CXCL8

Chr 4

C-X-C motif chemokine ligand 8

Also known as: GCP-1, GCP1, IL8, LECT, LUCT, LYNAP, MDNCF, MONAP

NCBI Gene: 3576 ENSG00000169429 UniProt: P10145 OMIM: 146930

The CXCL8 protein (interleukin-8) is a chemokine that attracts and activates neutrophils and other immune cells to sites of infection and inflammation. Mutations in CXCL8 cause autosomal recessive severe congenital neutropenia, characterized by recurrent bacterial infections due to impaired neutrophil chemotaxis and immune dysfunction. This gene shows low constraint against loss-of-function variants (pLI 0.0003, LOEUF 1.86), consistent with its recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the CXC chemokine family and is a major mediator of the inflammatory response. The encoded protein is commonly referred to as interleukin-8 (IL-8). IL-8 is secreted by mononuclear macrophages, neutrophils, eosinophils, T lymphocytes, epithelial cells, and fibroblasts. It functions as a chemotactic factor by guiding the neutrophils to the site of infection. Bacterial and viral products rapidly induce IL-8 expression. IL-8 also participates with other cytokines in the proinflammatory signaling cascade and plays a role in systemic inflammatory response syndrome (SIRS). This gene is believed to play a role in the pathogenesis of the lower respiratory tract infection bronchiolitis, a common respiratory tract disease caused by the respiratory syncytial virus (RSV). The overproduction of this proinflammatory protein is thought to cause the lung inflammation associated with csytic fibrosis. This proinflammatory protein is also suspected of playing a role in coronary artery disease and endothelial dysfunction. This protein is also secreted by tumor cells and promotes tumor migration, invasion, angiogenesis and metastasis. This chemokine is also a potent angiogenic factor. The binding of IL-8 to one of its receptors (IL-8RB/CXCR2) increases the permeability of blood vessels and increasing levels of IL-8 are positively correlated with increased severity of multiple disease outcomes (eg, sepsis). This gene and other members of the CXC chemokine gene family form a gene cluster in a region of chromosome 4q. [provided by RefSeq, May 2020]

GeneReviews OMIM ResearchGenerating clinical summary…

Active trials

1018

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.86

LOEUF

Mechanism· predicted

📖

GeneReview available — CXCL8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.86LOEUF

pLI 0.000

Z-score -0.23

OE 1.12 (0.56–1.86)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.52Z-score

OE missense 1.21 (0.98–1.50)

59 obs / 48.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.12 (0.56–1.86)

0≤0.351.4

Missense OE?1.21 (0.98–1.50)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 5 / 4.5Missense obs/exp: 59 / 48.8Syn Z: -0.46

Background carrier burden — how many people carry a rare variant somewhere in CXCL8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 610

156 rare PASS variants

Rare truncating (LoF)

1 in 400

35 rare PASS variants

Rare synonymous (reference)

1 in 950

46 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CXCL8; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 780	1 in 680
South Asian	~43k	1 in 440	1 in 380
Remaining (unassigned)	~30k	1 in 330	1 in 360
European (Finnish)	~27k	1 in 550	none seen
Admixed American	~22k	1 in 380	1 in 440
African / African American	~21k	1 in 510	1 in 2,800
East Asian	~20k	1 in 340	1 in 2,200
Ashkenazi Jewish	~13k	1 in 2,000	none seen
Middle Eastern	~2,884	1 in 260	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 2 of 4 coding exons well covered in gnomAD exomes; exon 4 poorly covered; exon 3 marginal. Genomes: all 4.? see exons ↓