rs1205 — CRP +1846C>T

C-Reactive Protein Levels — A Genetic Thermostat for Inflammation

C-reactive protein (CRP) is one of the body's oldest inflammatory markers, a pentameric protein synthesized by the liver in response to interleukin-6 signaling. During acute infection or injury, CRP levels can surge 1,000-fold within 24 hours¹¹ CRP levels can surge 1,000-fold within 24 hours
CRP is a sensitive acute-phase reactant, making it a valuable clinical marker. But baseline CRP levels — the levels you carry when you're healthy — are substantially influenced by genetics, with 30-40% of variation explained by genetic factors²² 30-40% of variation explained by genetic factors
Heritability studies estimate genetic contribution at 30-40%. The rs1205 polymorphism in the 3' untranslated region (3' UTR) of the CRP gene is among the strongest genetic determinants of these baseline levels.

The Mechanism

The rs1205 variant sits at position +1846 in the 3' UTR of the CRP gene on chromosome 1q23.2 . This region doesn't change the amino acid sequence of the CRP protein, but it regulates how much protein gets made. The 3' UTR contains binding sites for microRNAs and RNA-binding proteins that control mRNA stability and translation efficiency.

The rs1205 polymorphism likely acts as a molecular switch, differentially influenced by distinct molecular environments .

The direction of effect is context-dependent and somewhat paradoxical.

In healthy populations, the G allele (encoded as C/G in dbSNP) associates with elevated CRP levels (P < 1.2 × 10⁻⁶) . However, in Chinese Han populations, the minor T allele associated with 24-38% decreases in plasma CRP levels . This ethnic variation reflects different baseline haplotype structures and linkage patterns with other functional variants in the CRP gene.

The Evidence

The rs1205-CRP relationship is one of the most consistently replicated associations in inflammation genetics.

A Stanford Asian Pacific Program study of 945 siblings found the G allele strongly associated with both elevated CRP (P < 1.2 × 10⁻⁶) and higher 2-hour post-glucose-challenge glucose levels (β = 0.46, P = 0.00090) , suggesting this variant influences glucose metabolism through inflammatory pathways.

In 327 postmenopausal Brazilian women, the CC genotype showed 1.53 times higher prevalence of low-grade chronic inflammation (hs-CRP ≥3 mg/L) compared to T allele carriers . This chronic low-grade inflammation is a key mechanism linking obesity, metabolic syndrome, and cardiovascular disease.

In early rheumatoid arthritis patients, the TT genotype was associated with a 50% reduction in baseline CRP levels (from 16.7 to 8.4 mg/L, P = 0.005) , though this effect disappeared after one year of treatment, suggesting the variant primarily affects constitutional rather than disease-driven CRP production.

The clinical implications extend to severe disease outcomes.

In COVID-19 patients, the TT genotype was associated with dramatically higher mortality rates (OR 9.74, 95% CI 7.87-12.06, P < 0.0001) , a finding that appears paradoxical given TT carriers typically have lower baseline CRP. This suggests the variant may impair CRP's normal acute-phase response capacity during severe infection.

The CRP-lowering T allele is overrepresented in systemic lupus erythematosus, where it interacts with type I interferon signaling to produce inappropriately low CRP responses despite active inflammation .

Practical Implications

Your rs1205 genotype influences your baseline inflammatory set point — the CRP level your body maintains in the absence of acute illness. This matters because elevated hs-CRP independently predicts all-cause mortality (RR 1.75), cardiovascular mortality (RR 2.03), and cancer mortality (RR 1.25) .

For CC homozygotes — particularly those with elevated waist circumference, obesity, or metabolic syndrome — the combination of genetic predisposition and environmental factors can create persistent low-grade inflammation. This inflammatory state accelerates atherosclerosis, insulin resistance, and risk of type 2 diabetes.

The good news: CRP levels are modifiable. Weight loss reduces CRP by approximately 0.13 mg/L per kilogram lost. Regular aerobic exercise lowers CRP by 0.34-0.59 mg/L. Mediterranean dietary patterns can reduce CRP by ~1.0 mg/L. Smoking cessation in people with established cardiovascular disease reduces CRP by 0.40 mg/L, with greater benefits the longer one remains smoke-free.

Interactions

The rs1205 variant commonly exists in haplotypes with other CRP SNPs, particularly rs1130864, rs3093059, and rs2794521.

The CGCA haplotype (rs1205-C, rs1130864-G, rs2794521-C, rs3093059-A) is associated with decreased type 2 diabetes risk (OR 0.83) .

In Asian/Pacific Islanders, rs1205 shows stronger effects on CRP than in Europeans (geometric mean change 1.65 vs 1.25 mg/L) , suggesting gene-environment or gene-ancestry interactions.