma glucose and use of insulin therapy as well as reducing HOMA-β, BMI, waist circumference and younger age of diagnosis of T2D. The addition of CGS marginally increased AUC (2%) but significantly improved the predictive ability on T2D risk by 11.2% and 11.3% for unweighted and weighted CGS, respectively using the NRI approach (P<0.001).
  
  
  CONCLUSIONS
  In a Chinese population, the use of a CGS of 8 SNPs modestly but significantly improved its discriminative ability to predict T2D above and beyond that attributed to clinical risk factors (sex, age and BMI).
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Claudia H T
authors.initials: CH
authors.lastname: Tam
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Janice S K
authors.initials: JS
authors.lastname: Ho
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Vincent K L
authors.initials: VK
authors.lastname: Lam
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Heung Man
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Eric S H
authors.initials: ES
authors.lastname: Lau
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China ; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China ; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Alice P S
authors.initials: AP
authors.lastname: Kong
authors.affiliation: Department of Statistics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Jean L F
authors.initials: JL
authors.lastname: Woo
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Stephen K W
authors.initials: SK
authors.lastname: Tsui
authors.affiliation: Center for Genomics and Personalized Medicine Research, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China ; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China ; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Wing Yee
authors.initials: WY
authors.lastname: So
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China ; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China ; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Juliana C N
authors.initials: JC
authors.lastname: Chan
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China ; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, China ; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ronald C W
authors.initials: RC
authors.lastname: Ma
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D044466:Asian People; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012372:ROC Curve; D012306:Risk; D012737:Sex Factors
chemical_list: D001786:Blood Glucose