title: Genetic and clinical variables identify predictors for chronic kidney disease in type 2 diabetes.
abstract: Type 2 diabetes and chronic kidney disease (CKD) may share common risk factors. Here we used a 3-stage procedure to discover novel predictors of CKD by repeatedly applying a stepwise selection based on the Akaike information criterion to subsamples of a prospective complete-case cohort of 2755 patients. This cohort encompassed 25 clinical variables and 36 genetic variants associated with type 2 diabetes, obesity, or fasting plasma glucose. We compared the performance of the clinical, genetic, and clinico-genomic models and used net reclassification improvement to evaluate the impact of top selected genetic variants to the clinico-genomic model. Associations of selected genetic variants with CKD were validated in 2 independent cohorts followed by meta-analyses. Among the top 6 single-nucleotide polymorphisms selected from clinico-genomic data, three (rs478333 of G6PC2, rs7754840 and rs7756992 of CDKAL1) contributed toward the improvement of prediction performance. The variant rs478333 was associated with rapid decline (over 4% per year) in estimated glomerular filtration rate. In a meta-analysis of 2 replication cohorts, the variants rs478333 and rs7754840 showed significant associations with CKD after adjustment for conventional risk factors. Thus, this novel 3-stage approach to a clinico-genomic data set identified 3 novel genetic predictors of CKD in type 2 diabetes. This method can be applied to similar data sets containing clinical and genetic variables to select predictors for clinical outcomes.
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, 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, Shatin, 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, Shatin, 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, Shatin, Hong Kong SAR, China.
authors.forename: Andrea O Y
authors.initials: AO
authors.lastname: Luk
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Alice P S
authors.initials: AP
authors.lastname: Kong
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, 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, Shatin, 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, Shatin, Hong Kong SAR, China.
authors.forename: Heung Man
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, 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, USA.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
authors.forename: Cheuk-Chun
authors.initials: CC
authors.lastname: Szeto
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Statistics, The Chinese University of Hong Kong, Shatin, 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, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Shatin, 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, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Shatin, 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, Shatin, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. Electronic address: rcwma@cuhk.edu.hk.
authors.forename: Ronald C W
authors.initials: RC
authors.lastname: Ma
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000209:etiology*
chemical_list: D001786:Blood Glucose
keywords: chronic kidney disease; genetic variants; predictor; type 2 diabetes; variable selection