Association analysis of different pustular skin diseases with rare variants in AP1S3, CARD14 and IL36RN in European individualsa
| Gene, variant | GPP (n =51) | AGEP (n =1) | ACH (n =4) | PPP (n =254) | ∑ Pustular psoriasis phenotypes (n =310) | Control groupb |
| AP1S3 | ||||||
| c.11T>G (p.Phe4Cys) | 1 (1·0) | 0 (0) | 0 (0) | 10 (2·0) | 11 (1·8) | 778 (1·2) |
| c.97C>T (p.Arg33Trp) | 1 (1·0) | 1 (0·5) | 0 (0) | 3 (0·6) | 5 (0·8) | 724 (1·1) |
| ∑ mutant alleles | 3 (2·7) | 13 (2·6) | 16 (2·6) | 1,502 (2·3) | ||
| ∑ wild‐type alleles | 109 (97·3) | 495 (97·4) | 604 (97·4) | 64 226 (97·7) | ||
| P‐value | 0·74 | 0·65 | 0·59 | |||
| CARD14 | ||||||
| c.206G>A (p.Arg69Gln) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 1 (0·007) |
| c.349G>A (p.Gly117Ser) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 0 (0) |
| c.526G>C (p.Asp176His) | 0 (0) | 0 (0) | 0 (0) | 2 (0·4) | 2 (0·31) | 7 (0·05) |
| c.536G>A (p.Arg179His) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 3 (0·02) |
| ∑ mutant alleles | 3 (2·7) | 2 (0·4) | 5 (0·8) | 11 (0·08) | ||
| ∑ wild‐type alleles | 109 (97·3) | 506 (99·6) | 615 (99·2) | 13 519 (99·92) | ||
| P‐value | 1·8 × 10−04 | 0·08 | 4·6 × 10−04 | |||
| IL36RN | ||||||
| Mutant alleles | 25 (24·5) | 0 (0) | 2 (0·25) | 3 (0·6) | 30 (4·8) | 358 (0·54) |
| ∑ mutant alleles | 27 (24·1) | 3 (0·6) | 30 (4·8) | 358 (0·54) | ||
| ∑ wild‐type alleles | 85 (75·9) | 505 (99·4) | 590 (95·2) | 65 384 (99·46) | ||
| P‐value | < 2·2 × 10−16 | 0·76 | < 2·2 × 10−16 | |||
| Gene, variant | GPP (n =51) | AGEP (n =1) | ACH (n =4) | PPP (n =254) | ∑ Pustular psoriasis phenotypes (n =310) | Control groupb |
| AP1S3 | ||||||
| c.11T>G (p.Phe4Cys) | 1 (1·0) | 0 (0) | 0 (0) | 10 (2·0) | 11 (1·8) | 778 (1·2) |
| c.97C>T (p.Arg33Trp) | 1 (1·0) | 1 (0·5) | 0 (0) | 3 (0·6) | 5 (0·8) | 724 (1·1) |
| ∑ mutant alleles | 3 (2·7) | 13 (2·6) | 16 (2·6) | 1,502 (2·3) | ||
| ∑ wild‐type alleles | 109 (97·3) | 495 (97·4) | 604 (97·4) | 64 226 (97·7) | ||
| P‐value | 0·74 | 0·65 | 0·59 | |||
| CARD14 | ||||||
| c.206G>A (p.Arg69Gln) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 1 (0·007) |
| c.349G>A (p.Gly117Ser) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 0 (0) |
| c.526G>C (p.Asp176His) | 0 (0) | 0 (0) | 0 (0) | 2 (0·4) | 2 (0·31) | 7 (0·05) |
| c.536G>A (p.Arg179His) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 3 (0·02) |
| ∑ mutant alleles | 3 (2·7) | 2 (0·4) | 5 (0·8) | 11 (0·08) | ||
| ∑ wild‐type alleles | 109 (97·3) | 506 (99·6) | 615 (99·2) | 13 519 (99·92) | ||
| P‐value | 1·8 × 10−04 | 0·08 | 4·6 × 10−04 | |||
| IL36RN | ||||||
| Mutant alleles | 25 (24·5) | 0 (0) | 2 (0·25) | 3 (0·6) | 30 (4·8) | 358 (0·54) |
| ∑ mutant alleles | 27 (24·1) | 3 (0·6) | 30 (4·8) | 358 (0·54) | ||
| ∑ wild‐type alleles | 85 (75·9) | 505 (99·4) | 590 (95·2) | 65 384 (99·46) | ||
| P‐value | < 2·2 × 10−16 | 0·76 | < 2·2 × 10−16 | |||
Numbers indicate absolute allele counts (percentages). w/o, without. aMutant and wild‐type alleles of variants in 51 patients with generalized pustular psoriasis (GPP), one with acute generalized exanthematous pustulosis (AGEP) patient, four with acrodermatitis continua of Hallopeau (ACH), 254 with palmoplantar pustular psoriasis (PPP) and (database) controls as well as results of association analysis are shown. b32 864 Non‐Finnish European individuals in the publicly available database, Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/),30 with available genotypes of the two AP1S3 variants, including 12 homozygous carriers of c.11T>G (p.Phe4Cys) and three homozygous carriers of c.97C>T (p.Arg33Trp) and of the IL36RN mutations (see also Table S2; see Supporting Information). Coverage of CARD14 in ExAC was not as good as in AP1S3 and IL36RN, therefore a combination of different control groups was used, similarly as described in Mossner et al.8 and indicated in detail in Table S5 (see Supporting Information).
Association analysis of different pustular skin diseases with rare variants in AP1S3, CARD14 and IL36RN in European individualsa
| Gene, variant | GPP (n =51) | AGEP (n =1) | ACH (n =4) | PPP (n =254) | ∑ Pustular psoriasis phenotypes (n =310) | Control groupb |
| AP1S3 | ||||||
| c.11T>G (p.Phe4Cys) | 1 (1·0) | 0 (0) | 0 (0) | 10 (2·0) | 11 (1·8) | 778 (1·2) |
| c.97C>T (p.Arg33Trp) | 1 (1·0) | 1 (0·5) | 0 (0) | 3 (0·6) | 5 (0·8) | 724 (1·1) |
| ∑ mutant alleles | 3 (2·7) | 13 (2·6) | 16 (2·6) | 1,502 (2·3) | ||
| ∑ wild‐type alleles | 109 (97·3) | 495 (97·4) | 604 (97·4) | 64 226 (97·7) | ||
| P‐value | 0·74 | 0·65 | 0·59 | |||
| CARD14 | ||||||
| c.206G>A (p.Arg69Gln) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 1 (0·007) |
| c.349G>A (p.Gly117Ser) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 0 (0) |
| c.526G>C (p.Asp176His) | 0 (0) | 0 (0) | 0 (0) | 2 (0·4) | 2 (0·31) | 7 (0·05) |
| c.536G>A (p.Arg179His) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 3 (0·02) |
| ∑ mutant alleles | 3 (2·7) | 2 (0·4) | 5 (0·8) | 11 (0·08) | ||
| ∑ wild‐type alleles | 109 (97·3) | 506 (99·6) | 615 (99·2) | 13 519 (99·92) | ||
| P‐value | 1·8 × 10−04 | 0·08 | 4·6 × 10−04 | |||
| IL36RN | ||||||
| Mutant alleles | 25 (24·5) | 0 (0) | 2 (0·25) | 3 (0·6) | 30 (4·8) | 358 (0·54) |
| ∑ mutant alleles | 27 (24·1) | 3 (0·6) | 30 (4·8) | 358 (0·54) | ||
| ∑ wild‐type alleles | 85 (75·9) | 505 (99·4) | 590 (95·2) | 65 384 (99·46) | ||
| P‐value | < 2·2 × 10−16 | 0·76 | < 2·2 × 10−16 | |||
| Gene, variant | GPP (n =51) | AGEP (n =1) | ACH (n =4) | PPP (n =254) | ∑ Pustular psoriasis phenotypes (n =310) | Control groupb |
| AP1S3 | ||||||
| c.11T>G (p.Phe4Cys) | 1 (1·0) | 0 (0) | 0 (0) | 10 (2·0) | 11 (1·8) | 778 (1·2) |
| c.97C>T (p.Arg33Trp) | 1 (1·0) | 1 (0·5) | 0 (0) | 3 (0·6) | 5 (0·8) | 724 (1·1) |
| ∑ mutant alleles | 3 (2·7) | 13 (2·6) | 16 (2·6) | 1,502 (2·3) | ||
| ∑ wild‐type alleles | 109 (97·3) | 495 (97·4) | 604 (97·4) | 64 226 (97·7) | ||
| P‐value | 0·74 | 0·65 | 0·59 | |||
| CARD14 | ||||||
| c.206G>A (p.Arg69Gln) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 1 (0·007) |
| c.349G>A (p.Gly117Ser) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 0 (0) |
| c.526G>C (p.Asp176His) | 0 (0) | 0 (0) | 0 (0) | 2 (0·4) | 2 (0·31) | 7 (0·05) |
| c.536G>A (p.Arg179His) | 1 (1·0) | 0 (0) | 0 (0) | 0 (0) | 1 (0·15) | 3 (0·02) |
| ∑ mutant alleles | 3 (2·7) | 2 (0·4) | 5 (0·8) | 11 (0·08) | ||
| ∑ wild‐type alleles | 109 (97·3) | 506 (99·6) | 615 (99·2) | 13 519 (99·92) | ||
| P‐value | 1·8 × 10−04 | 0·08 | 4·6 × 10−04 | |||
| IL36RN | ||||||
| Mutant alleles | 25 (24·5) | 0 (0) | 2 (0·25) | 3 (0·6) | 30 (4·8) | 358 (0·54) |
| ∑ mutant alleles | 27 (24·1) | 3 (0·6) | 30 (4·8) | 358 (0·54) | ||
| ∑ wild‐type alleles | 85 (75·9) | 505 (99·4) | 590 (95·2) | 65 384 (99·46) | ||
| P‐value | < 2·2 × 10−16 | 0·76 | < 2·2 × 10−16 | |||
Numbers indicate absolute allele counts (percentages). w/o, without. aMutant and wild‐type alleles of variants in 51 patients with generalized pustular psoriasis (GPP), one with acute generalized exanthematous pustulosis (AGEP) patient, four with acrodermatitis continua of Hallopeau (ACH), 254 with palmoplantar pustular psoriasis (PPP) and (database) controls as well as results of association analysis are shown. b32 864 Non‐Finnish European individuals in the publicly available database, Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/),30 with available genotypes of the two AP1S3 variants, including 12 homozygous carriers of c.11T>G (p.Phe4Cys) and three homozygous carriers of c.97C>T (p.Arg33Trp) and of the IL36RN mutations (see also Table S2; see Supporting Information). Coverage of CARD14 in ExAC was not as good as in AP1S3 and IL36RN, therefore a combination of different control groups was used, similarly as described in Mossner et al.8 and indicated in detail in Table S5 (see Supporting Information).
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