SUPPLEMENTARY INFORMATION

Transcription

1 SUPPLEMENTARY INFORMATION Study populations Inter99 The Inter99 study is a population-based non-pharmacological intervention study for ischemic heart disease conducted at the Research Centre for Prevention and Health in Glostrup, Denmark ( (ClinicalTrials.gov ID-no: NCT ; KA98155). A randomized sample of 13,016 individuals living in Copenhagen County (30-60 years) was drawn from the Civil Registration System and invited for examination. 6,784 (52%) attended the baseline health examination. Anthropometric and all biochemical measures were obtained after an overnight fast. All participants without previously diagnosed diabetes were characterized by a standardized 75g OGTT with plasma glucose and serum insulin measured at fasting, 30 min and 120 min after the ingestion of the oral glucose load.[21] Health2006 Health2006 is a population-based observational study of cardiovascular disease, diabetes, asthma and allergy conducted at the Research Center for Prevention and Health in Glostrup, Denmark (ClinicalTrials.gov ID-no: NCT ; KA ).[20] The participants in the Health2006 cohort were drawn as a random sample from the background population aged years living in the South-western part of the greater Copenhagen area. A total of 3,471 patients participated in a health examination. Health2008 The Health2008 is an extension of the Health2006. A random sample of the general population aged 30 to 60 years living in the same 11 municipalities was drawn and invited to participate (H-KA ). Persons with certain pre-specified chronic diseases such as diabetes or cardiovascular disease were not eligible. A total of 795 were examined.[19] ADDITION study The Danish ADDITION Study (Anglo Danish Dutch Study of Intensive Treatment in People with Screen- Detected Diabetes in Primary Care) is a screening and intervention study for individuals with high-risk of type 2 diabetes in the general practice sampled by Department of General Practice at University of Aarhus, Denmark (ClinicalTrials.gov ID-no: NCT , ethical approval number ).[22] Out of 8,662 participants from the initial screening, 1,626 participants with available DNA had screen-detected type 2 diabetes. Patients with type 2 diabetes were diagnosed by two independent diabetic values at baseline investigation or at one-year follow-up. A total of 1,435 individuals from this study were used as obesity cases in the case-control study of obesity. Vejle biobank Vejle Biobank is a sample of clinical-onset type 2 diabetes patients and non-diabetic control individuals with similar age and sex distribution examined at Vejle Hospital during a three-year period (ethical approval number S ). Control individuals were non-diabetic by self-report and by a fasting plasma glucose test according to WHO 1999 criteria. A total of 943 individuals were included as obesity cases in casecontrol study of obesity. Steno diabetic patients

2 A sample of clinically defined type 2 diabetes patients was ascertained at the outpatient clinic at Steno Diabetes Center, Copenhagen (KA99081gm). A total of 381 individuals from this study were included as obesity cases in the case control study of obesity. SUPPLEMENTARY TABLES Supplementary Table 1: Clinical characteristics of study participants in the Danish Inter99 cohort Inter99 all N 6,161 Age (years) 46.2+/-7.9 Sex (men/women) 3020/3141 BMI (kg/m2) 26.3+/-4.6 Inter99 non-diabetics N 5,530 Age (years) /-7.9 Sex (men/women) 2719/2811 BMI (kg/m2) 26.0+/-4.4 Waist-hip ratio 0.85+/ Fasting serum triglyceride (mmol/l) 1.0 (0.8;1.5) Fasting serum total cholesterol (mmol/l) 5.4 (4.8;6.2) Fasting serum LDL cholesterol (mmol/l) 3.4 (2.8;4.1) Fasting serum HDL cholesterol (mmol/l) 1.4 (1.2;1.7) Hba1c (%) /-0.4 Fasting plasma glucose (mmol/l) 5.54+/ min plasma glucose (mmol/l) 5.95+/-1.5 Fasting serum insulin (pmol/l) 34 (23;49) 120min serum insulin (pmol/l) 152 (94;245) HOMA-IR 1.4 (0.9;2.0) Matsuda index of insulin sensitivity 7.8 (5.3;11.1) Insulinogenic index 73.3 (46.3;121.2) High-sensitive CRP (mg/l) 1.1 (0.5;2.5) ALAT (µkatal/l) 0.16 (0.13;0.19) Leptin (ng/ml) 5.5 (2.6;11.6) Adiponectin (μg/ml) 7106 (4236;12102)

3 Supplementary Table 2: Clinical characteristics of study participants in the Danish Health2006 cohort Health2006 all N 2,914 Age (years) 49.6+/-12.9 Sex (men/women) 1323/1591 BMI (kg/m2) 25.9+/-4.7 Health2006 non-diabetics N 2,573 Age (years) 49.2+/-12.9 Sex (men/women) 1127/1446 BMI (kg/m2) 25.7+/-4.5 Waist-hip ratio 0.87+/-0.09 Fasting serum triglyceride (mmol/l) 1.1 (0.8;1.5) Fasting serum total cholesterol (mmol/l) 5.4 (4.7;6.1) Fasting serum LDL cholesterol (mmol/l) 3.3 (2.7;3.9) Fasting serum HDL cholesterol (mmol/l) 1.5 (1.2;1.8) Hba1c (%) 5.4+/-0.3 Fasting plasma glucose (mmol/l) 5.4+/-0.5 Fasting serum insulin (pmol/l) 33 (23;49) HOMA-IR 1.3 (0.9;2.0)

4 Supplementary Table 3: Clinical characteristics of study participants in the Danish Health2008 cohort Health2008 all N 652 Age (years) 46.6+/-8.2 Sex (men/women) 291/361 BMI (kg/m2) 25.6+/-4.3 Health2008 non-diabetics N 617 Age (years) 46.5+/-8.1 Sex (men/women) 268/349 BMI (kg/m2) 25.6+/-4.3 Waist-hip ratio 0.87+/-0.08 Fasting serum triglyceride (mmol/l) 1.1 (0.8;1.6) Fasting serum total cholesterol (mmol/l) 5.3 (4.6;6.0) Fasting serum LDL cholesterol (mmol/l) 3.2 (2.6;3.9) Fasting serum HDL cholesterol (mmol/l) 1.4 (1.2;1.7) Hba1c (%) 5.4+/-0.3 Fasting plasma glucose (mmol/l) 5.5+/ min plasma glucose (mmol/l) 5.3+/-1.3 Fasting serum insulin (pmol/l) 27 (19;40) 120min serum insulin (pmol/l) 145 (89;230) HOMA-IR 1.1 (0.7;1.7) Matsuda index of insulin sensitivity 9.3 (6.4;13.4) Insulinogenic index 89.3 (56.3;140.5)

5 Supplementary Table 4: Characteristics of Danish obese cases from ADDITION, Vejle Biobank and Steno Diabetes Center used in the case-control study of obesity ADDITION mean +/- sd N 1,435 Age (years) 58.9+/-7.2 Sex (men/women) 686/739 BMI (kg/m2) /-4.3 Vejle Biobank N 943 Age (years) 62.2+/-9.0 Sex (men/women) 561/382 BMI (kg/m2) 34.9+/-4.4 Steno Diabetes Center N 381 Age (years) 64.3+/-9.8 Sex (men/women) 235/146 BMI (kg/m2) 35.1+/-4.6 Data are means +/- sd Supplementary Table 5: Association analyses between p.r270h and risk of type 2 diabetes (T2D), impaired glucose regulation (IGR), combined IGR and T2D, dyslipidemia and hypertension. Controls (NGT) Cases (T2D) Odds ratio P N (RR/RH+HH) 4,603/213 4,839/ ( ) 0.6 Controls (NGT) Cases (IGR) Odds ratio P N (RR/RH+HH) 4,603/213 1,394/ ( ) 0.36 Controls (NGT) Cases (IGR+T2D) Odds ratio P N (RR/RH+HH) 4,603/213 6,233/ ( ) 0.64 Controls Cases (dyslipidemia) Odds ratio P N (RR/RH+HH) 7,450/383 5,864/ ( ) 0.32 Controls Cases (hypertension) Odds ratio P N (RR/RH+HH) 7,872/398 6,367/ ( ) 0.28 All analyses are adjusted for age, sex and first four principal components applying a dominant genetic model. Cases of dyslipidemia were defined as individuals receiving lipid lowering medication or had increased triglyceride (>1.7 mmol/l) or had lowered HDL cholesterol (men: <1.03; women<1.29). Cases of hypertension were defined as individuals receiving anti-hypertensive medication or with resting high systolic blood-pressure (>140mmHg) or high resting diastolic blood pressure (>90mmHg). T2D, type 2 diabetes; IGR, impaired glucose regulation based on oral glucose tolerance test; NGT, normal glucose tolerance based on an oral glucose tolerance test.