lists the characteristics of 592 patients and 670 controls with available serum and 378 patients and 447 controls with available DNA. By virtue of matching, patients and controls had similar distributions of age at enrollment, sex, and smoking behavior. For subjects with available serum, no significant differences were observed between patients and controls for race, BMI, regular use of aspirin/ibuprofen, or history of heart disease. Compared with controls, patients more often had lower educational attainment (P = .017), a personal history of bronchitis/emphysema (P < .001), and a family history of lung cancer (P = .004). Similar differences, albeit at a lower significance level, were observed among subjects with available DNA, and patients were significantly more likely to have a family history of lung cancer. All CRP SNPs conformed to the Hardy-Weinberg equilibrium among controls.
Characteristics of Lung Cancer Patients and Controls From the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Individuals with CRP values in the highest quartile had a two-fold increased risk of lung cancer when compared with individuals having CRP levels in the lowest quartile (OR, 1.98; 95% CI, 1.35 to 2.89; ), and a significant trend for increasing risk with increasing CRP levels was observed (P-trend < .001). In contrast, none of the five CRP SNPs was associated with lung cancer risk (). Of the five CRP SNPs, four SNPs formed haplotype blocks, and these haplotypes were also unrelated to lung cancer (Appendix Table A1, online only).
Association of Lung Cancer Risk With Circulating CRP Levels and CRP Genotypes
In analyses stratified by histology (A), elevated CRP levels (Q3 and Q4) were associated with increased risk of SCC lung cancers (eg, Q4 v Q1: OR, 2.92; 95% CI, 1.30 to 6.54; P-trend = .008), but not lung ACs (Q4 v Q1: OR, 1.34; 95% CI, 0.83 to 2.17; P-trend = .172). Elevated CRP levels were also associated with increased risk of small-cell carcinomas (Q4 v Q1: OR, 3.03; 95% CI, 1.04 to 8.83; P- trend = .040). However, this difference across subtypes was not statistically significant (P value for difference in slopes = .361). The mean time between serum sampling and subject selection was 3.36 years (standard deviation, 2.59). The relationship of CRP with lung cancer did not vary significantly by follow-up time (B; P- interaction = .581), although the association appeared strongest in the period 2 to 5 years before lung cancer diagnosis (Q4 v Q1: OR, 2.33; 95% CI, 1.24 to 4.39).
Fig 1. Association of circulating C-reactive protein (CRP) levels with lung cancer risk across (A) lung cancer histologies (squamous cell carcinomas [SCCs; n = 126 lung cancers], adenocarcinomas [ACs; n = 269], small-cell carcinomas [n = 75], large-cell carcinomas (more ...)
Elevated CRP levels were associated with increased lung cancer risk among former smokers (C; Q4 v Q1: OR, 2.48; 95% CI, 1.53 to 4.03; P-trend = .001) and current smokers (Q4 v Q1: OR, 1.90; 95% CI, 1.06 to 3.41; P-trend = .019), but not among never smokers. However, the difference across smoking strata was not statistically significant (P-interaction = .589). For former smokers, elevated CRP levels were associated with increased lung cancer risk among individuals who quit smoking for < 15 years (Q4 v Q1: OR, 2.70; 95% CI, 1.47 to 4.95) as well as among those who quit for > 15 years (OR, 2.17; 95% CI, 0.94 to 5.01).
Among controls (), CRP levels varied significantly by age and were higher among current smokers, Hispanics, individuals with a high BMI, and among individuals with a family history of lung cancer. CRP levels increased with cumulative amount of smoking and smoking intensity but were unrelated to time since quitting among former smokers.
Predictors of Circulating CRP Levels Among Controls
CRP levels were significantly associated with CRP SNPs rs1800947 (decreased levels for CC or CG v GG genotype; P-trend = .016), rs1205 (decreased levels for TT or CT v CC genotype; P-trend = .008), and rs3093077 (increased levels for GG or GT v TT genotype; P-trend = .003; ). Likewise, CRP levels differed across haplotypes formed by four SNPs: rs1417938, rs1800947, rs1205, and rs2808630 (Appendix Table A1). Compared with the most common haplotype (TGCT), haplotypes AGTT and ACTT were associated with lower CRP levels, whereas haplotype AGCT was associated with higher CRP levels. The individual CRP SNPs rs1417938, rs1800947, rs1205, rs2808630, and rs3093077 accounted for 0.5%, 1.4%, 2.5%, 0.4%, and 2.6%, respectively, of the total variability in circulating CRP levels (Appendix Table A2, online only).
Standardized absolute risks of lung cancer over 10 years of follow-up across CRP quartiles among former and current smokers are shown in . For former smokers, the 10-year absolute risk was 2.55% (95% CI, 1.98% to 3.27%) among individuals with CRP levels ≥ 5.6 mg/L versus 1.39% (95% CI, 1.07% to 1.81%) among those with CRP levels of < 1.0 mg/L (risk difference, 1.15%; 95% CI, 0.41% to 1.89%). For current smokers, the 10-year absolute risk was much higher among individuals with CRP levels ≥ 5.6 mg/L compared with those with CRP levels of < 1.0 mg/L (absolute risk, 7.37%; 95% CI, 5.81% to 9.33% v 4.03%; 95% CI, 3.01% to 5.40%; risk difference, 3.33%; 95% CI, 1.24% to 5.42%).
Standardized 10-Year Absolute Risks of Lung Cancer Across CRP Quartiles Among Former and Current Smokers