Common Variants in CRP and LEPR Influence High Sensitivity C-Reactive Protein Levels in North Indians

Background: High sensitivity C-reactive protein (hsCRP) levels are shown to be influenced by genetic variants in Europeans; however, little is explored in Indian population. Methods: Herein, we comprehensively evaluated association of all previously reported genetic determinants of hsCRP levels, including 18 cis (proximal to CRP gene) and 73 trans-acting (distal to CRP gene) variants in 4,200 North Indians of Indo-European ethnicity. First, we evaluated association of 91 variants from 12 candidate loci with hsCRP levels in 2,115 North Indians (1,042 non-diabetic subjects and 1,073 patients with type 2 diabetes). Then, cis and trans-acting variants contributing maximally to hsCRP level variation were further replicated in an independent 2,085 North Indians (1,047 patients with type 2 diabetes and 1,038 non-diabetic subjects). Results: We found association of 12 variants from CRP, LEPR, IL1A, IL6, and IL6R with hsCRP levels in non-diabetic subjects. However, only rs3093059-CRP [beta = 0.33, P = 9.6x10(-5)] and the haplotype harboring rs3093059 risk allele [beta = 0.32 mu g/mL, P = 1.4x10(-4)/P-perm = 9.0x10(-4)] retained significance after correcting for multiple testing. The cis-acting variant rs3093059-CRP had maximum contribution to the variance in hsCRP levels (1.14%). Among, trans-acting variants, rs1892534-LEPR was observed to contribute maximally to hsCRP level variance (0.59%). Associations of rs3093059-CRP and rs1892534-LEPR were confirmed by replication and attained higher significance after meta-analysis [beta(meta) = 0.26/0.22; P-meta = 4.3x10(-7)/7.4x10(-3) and beta(meta) = -0.15/-0.12; P-meta = 2.0x10(-6)/1.6x10(-6) for rs3093059 and rs1892534, respectively in non-diabetic subjects and all subjects taken together]. Conclusion: In conclusion, we identified rs3093059 in CRP and rs1892534 in LEPR as major cis and trans-acting contributor respectively, to the variance in hsCRP levels in North Indian population.