Introduction 1 2 3 4 5 2 6 7 8 9 COLIA1 10 12 COLIA1 13 14 15 COLIA1 T 11 T 10 15 10 12 16 17 COLIA1 18 19 COLIA1 T COLIA1 Materials and Methods Study Population 20 Study Design n n COLIA1 n Measurements 2 21 2 Fracture Follow-up n Nonvertebral fracture events were retrieved from computerized records of the general practitioners (GPs) in the research area. Research physicians regularly followed participant information in GP records outside the research area and made an independent review, encoding all reported events. Subsequently, a medical expert in the field reviewed all coded events for final classification. We excluded fractures that were considered nonosteoporotic, i.e., caused by cancer and high trauma, including fractures of the hand, foot, skull, and face. Subsequently, we analyzed separately “fragility” fractures, which were defined as any fracture of the hip, pelvis, or proximal humerus that had occurred with minimal trauma at older age (mean >75 years). Vertebral Fracture Assessment 22 Genotyping http://www.appliedbio-systems.com Statistical Analysis COLIA1 23 r 2  24 COLIA1 http://www.cran.r-project.org P Results P P 1 Table 1 General characteristics of the study population at baseline and second follow-up  Women Men Baseline Second follow-up Baseline Second follow-up Number n n n n Age (years) 68.3 ± 8.2 72.7 ± 6.8 67.6 ± 7.7 72.2 ± 6.5 Height (cm) 161.1 ± 6.8 160.6 ± 6.4 174.6 ± 6.8 174.0 ± 6.7 Weight (kg) 69.3 ± 11.4 70.3 ± 12.2 78.2 ± 10.8 79.5 ± 11.3 2 26.7 ± 4.1 27.2 ± 4.4 25.6 ± 3.0 26.3 ± 3.2 2 a 0.83 ± 0.14 0.80 ± 0.13 0.92 ± 0.14 0.90 ± 0.14 2 1.03 ± 0.18 - 1.16 ± 0.20 - FN-BMD change n n b −0.84 ± 1.09 - Values are means ± SD. Anthropometric measurement based on 5,826 individuals at baseline and 3,011individuals at follow-up a b COLIA1 2 COLIA1 2 P T P 2 2 2 Table 2 COLIA1  Promoter -1997 G/T Intron 1 Sp1 G/T GG GT TT P* GG GT TT P* Men n n n  n n n  2 0.92 ± 0.13 0.92 ± 0.14 0.90 ± 0.14 1.00 0.92 ± 0.14 0.92 ± 0.14 0.90 ± 0.12 0.45 2 1.16 ± 0.19 1.17 ± 0.20 1.15 ± 0.22 0.96 1.17 ± 0.19 1.16 ± 0.20 1.16 ± 0.20 0.91 Number n n n  n n n  FN-BMD change (relative % of baseline year) −0.46 ± 0.91 −0.36 ± 0.93 −0.38 ± 0.60 0.62 −0.39 ± 0.93 −0.56 ± 0.87 −0.30 ± 0.82 0.01 Women n n n  n n n  2 0.83 ± 0.14 0.84 ± 0.13 0.85 ± 0.13 0. 22 0.83 ± 0.13 0.82 ± 0.14 0.80 ± 0.14 0.09** 2 1.03 ± 0.18 1.04 ± 0.18 1.01 ± 0.18 0.69 1.04 ± 0.18 1.04 ± 0.19 1.01 ± 0.20 0.52 Number n n n  n n n  FN-BMD change (relative % of baseline year) −0.84 ± 1.11 −0.83 ± 1.01 −0.78 ± 1.03 0.85 −0.85 ± 1.08 −0.80 ± 1.04 −0.74 ± 1.49 0.55 Values are expressed as mean ± SD. Adjustments for age and BMI. Femoral neck (FN) BMD change was measured between second follow-up and baseline * P ** P COLIA1 COLIA1 3 T P T P 3 Table 3 COLIA1 COLIA1 Types of fracture Event (%) Risk ratio (95% CI) GG GT TT GG GT TT Men Promoter -1997 G/T  Nonvertebral 147/1952 (7.5) 49/592 (8.3) 1/46 (2.2) 1.0 (reference) 3.18 (0.45–22.74) 3.44 (0.47–29.94) Fragility 72/1952 (3.7) 14/592 (2.4) 1/46 (1.8) 1.0 (reference) 1.46 (0.20–10.55) 0.94 (0.12.7.14) Vertebral 100/1056 (9.5) 35/340 (10.3) 3/28 (10.7) 1.0 (reference) 1.07 (0.71–1.61) 1.23 (0.36–4.18) Intron 1 Sp1 G/T  Nonvertebral 91/1254 (7.3) 39/574 (6.8) 4/44 (9.1) 1.0 (reference) 0.97 (0.71–1.33) 1.40 (0.65–3.00) Fragility 36/1254 (2.9) 14/574 (2.4) 2/44 (4.5) 1.0 (reference) 0.94 (0.58–1.51) 2.34 (0.94–5.85) Vertebral 68/719 (9.5) 31/350 (8.9) 2/22 (9.1) 1.0 (reference) 0.83 (0.55–1.24) 1.59 (0.60–4.22) Women Promoter -1997 G/T  Nonvertebral 528/2721 (19.4) 182/879 (20.7) 8/63 (12.7) 1.0 (reference) 1.53 (0.76–3.09) 1.66 (0.82–3.36) Fragility 216/2721 (7.9) 73/879 (8.3) 4/63 (6.3) 1.0 (reference) 1.13 (0.42–3.05) 1.19 (0.44–3.26) Vertebral 159/1320 (12.0) 52/445 (11.7) 5/35 (14.3) 1.0 (reference) 0.98 (0.70–1.37) 1.31 (0.49–3.45) Intron 1 Sp1 G/T  Nonvertebral 279/1626 (17.2) 121/710 (17.0) 17/76 (22.4) 1.0 (reference) 1.05 (0.90–1.23) 1.34 (0.92–1.23) Fragility 98/1626 (6.0) 42/710 (5.9) 10/76 (13.2) 1.0 (reference) 1.01 (0.78–1.31) 2.33 (1.39–3.87)  Vertebral 98/891 (11.0) 51/401 (12.7) 3/34 (8.8) 1.0 (reference) 1.21 (0.88–1.65) 1.37 (0.56–3.35) Adjustments for age and BMI Haplotype Analysis r 2  1 promoter Intron promoter Intron promoter Intron promoter Intron 1 P promoter Intron promoter Intron 2 promoter Intron Fig. 1 COLIA1  COLIA1 4 promoter Intron P P promoter Intron Table 4 COLIA1 Types of fracture Men, OR (95% CI) Women, OR (95% CI) Haplotype 1 Haplotype 2 Haplotype 3 Haplotype 1 Haplotype 2 Haplotype 3 Nonvertebral 1 (reference) 1.29 (0.55–3.02) 0.00 (0.00-∞) 1 (reference) 1.31 (0.83–2.07) 0.61 (0.29–1.29) Fragility 1 (reference) 2.01 (0.71–5.67) 0.00 (0.00-∞) 1 (reference) 2.12 (1.23–3.66) 0.80 (0.29–2.23) Vertebral 1 (reference) 1.64 (0.62–4.31) 1.19 (0.35–4.00) 1 (reference) 1.23 (0.51–2.95) 1.31 (0.50–3.42) promoter Intron promoter Intron promoter Intron Discussion T 19 COLIA1 GG 25 26 COLIA1 11 27 28 GT GG 11 T COLIA1 COLIA1/COLIA2 11 T n COLIA1 COLIA1 T