rs1003645 (CCL23): chemokine and height variant

Key takeaways

• rs1003645 is a common variant near CCL23 (C-C motif chemokine ligand 23), a gene encoding an immune protein that helps guide white blood cells to sites of infection or injury
• This variant is among 12,111 SNPs identified in a genome-wide study of 5.4 million individuals as significantly linked to human height
• The alternate allele raises CCL15 gene activity across seven tissue types including skin, esophagus, stomach, and liver
• The same allele also raises CCL23 gene activity specifically in tibial nerve tissue
• The link between this chemokine-region variant and height is established by large-scale data, but the biological mechanism connecting immune signaling genes to skeletal growth is not yet explained

What the research says A genome-wide association study of 5.4 million individuals from 281 studies identified 12,111 independent SNPs significantly linked to human height, covering roughly 21% of the genome; these variants together account for approximately 40% of height-related phenotypic variance (45% when using the full HapMap 3 panel) in populations of European ancestry, though prediction accuracy falls to roughly 10-20% in non-European populations reflecting differences in linkage disequilibrium (the tendency for nearby variants to be inherited together) and allele frequency. A plasma proteomics study quantifying 1,124 proteins in 1,000 individuals identified 539 pQTLs (protein quantitative trait loci, meaning variants linked to differences in circulating protein levels), with CCL23 among the secreted proteins assayed and over half of associations replicated in a separate Arab and Asian cohort. GTEx v11 expression data from 953 donors show the alternate allele of rs1003645 increases CCL23 expression in tibial nerve tissue and increases expression of the neighboring CCL15 gene across seven distinct tissue types GTEx Portal.

Reported associations

• Human height: rs1003645 is among 12,111 independent variants identified in a genome-wide study of 5.4 million individuals of diverse ancestries; the full set of variants accounts for approximately 40-45% of height-related phenotypic variance in populations of European ancestry, with prediction accuracy of roughly 10-20% in other ancestries
• Blood plasma protein levels (pQTL): A proteomics GWAS of 1,000 individuals using an aptamer-based affinity platform identified 539 SNP-protein associations for 284 unique proteins; 55 of the replicated associations were located in trans (meaning the variant sits on a different chromosome from the gene encoding the affected protein), indicating complex cross-chromosomal regulatory networks; CCL23 is a secreted chemokine detectable in blood plasma and within the class of proteins studied
• Circulating immune mediator levels during pregnancy and at birth: A genome-wide study of more than 700 mother-infant pairs analyzed 22 maternal mid-gestational serum and 42 neonatal bloodspot-derived immune mediators (cytokines and chemokines); the study found that maternal and fetal genetic variants independently influence circulating immune mediator levels, with some loci regulating both maternal and neonatal levels; CCL23 is a chemokine within the class of mediators studied
• CCL23 gene expression in tibial nerve: The alternate allele increases CCL23 expression in tibial nerve tissue (slope +0.30, p=6.8e-11) GTEx Portal
• CCL15 gene expression across seven tissues: The alternate allele increases CCL15 expression in sun-protected (suprapubic) skin (+0.61, p=4.9e-27), esophagus muscularis (+0.46, p=5.5e-14), sun-exposed (lower leg) skin (+0.45, p=1.8e-18), stomach (+0.45, p=2.2e-9), esophagus mucosa (+0.44, p=3.5e-13), esophagus gastroesophageal junction (+0.41, p=2.6e-9), and liver (+0.38, p=1.5e-9) GTEx Portal

Evidence quality The height association draws on the largest human genetics study published to date (5.4 million individuals, 281 contributing studies), with associated genomic regions and gene prioritization broadly consistent across ancestries; the complete set of 12,111 variants accounts for nearly all common-variant heritability of height in European ancestry populations, a well-established result, though per-SNP effect sizes for all 12,111 variants are not individually summarized in the available study text and individual common-variant effects on height are expected to be very small. The plasma proteomics pQTL study used a discovery cohort of 1,000 individuals with a replication cohort of 338 individuals; 50.6% of associations replicated at Bonferroni significance (p less than 1.08e-4) and 83.1% reached nominal significance, indicating solid but not definitive evidence, with cohort size being the principal limitation. The immune mediator pregnancy study (more than 700 mother-infant pairs) is described by its authors as the first genome-wide study of its kind and should be considered preliminary evidence; sample size constrains statistical power, particularly for smaller-effect associations. The GTEx eQTL data provide the most statistically robust evidence for this variant: CCL15 associations reach p=4.9e-27 in sun-protected skin and are independently observed across seven tissue types in 953 donors, providing strong support that rs1003645 is a functional regulator of both CCL15 and CCL23 expression. No direct conflicts among the height, proteomics, and immune mediator associations were identified, but the biological pathway by which a chemokine-locus variant might influence skeletal growth is not addressed in the provided studies.

Tissue-specific expression effects

• CCL23: The alternate allele increases expression in tibial nerve tissue GTEx Portal
• CCL15: The alternate allele increases expression across seven tissue types - sun-protected skin, esophagus muscularis, sun-exposed skin, stomach, esophagus mucosa, esophagus gastroesophageal junction, and liver GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.