Polymorphisms of the CRP gene inhibit inflammatory response and increase susceptibility to depression: the Health in Men Study.

BACKGROUND Depression has been associated with chronic changes in the serum concentration of C-reactive protein (CRP) in observational studies, but it is unclear if this association is causal or is due to confounding and bias. Genetic studies are less subject to this type of error and offer an opportunity to investigate if CRP is causally linked to depression, particularly because known polymorphisms of the CRP gene have been associated with high- and low-basal serum concentrations of CRP [single nucleotide polymorphisms (SNPs) rs1130864 and rs1205, respectively]. The aim of this study is to determine if polymorphisms of SNPs rs1130864 and rs1205 are associated with prevalent depression. METHODS We completed a cross-sectional study of a community sample of 3700 men aged > or = 70 years, and used the 15-item Geriatric Depression Scale (GDS-15) to assess depressive symptoms. A GDS-15 score 7 or more indicates the presence of clinically significant depressive symptoms. Physical morbidity was assessed with the physical component summary score (PCS) of the SF-36 Health Survey. We collected fasting blood samples to measure high sensitivity CRP and to extract DNA for the genotyping of SNPs rs1130864 and rs1205 of the CRP gene. RESULTS One hundred and eighty-two men were depressed (4.9%). The odds of depression increased by 2% (95% CI = 1-4%) for every unit (mg/l) increase of CRP and nearly doubled for men with CRP > or = 3 mg/l vs <1 mg/l [odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.27-2.98]. However, the association between high CRP (> or = 3 mg/l) and depression was no longer significant after the analyses were adjusted for smoking, age, body mass index (BMI) and PCS. Men with the CT and TT genotypes of rs1130864 had 1.36 (95% CI = 1.13-1.63) and 2.31 (95% CI = 1.65-3.24) greater odds of CRP > or = 3 mg/l than CC carriers, but there was no association between this polymorphism and the presence of prevalent depression. The G > A polymorphism of SNP rs1205 was associated with 24% (95% CI = 16-32%) lower concentration of CRP compared with other genotypes. Men with the rs1205 AA genotype had 1.66 (95% CI = 1.07-2.57) and 1.67 (95% CI = 1.08-2.58) greater odds of having clinically significant depression than participants with the GA and GG genotypes, respectively. CONCLUSION Our study shows that clinically significant depressive symptoms in later life are unlikely to be caused by an increase in the serum concentration of CRP. Instead, we found that the risk of depression was greater amongst people who carry the rs1205 G > A genetic polymorphism of the CRP gene, which was associated with approximately 20% lower serum concentration of CRP compared with other genotypes. This suggests that CRP may be a compensatory response to external insults that predispose to depression, and that an increase in the concentration of CRP might be adaptive.