C-reactive protein (CRP) is a component of non-specific immune defense and is a reliable marker of low-grade inflammation involved in obesity, type 2 diabetes and cardiovascular disease. Genome-wide association studies (GWAS) in middle-aged and elderly populations, predominantly of European descent, demonstrated associations of CRP levels with SNPs at several loci. To examine whether the variants identified are replicated in Filipino young adults, we applied Tobit regression models to study the association of plasma CRP with 12 SNPs at seven loci in a cohort of 1,691 Filipino young adults (aged 21.5 ± 0.3 years) from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). Twelve SNPs at seven loci were investigated in 1,691 CLHNS young adults. Based on the results from Tobit regression models, we observed evidence of significant association with plasma CRP for SNPs at five loci, including CRP (P for rs1205 = 3.2 × 10-11 and P for rs3091244 = 5.6 × 10-10), HNF1A (P for rs7310409 = 4.1 × 10-5 and P for rs1169288 = 1.0 × 10-4), IL6R (P for 2228145 = 6.2 × 10-4), APOE-APOC1 (P for rs769449 = 0.0068, P for rs429358 = 0.0060, and P for rs4420638 = 0.044), and LEPR (P for rs1892534 = 0.018), all showing the same direction of effect. The associations for variants at CRP, HNF1A and IL6R remained significant after Bonferroni correction for multiple testing (P < 0.0042, 0.05/12 tests). No evidence for association was observed for variants at GCKR (P = 0.46 for rs1260326) or the gene desert region of 12q23.2 (P = 0.73 for rs10778213). A third SNP in the APOE gene, rs7412, showed no association with CRP level in CLHNS young adults (P = 0.51). Consistent results for association were observed using linear regression models. We further examined whether these associations with CRP level were affected by adjustment for waist circumference. None of the associations substantially changed, suggesting that the genetic associations with plasma CRP were independent of central adiposity. An association between CRP level and APOE haplotype consisting of the SNPs rs429358 and rs7412 was previously reported in middle-aged and elderly Caucasians. Our results provided confirmatory evidence of the haplotype association in this cohort of Filipino young adults. Haplotype analysis based on score statistic revealed an overall association between haplotypes and CRP levels (global P value = 0.018). Specifically, the APOE ε4 haplotype with a frequency of 0.099 was significantly associated with lower CRP level (P = 0.0047). Complementary analysis that assessed the effect on CRP level of each additional copy of the specific haplotype compared to the homozygote reference haplotype found that the APOE ε4 haplotype was significantly associated with decreased plasma CRP (β = -0.210, P = 5.4 × 10-3) compared to the most common APOE ε3 haplotype. We next performed conditional analysis at APOE-APOC1 to examine whether the associated SNPs represent a single signal. Reciprocal conditional analysis on APOC1-rs4420638 and APOE- rs429358 (LD r2 = 0.51) showed that the effect of association with rs4420638 was substantially attenuated (P conditional = 0.76) whereas the association with rs429358 remained significant (P conditional= 0.0093). Therefore, the SNPs at the APOE-APOC1 cluster appear to represent a single signal best represented by APOE-rs429358. We next investigated whether the genetic associations with plasma CRP are modified by waist circumference or pathogen exposure, both of which are predictors of baseline CRP level. Modest evidence was detected for the interaction of waist circumference with rs1892534 at LEPR (uncorrected P interaction = 0.020). In a secondary analysis stratifying by waist circumference above or below the median value, the estimated increase in log-CRP level for each additional C allele of rs1892534 was 0.232 (P = 0.0062) in individuals with smaller waist circumference and 0.015 (P = 0.86) in those with larger waist circumference. We also observed evidence for interaction between APOE variant rs769449 and pathogen exposure on plasma CRP (uncorrected P interaction = 0.0073). When stratified analysis was conducted, we found that the significant and strong association between CRP level and the APOE variant was predominantly observed in individuals with lower exposure to a pathogenic environment (β = 0.419, P = 6.8 × 10-5) compared to those with higher exposure (β = 0.017, P = 0.88). Given that the observed interaction was not significant after Bonferroni correction (corrected P interaction > 0.0045, 0.05/ 11 tests), further studies in larger populations are warranted. We observed no evidence of multiplicative SNP-SNP interaction among variants CRP- rs1205, LEPR-rs1892534, IL6R-rs2228145, HNF1A-rs7310409 and APOE-rs429358 (all uncorrected P interaction > 0.12). In assessing the combined effects of multiple SNPs on plasma CRP, we observed a dose response. Individuals carrying a greater number of alleles associated with elevated level of CRP had increased circulating CRP level (P for trend = 1.0 × 10-17). The geometric mean of plasma CRP in the group of individuals in the highest quintile (Q5) was 0.648 mg/L (SE = 0.048), a 2.4-fold increase compared to that in the lowest quintile group (geometric mean = 0.273, SE = 0.019). Our results demonstrated that variants in several loci are significantly associated with plasma CRP in Filipino young adults, suggesting shared genetic influences on circulating CRP across populations and age groups.