rs10512597 (CD300LF): fibrinogen and inflammation

Key takeaways

• Associated with plasma fibrinogen levels at genome-wide significance (P=7.72×10^-¹¹) in a GWAS of 17,686 women
• The 17q25.1 locus containing CD300LF was previously linked to psoriasis, pointing to shared inflammatory biology
• A meta-analysis in over 100,000 individuals confirmed 23 fibrinogen-associated loci but found no causal connection to coronary artery disease, stroke, or blood clots
• GTEx eQTL data from 953 donors show the alternative allele is associated with increased CD300LF expression in testis, tibial nerve, sigmoid colon, and whole blood

What the research says A genome-wide association study (GWAS - a method systematically testing hundreds of thousands of genetic variants to find trait-linked positions) of 17,686 apparently healthy women in the Women's Genome Health Study identified the 17q25.1 chromosomal region near CD300LF, SLC9A3R1, and NAT9 as a significant genetic determinant of plasma fibrinogen levels (P=7.72×10^-¹¹); this region had previously been associated with psoriasis, a chronic inflammatory skin condition, and lead variants at this position showed little dual association with C-reactive protein (CRP - a separate circulating inflammation marker) PMID 20926764. A multi-ethnic meta-analysis of over 100,000 individuals confirmed 23 robustly associated fibrinogen loci accounting for 3.7% of plasma fibrinogen variation, but Mendelian randomization analyses did not support a causal role for fibrinogen in coronary artery disease (CAD), stroke, or venous thromboembolism (VTE) PMID 24026080. A parallel GWAS of CRP in 204,402 Europeans identified 58 distinct inflammation loci with lead variants explaining up to 7.0% of CRP variance, confirming that fibrinogen and CRP genetics are largely distinct PMID 30388399.

Reported associations

• Plasma fibrinogen (discovery, n=17,686 women): The 17q25.1 region (CD300LF, SLC9A3R1, NAT9) reached P=7.72×10^-¹¹ for fibrinogen levels; this same position had previously been linked to psoriasis; lead variants showed little dual association with CRP PMID 20926764
• Plasma fibrinogen (multi-ethnic meta-analysis, n>100,000): One of 23 confirmed fibrinogen loci collectively explaining 3.7% of plasma fibrinogen variation; outcome analyses in up to 40,695 CAD cases, 4,752 stroke cases, and 3,208 VTE cases found no significant causal effect PMID 24026080
• C-reactive protein / chronic low-grade inflammation (n=204,402 Europeans): GWAS of circulating CRP identified 58 distinct loci with lead variants explaining up to 7.0% of CRP variance; Mendelian randomization found a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder PMID 30388399

Evidence quality The fibrinogen association at this locus rests on genome-wide significance (P=7.72×10^-¹¹) in 17,686 women PMID 20926764, contextualized by a multi-ethnic meta-analysis in over 100,000 individuals; the 23 confirmed loci explain only 3.7% of fibrinogen variation against an estimated heritability of 34-50%, indicating most genetic contribution remains unaccounted for PMID 24026080. A reference-panel comparison in 91,953 individuals showed 1000 Genomes imputation identifies roughly 20% more fibrinogen loci than the older HapMap panel, suggesting the full set of associated variants at this locus may yet be incomplete PMID 28498891. Trans-ethnic GWAS of 15 hematological traits in 746,667 individuals demonstrated that multi-ethnic analyses produce credible sets 30% smaller than European-only designs, indicating precise causal variant localization at this locus awaits more ancestrally diverse populations PMID 34385711. No conflicting findings on the direction of the fibrinogen association were identified across the reviewed studies. GTEx eQTL evidence from 953 donors corroborates a mechanistic role for this variant in CD300LF gene regulation GTEx Portal.

Tissue-specific expression effects

• CD300LF: The alternative allele is associated with increased expression in all four GTEx-examined tissues - testis (strongest signal), tibial nerve, sigmoid colon, and whole blood - with no tissue showing decreased expression GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.