SUPPLEMENTARY DATA Supplementary Table 1

SUPPLEMENTARY DATA

Supplementary Table 1. Demographic information of the study participants by study center

OK AZ DK P-value (n=1,210) (n=1,235) (n=1,220) (years) 43.6±17.3 37.2±16.0 39.0±17.1 <0.0001 e (%) 41.2 37.7 41.2 0.12 I (kg/m2) 31.1±6.9 35.4±8.8 30.1±6.8 <0.0001 st/hip ratio 0.90±0.08 0.93±0.07 0.91±0.09 <0.0001 (mmHg) 126.7±17.3 121.0±17.1 120.2±16.3 <0.0001 P (mmHg) 76.8±11.5 76.6±11.5 75.3±10.5 0.002 L (mg/dL) 52.9±15.4 48.5±14.1 50.8±13.8 <0.0001 L (mg/dL) 99.9±30.4 L3.8±25.8 100.7±31.0 <0.0001 Fibrinogen (mg/dL) 384.6±87.2 416.8±89.7 368.3±86.8 <0.0001 Glomerular filtration rate 92.9±23.9 111.9±32.5 95.6±24.7 <0.0001 Total cholesterol (mg/dL) 185.8±37.2 174.3±34.1 181.8±39.0 <0.0001 Blood fasting glucose (mg/dL) 108.5±43.8 127.6±66.8 105.9±39.8 <0.0001 Insulin (uU/mL) 16.5±18.2 20.3±18.1 19.3±23.8 <0.0001 Smoking <0.0001 Current smoking 33.2% 25.5% 42.5% Former smoking 24.7% 24.8% 23.3% Never smoking 42.2% 49.7% 34.2% # of cigarettes (pack per year) 12.2±16.6 5.0±7.6 12.3±19.3 <0.0001

Type 2 Diabetes (%) 20.6 33.2 14.3 <0.0001 Insulin resistance (HOMA, mean±SD) 4.7±6.3 6.3±6.6 5.5±8.2 <0.0001 Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; HOMA, the homeostatic model assessment

Supplementary Table 2. Demographic information of the study participants by diabetes status

Diabetes non-diabetes P-value (n=2,814) (n=829) (years) 51.0±14.8 36.6±16.2 <0.0001 e (%) 37 41 0.035 I (kg/m2) 35.1±8.1 31.4±7.6 <0.0001 st/hip ratio 0.95±0.07 0.90±0.08 <0.0001 (mmHg) 128.0±20.1 121.0±15.8 <0.0001 P (mmHg) 76.4±11.7 76.2±11.1 0.78 L (mg/dL) 47.4±13.1 51.7±14.8 <0.0001 L (mg/dL) 98.2±29.8 98.1±29.2 0.88 Fibrinogen (mg/dL) 436.7±95.4 376.5±83.8 <0.0001 Glomerular filtration rate 97.9±38.8 100.9±24.8 0.007 Total cholesterol (mg/dL) 186.9±42.8 178.8±35.0 <0.0001 Blood fasting glucose (mg/dL) 182.1±76.2 94.2±10.7 <0.0001 Insulin (uU/mL) 27.0±28.9 16.3±16.1 <0.0001 Smoking (%) Current smoking 27 36 <0.0001 Former smoking 34 21 Never smoking 39 43 # of cigarettes (pack per year) 14.0±19.6 9.0±14.8 <0.0001

Insulin resistance (HOMA, mean±SD) 11.0±11.0 3.9±4.3 <0.0001

Supplementary Table 3. Single SNP association analysis with insulin resistance by study center

SNP Gene P Center SNP Gene P Center rs11637630 CHRNA3 0.0279 OK rs17486278 CHRNA5 0.0281 AZ rs12910984 CHRNA3 0.0325 OK rs2036527 CHRNA5 0.0055 AZ rs1878399 CHRNA3 0.0410 OK rs514743 CHRNA5 0.0004 AZ rs3743074 CHRNA3 0.0332 OK rs569207 CHRNA5 0.0120 AZ rs3743078 CHRNA3 0.0418 OK rs637137 CHRNA5 0.0120 AZ rs578776 CHRNA3 0.0185 OK rs684513 CHRNA5 0.0129 AZ rs6495308 CHRNA3 0.0343 OK rs8034191 CHRNA5 0.0098 AZ rs7177514 CHRNA3 0.0324 OK rs2072659 CHRNB2 0.0006 AZ rs2273504 CHRNA4 0.0187 OK rs3811450 CHRNB2 0.0173 AZ rs3787116 CHRNA4 0.0167 OK rs11633223 CHRNB4 0.0124 AZ rs514743 CHRNA5 0.0455 OK rs12914008 CHRNB4 0.0001 AZ rs569207 CHRNA5 0.0245 OK rs1996371 CHRNB4 0.0006 AZ rs588765 CHRNA5 0.0416 OK rs11637630 CHRNA3 0.0253 DK rs615470 CHRNA5 0.0491 OK rs12910984 CHRNA3 0.0261 DK rs637137 CHRNA5 0.0245 OK rs12914385 CHRNA3 0.0417 DK rs680244 CHRNA5 0.0419 OK rs3743078 CHRNA3 0.0235 DK rs684513 CHRNA5 0.0060 OK rs6495308 CHRNA3 0.0245 DK rs2072658 CHRNB2 0.0398 OK rs7177514 CHRNA3 0.0299 DK rs2072659 CHRNB2 < OK rs2236196 CHRNA4 0.0374 DK rs4952 CHRNB3 0.0399 OK rs637137 CHRNA5 0.0202 DK rs4953 CHRNB3 0.0399 OK rs684513 CHRNA5 0.0257 DK rs11633223 CHRNB4 0.0129 OK rs2072660 CHRNB2 0.0291 DK rs11636605 CHRNB4 0.0171 OK rs2072661 CHRNB2 0.0461 DK rs12440014 CHRNB4 0.0031 OK rs11633223 CHRNB4 0.0008 DK rs1316971 CHRNB4 0.0199 OK rs11636605 CHRNB4 0.0024 DK rs1948 CHRNB4 0.0185 OK rs12440014 CHRNB4 0.0029 DK rs8023462 CHRNB4 0.0125 OK rs1316971 CHRNB4 0.0021 DK rs950776 CHRNB4 0.0206 OK rs16970006 CHRNB4 0.0028 DK rs11637630 CHRNA3 0.0120 AZ rs1996371 CHRNB4 0.0299 DK rs1317286 CHRNA3 0.0019 AZ rs3813567 CHRNB4 0.0009 DK rs3743074 CHRNA3 0.0024 AZ rs7178270 CHRNB4 0.0107 DK rs3743078 CHRNA3 0.0371 AZ rs950776 CHRNB4 0.0184 DK rs17483686 CHRNA5 0.0014 AZ All p-values were obtained by GEE, adjusting for age, sex, WHR, smoking status, alcohol consumption, HDL, LDL, systolic blood pressure, physical activity, fibrinogen and renal function. P-values in bold represent statistical significance after Bonferroni correction

Supplementary Table 4. Single SNP association analysis with type 2 diabetes by study center

SNP Gene P Center SNP Gene P Center rs17483686 CHRNA5 0.0308 OK rs8034191 CHRNA5 < AZ rs684513 CHRNA5 0.0231 OK rs2072660 CHRNB2 0.0180 AZ rs2304297 CHRNA6 0.0303 OK rs2072661 CHRNB2 0.0240 AZ rs2072660 CHRNB2 0.0185 OK rs17487223 CHRNB4 0.0261 AZ rs2072661 CHRNB2 0.0230 OK rs11633585 CHRNA5 0.0005 DK rs10958726 CHRNB3 0.0284 OK rs10958726 CHRNB3 0.0459 DK rs13277254 CHRNB3 0.0330 OK rs13277254 CHRNB3 0.0456 DK rs13280604 CHRNB3 0.0420 OK rs11633223 CHRNB4 0.0001 DK rs4950 CHRNB3 0.0435 OK rs11636605 CHRNB4 0.0087 DK rs4954 CHRNB3 0.0180 OK rs12440014 CHRNB4 0.0146 DK rs6474413 CHRNB3 0.0336 OK rs12914008 CHRNB4 < DK rs2236196 CHRNA4 0.0477 AZ rs1316971 CHRNB4 0.0088 DK rs3787137 CHRNA4 0.0231 AZ rs16970006 CHRNB4 0.0398 DK rs17483686 CHRNA5 0.0302 AZ rs3813567 CHRNB4 0.0211 DK rs17486278 CHRNA5 0.0002 AZ rs7178270 CHRNB4 0.0006 DK rs2036527 CHRNA5 0.0002 AZ All p-values were obtained by GEE, adjusting for age, sex, WHR, smoking, alcohol intake, HDL, LDL, systolic blood pressure, physical activity, fibrinogen and renal function. P-values in bold represent statistical significance after Bonferroni correction

Supplementary Table 5. Single SNP association with insulin resistance by FBAT

SNP Gene P Center rs2072659 CHRNB2 0.0097 OK rs2304297 CHRNA6 0.0358 OK rs3811450 CHRNB2 0.0374 OK rs684513 CHRNA5 0.0012 AZ rs1316971 CHRNB4 0.0255 AZ rs11636605 CHRNB4 0.0255 AZ rs637137 CHRNA5 0.0279 AZ rs3787137 CHRNA4 0.0318 AZ rs12440014 CHRNB4 0.0366 AZ rs6122429 CHRNA4 0.0367 AZ rs3971872 CHRNB4 0.0420 AZ rs7178270 CHRNB4 0.0262 AZ rs2273504 CHRNA4 0.0273 AZ rs3743074 CHRNA3 0.0379 AZ rs3787116 CHRNA4 0.0237 DK rs2072660 CHRNB2 0.0269 DK rs2072661 CHRNB2 0.0272 DK rs2236196 CHRNA4 0.0483 DK rs13277254 CHRNB3 0.0186 DK rs6474413 CHRNB3 0.0286 DK rs10958726 CHRNB3 0.0390 DK rs578776 CHRNA3 0.0411 DK

Supplementary Table 6. Single SNP association with type 2 diabetes by FBAT

SNP Gene P Center rs2072659 CHRNB2 0.0030 OK rs3811450 CHRNB2 0.0058 OK rs2304297 CHRNA6 0.0480 OK rs17487223 CHRNB4 0.0156 OK rs4950 CHRNB3 0.0395 AZ rs13277254 CHRNB3 0.0411 AZ rs13280604 CHRNB3 0.0211 AZ rs4954 CHRNB3 0.0217 AZ rs10958726 CHRNB3 0.0181 AZ rs2236196 CHRNA4 0.0258 DK rs2072661 CHRNB2 0.0371 DK rs2072660 CHRNB2 0.0479 DK rs7178270 CHRNB4 0.0183 DK rs588765 CHRNA5 0.0285 DK

Supplementary Table 7. Gene-based and gene-family association analysis by study center

Phenotype Gene OK AZ DK CHRNA3 < < < CHRNA4 0.2228 0.2404 0.0368 CHRNA5 < < 0.0698 Insulin resistance CHRNA6 0.5233 0.0924 0.2056 CHRNB2 0.2876 < 0.0012 CHRNB3 0.0084 0.2106 0.3940 CHRNB4 0.0152 < 0.0176 The nAChRs gene-family < < < CHRNA3 0.4178 0.2838 0.0652 CHRNA4 0.1888 0.0858 0.2630 CHRNA5 0.2708 < 0.0048 Type 2 diabetes CHRNA6 0.0303 0.4853 0.5654 CHRNB2 0.0148 0.0004 0.1704 CHRNB3 0.0420 0.1280 0.0782 CHRNB4 0.3040 0.1154 < The nAChRs gene-family 0.0534 < < P-values in bold indicate statistical significance after Bonferroni correction

Supplementary Figure 1. Supplementary Figure 1: LD patterns for the 61 SNPs in the seven nAChRs genes among participants from Oklahoma

Supplementary Figure 2. LD patterns for the 61 SNPs in the seven nAChRs genes among participants from Arizona

Supplementary Figure 3. LD patterns for the 61 SNPs in the seven nAChRs genes among participants from Dakota