Supplemental Table 1 Age and gender-specific cut-points used for MHO.

Transcription

1 Supplemental Table 1 Age and gender-specific cut-points used for MHO. Age SBP (mmhg) DBP (mmhg) HDL-C (mmol/l) TG (mmol/l) FG (mmol/l) Boys th * 90th * Girls th * 90th * SBP: systolic blood pressure; DBP: diastolic blood pressure; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; FG: fasting glucose * for age, sex and height

2 Supplemental Table 2 Agreement of MHO according to CR definition and IR definition IR definition CR definition MHO MUO Total MHO MUO Total Supplementary Table 1 described the proportion of each type of MHO and MUO divided from the CR definition within the IR definition. First, 14.9% of the overweight were classified as MHO and 50.6% as MUO by both definitions. Second, 40.1% of the subjects with MHO-IR were classified as MHO-CR. Of the subjects in the MUO-IR, 80.6% of them showed MUO-CR, whereas 19.4% were MHO-CR. Thus, the CR definition missed approximately two-thirds of the subjects who were considered as MHO by using the IR definition. In the other words, the IR definition missed above half of the subjects who were considered as MUO by using the CR definition. The k coefficient of agreement for the categorical data was (P < 0.001), which also indicated a poor agreement between CR definition and IR definition.

3 Supplemental table 3 Prevalence of MHO in overweight and/or obesity under different definitions China BMI cut- point a CR1 CR2 IR1 IR2 MHO/obesity; n (%) 341/ / / /1212 (28.1%) (27.1%) (56.4%) (37.2%) MHO/overweight and obesity; n 606/ / / /1855 (%) (32.7%) (32.6%) (61.6%) (42.7%) IOTF BMI cut- point b MHO/obesity; n (%) 182/ / / /777 (23.4%) (28.8%) (50.6%) (32.0%) MHO/overweight and obesity; 562/ / / /1778 n(%) (31.6%) (31.5%) (60.7%) (41.7%) CR: cardio-metabolic risk factors; IR: insulin resistance. CR1: A modified Adult Treatment Panel III cut-point for each component: SBP or DBP 90th percentile for age, sex and height; TG 1.24 mmol/l; HDL-C 1.03 mmol/l and FG 5.6 mmol/l; (MHO-CR: 0 risk factors; MUO-CR: 1 risk factors). CR2: The cut-points by Jolliffe et al were used to define CR factors for individuals 12 years old; while a criteria based on the modified ATP-III MS definition were applied for those aged below 12 years old. All details can be found in Supplemental Table 1. (MHO-CR: 0 risk factors; MUO-CR: 1 risk factors). IR1: MHO-CR: HOMA-IR 3.0; MUO-CR: HOMA-IR > 3.0 (which was the 95th percentile of our healthy reference children in BCAMS). IR2: MHO-CR: HOMA-IR 2.3; MUO-CR: HOMA-IR > 2.3 (which was the optimal point for diagnosis of metabolic syndrome in our previous study in BCAMS). a Overweight and obesity were defined by using the sex- and age-specific 85th and 95th percentile of BMI, respectively, recommended by the Working Group on Obesity in China. b Overweight and obesity were defined by using the sex- and age-specific 85th and 95th percentile of BMI, respectively, recommended by 2012-IOTF.

4 Supplemental table 4 Associations of the 22 candidate SNPs with MHO among children and adolescents SNP Gene a/a* MAF P(HWE) Allele(a/A) Genotype (aa/aa/aa) (%) P(logistic) Case Control Case Control Addictive Dominant Recessive MHO-CR BMI related rs FTO T/A / / /21.4/ /24.9/ rs KCNQ1 T/C / / /48.9/ /41.4/ rs KCNQ1 T/C / / /50.9/ /44.9/ rs GNPDA2 C/T / / /46.4/ /46.3/ rs MC4R A/G / / /39.1/ /38.3/ rs MAP2K5 T/A / / /35.8/ /38.2/ rs BNDF T/G / / /27.4/ /49.4/ rs ADCY3/RBJ A/G / / /46.8/ /47.4/ rs PCSK1 A/C / / /49.4/ /52.7/ rs PAX6 T/C / / /45.6/ /44.7/ rs GP2 T/C / / /42.1/ /37.1/ rs SEC16B C/A / / /38.2/ /36.1/ rs ITIH4 C/G / / /43.8/ /47.2/ rs GIPR/QPCTL A/G E / / /40.7/ /39.0/31.1 / / / Type 2 diabetes related rs CDKAL1 T/C / / /49.8/ /50.6/ rs TCF7L2 C/T / / /7.6/ /8.0/ / rs IGF2BP2 T/C E / / /12.9/ /10.7/7.4 / / / rs PPARG G/C / / /12.9/ /12.3/ rs SLC30A8 T/C E / / /43.8/ /46.6/31.6 / / / Birth weight related rs HHEX/IDE C/T / / /43.7/ /40.9/ rs ADCY5 T/C / / /0.6/ /0.4/ / 0.68 rs HMGA2 C/T / / /33.6/ /32.4/ MHO-IR BMI related rs FTO T/A / / /23.6/ /24.2/ rs KCNQ1 T/C / / /43.9/ /43.2/ rs KCNQ1 T/C / / /48.0/ /45.7/

5 rs GNPDA2 C/T / / /46.9/ /46.0/ rs MC4R A/G / / /37.5/ /39.0/ rs MAP2K5 T/A / / /35.8/ /38.5/ rs BNDF T/G / / /45.7/ /51.6/ rs ADCY3/RBJ A/G / / /46.9/ /47.4/ rs PCSK1 A/C / / /50.8/ /52.4/ rs PAX6 T/C / / /50.6/ /41.6/ rs GP2 T/C / / /39.0/ /38.1/ rs SEC16B C/A / / /34.6/ /37.8/ rs ITIH4 C/G / / /43.0/ /48.2/ rs GIPR/QPCTL A/G E / / /43.0/ /37.5/32.4 / / / Type 2 diabetes related rs CDKAL1 T/C / / /51.5/ /49.7/ rs TCF7L2 C/T / / /7.4/ /8.2/ rs IGF2BP2 T/C E / / /13.6/ /10.0/6.8 / / / rs PPARG G/C / / /13.1/ /12.0/ rs SLC30A8 T/C E / / /45.9/ /45.8/33.7 / / / Birth weight related rs HHEX/IDE C/T / / /41.2/ /41.9/ rs ADCY5 T/C / / /0.7/ /0.3/ / 0.48 rs HMGA2 C/T / / /32.6/ /32.8/ *a: non-effect; A: effect; minor allele frequency; P value for Hardy-Weinberg equilibrium test; P value for logistic regression adjusted for gender, age and Tanner stage in genotype. FTO, fat mass and obesity associated; KCNQ1, potassium channel, voltage gated KQT-like subfamily Q, member 1; GNPDA2, glucosamine-6-phosphate deaminase 2; MC4R, melanocortin 4 receptor; MAP2K5, mitogen-activated protein kinase 5; BNDF, brain-derived neurotrophic factor ; ADCY3/RBJ, adenylate cyclase 3; PCSK1, proprotein convertase subtilisin/kexin type 1; PAX6, paired box 6; GP2, glycoprotein 2; SEC16B, SEC16 homolog B, endoplasmic reticulum export factor; ITIH4, inter-alpha-trypsin inhibitor heavy chain family, member 4; GIPR/QPCTL, gastric inhibitory polypeptide receptor; CDKAL1, CDK5 (cyclin-dependent kinase 5 ) regulatory subunit associated protein 1-like 1; TCF7L2, transcription factor 7-like 2; IGF2BP2, insulin-like growth factor 2 mrna binding protein 2; PPARG, peroxisome proliferator-activated receptor gamma; SLC30A8, solute carrier family 30 (zinc transporter), member 8; HHEX/IDE, hematopoietically expressed homeobox/insulin-degrading enzyme; ADCY5, adenylate cyclase 5; HMGA2, high mobility group AT-hook 2. Boldface type indicates nominally significant values (P < 0.05)

6 Supplemental table 5 Associations of the 4 SNPs with the components of MHO among children and adolescents KCNQ1- rs KCNQ -rs GNPDA2-rs β P β P β P BMI z-score WC z-score FAT% z-score SBP (mmhg) DBP (mmhg) TG (mmol/l) HDL-C (mmol/l) FG (mmol/l) Ln-insulin* Ln-HOMA-IR* βmeans standardized coefficients, which was adjusted for gender, age and Tanner stage. BMI z-score: Body mass index z-score by CDC2000; WC z-score: Waist circumference z-score for per SD; FAT% z-score Fat mass percentage z-score for per SD; SBP: systolic blood pressure; DBP: diastolic blood pressure; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; FG: fasting glucose; HOMA-IR: homeostasis model assessment-insulin resistance index. * natural logarithm transformed. Boldface type indicates nominally significant values (P < 0.05). 6