Several gene variants were found to be independent modifiers of disease severity in patients with hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE). These variants, according to a study published in Frontiers in Allergy, could serve as potential prognostic biomarkers.

“Our study provides clear evidence that variants other than the SERPING1 causal variants act as independent modifiers of C1-INH-HAE severity and could serve as possible prognostic biomarkers,” the study authors said.

The study confirmed previously reported correlations between C1-INH-HAE disease severity and 5 common functional variants: F12-rs1801020, KLKB1-rs3733402, CPN1-rs61751507, SERPING1-rs4926, and SERPING1-rs28362944.

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Correlations were also found between several variants and at least 1 of 3 distinct phenotypic traits of patients including age at disease onset, the need for long-term prophylaxis (LTP), and the severity score of the disease measured using the Cutaneous Abdominal Laryngeal Score (CALS). These variants included F13B-rs6003, PLAU-rs2227564, SERPINA1-rs28929474, SERPINA1-rs17580, KLK1-rs5515, SERPINE1-rs6092, and F2-rs1799963.

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In regard to correlations with the need for LTP, patients with SERPING1-rs28362944 variants carrying the C allele (c.-21 T>C) were found to have a 4.2-fold increase when carrying a missense SERPING1 mutation and a 2.5-fold increase independent of the SERPING1 variation.

Variations of SERPINA1-rs17580 and KLKB1-rs3733402 were found to correlate with earlier onsets of the disease by 8 and 7 years, respectively. In contrast, SERPING1-rs4926 (c.1438 G>A, p.Val480Met) was found to be benign, with heterozygous patients having a significant 3.6-year delay in onset (P =.018) and homozygous patients showing a trend toward a 6.3-year delay (P =.058). KLK1-rs5515 (c.230 G>A), SERPINE1-rs6092 (c.43 G>A), and F12-rs1801020 (c.-4 T>C) were also statistically associated with a longer time until disease onset.

In terms of CALS, F12-rs1801020 (c.-4 T>C), SERPINA1-rs28929474 (c.1096 G>A), and KLKB1-rs3733402 (c.428 G>A) were significantly correlated with increased scores. F13B-rs6003 (c.344 G>A), PLAU-rs2227564 (c.422 T>C), and KLK1-rs5515 (c.230 G>A) were associated with lowers scores on the CALS.

The study included 233 patients with HAE from 144 unrelated families across 5 European countries including Bulgaria, Germany, Greece, Hungary, and Poland. The average patient age was 40 years (range, 2.5-85), and there were 104 men and 129 women.


Parsopoulou F, Loules G, Zamanakou M, et al. Searching for genetic biomarkers for hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). Front Allergy. 2022;3:868185. doi:10.3389/falgy.2022.868185