rs3091244

Case-control study of 232 HLA-B27-positive ankylosing spondylitis (AS) patients and 314 controls in a Chinese Han population. CRP gene rs3091244 polymorphism (G>A variant) was associated with increased AS risk (AA vs GG: OR 1.94, 95% CI 1.06-3.57, p=0.033). The AA genotype was also associated with better response to etanercept treatment (ASAS20: OR 3.39, p=0.016; ASAS40: OR 2.43, p=0.049) and higher baseline serum CRP levels (16.3 vs 8.8 mg/L for AA vs GG).

This Mendelian Randomization study examined whether CRP genetic variants associated with higher blood CRP concentrations are causally related to colorectal cancer risk in 727 cases and 727 controls from the EPIC cohort. Using CRP SNPs (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) as instrumental variables, the authors found that genetically 2-fold higher CRP concentrations were associated with 74% higher colorectal cancer risk (OR 1.74, 95% CI 1.06–2.85) using the unweighted CRP-score, supporting a causal role for elevated CRP in colorectal carcinogenesis.

This study examined associations between CRP gene haplotypes and dispositional optimism in 1,084 elderly Dutch subjects using a Mendelian randomization design. Six CRP polymorphisms (rs2808628, rs2808630, rs1205, rs1800947, rs1417938, rs3091244) were genotyped and CRP haplotypes were found to determine plasma CRP levels (adjusted β=0.094, p<0.001). However, CRP haplotypes were associated with dispositional optimism only in obese subjects (adjusted β=-0.068, p=0.03), suggesting obesity modulates the relationship between genetic CRP elevation and optimism.

Genome-wide association study identified five genetic loci influencing C-reactive protein (CRP) levels: rs6700896 in LEPR (-14.7% per allele, OR 1.06 for CHD), rs4537545 in IL6R (-10.8%, OR 0.94 for CHD), rs7553007 in CRP locus (-20.7%, OR 0.98 for CHD), rs1183910 in HNF1A (-13.6%), and rs4420638 in APOE-CI-CII (-21.8%, OR 1.16 for CHD). Mendelian randomization analysis of 28,112 CHD cases and 100,823 controls found no causal association between CRP genetic variants and coronary heart disease (OR 1.00, 95% CI 0.97-1.02), arguing against CRP having a causal role in atherosclerosis.

Case-control study in a Chinese population (1,046 cases, 1,035 controls) examining six CRP gene SNPs and endometrial cancer risk. While CRP SNPs alone were not significantly associated with endometrial cancer, rs1130864 and rs2794520 were found to significantly modify the association between central obesity (WHR and waist circumference) and endometrial cancer risk, with stronger effects in premenopausal women (p<0.001 for WHR).

Fine-mapping study of C-reactive protein (CRP) regulation in 594 African Americans using dense SNP genotyping and Bayesian model selection. Found rs3091244(T) allele as the key functional variant regulating CRP expression with additive effects (Bayes factor >100), explaining 5.20% of CRP variance with β=0.312 (95% CI 0.146-0.491). Secondary analysis supported a two-SNP model including rs12728740, which segregated with European-origin haplotypes. The study demonstrates that weaker linkage disequilibrium in African Americans resolved genetic ambiguity seen in European populations.

This study re-sequenced ~1,000 chromosomes of the CRP gene across diverse populations (European-American, African-American, Asian, Mexican, and Indo-Pakistani) to catalog both common and rare genetic variation. The authors identified 40 SNPs total, including three with rsIDs (rs3091244, rs1800947, rs3093058), and discovered novel nonsynonymous variants such as Pro133Lys (site 2513), Tyr67His (site 2314), and Gly166Glu (site 2612). When the novel nonsynonymous variants were genotyped in 7,296 individuals from NHANES III, they were found to be extremely rare, with minor allele frequencies below 1%, suggesting that while deep re-sequencing identifies potentially damaging coding variants, most occur at frequencies too low to study in large population surveys.