HLA-DRB1*03: 01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1

N. M. F. van Gerven; Y. S. de Boer; A. Zwiers; B. J. Verwer; J. P. H. Drenth; B. van Hoek; K. J. van Erpecum; U. Beuers; H. R. van Buuren; J. W. den Ouden; R. C. Verdonk; G. H. Koek; J. T. Brouwer; M. J. Guichelaar; J. M. Vrolijk; M. J. Coenraad; G. Kraal; C. J. J. Mulder; C. M. J. van Nieuwkerk; E. Bloemena; H. W. Verspaget; V. Magadi Gopalaiah; A. Zhernakova; C. Wijmenga; L. Franke; G. Bouma; Dutch Autoimmune Hepatitis Study G

doi:10.1038/gene.2014.82

HLA-DRB103: 01 and HLA-DRB104:01 modify the presentation and outcome in autoimmune hepatitis type-1

N. M. F. van Gerven, Y. S. de Boer^*, A. Zwiers, B. J. Verwer, J. P. H. Drenth, B. van Hoek, K. J. van Erpecum, U. Beuers, H. R. van Buuren, J. W. den Ouden, R. C. Verdonk, G. H. Koek, J. T. Brouwer, M. J. Guichelaar, J. M. Vrolijk, M. J. Coenraad, G. Kraal, C. J. J. Mulder, C. M. J. van Nieuwkerk, E. BloemenaH. W. Verspaget, V. Magadi Gopalaiah, A. Zhernakova, C. Wijmenga, L. Franke, G. Bouma, Dutch Autoimmune Hepatitis Study G

^*Corresponding author voor dit werk

Onderzoeksoutput: Article › Academic › peer review

102 Citaten (Scopus)

Samenvatting

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P <0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P = 0.2; HLA-DRB1*04:01; P = 0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P = 0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P = 0.03) and a female predominance (P = 0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Originele taal-2	English
Pagina's (van-tot)	247-252
Aantal pagina's	6
Tijdschrift	Genes & Immunity
Volume	16
Nummer van het tijdschrift	4
DOI's	https://doi.org/10.1038/gene.2014.82
Status	Published - jun.-2015

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van Gerven, N. M. F., de Boer, Y. S., Zwiers, A., Verwer, B. J., Drenth, J. P. H., van Hoek, B., van Erpecum, K. J., Beuers, U., van Buuren, H. R., den Ouden, J. W., Verdonk, R. C., Koek, G. H., Brouwer, J. T., Guichelaar, M. J., Vrolijk, J. M., Coenraad, M. J., Kraal, G., Mulder, C. J. J., van Nieuwkerk, C. M. J., ... Dutch Autoimmune Hepatitis Study G (2015). HLA-DRB1*03: 01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes & Immunity, 16(4), 247-252. https://doi.org/10.1038/gene.2014.82

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title = "HLA-DRB1*03: 01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1",

abstract = "The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P <0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P = 0.2; HLA-DRB1*04:01; P = 0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P = 0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P = 0.03) and a female predominance (P = 0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.",

keywords = "LIVER-DISEASE, SUSCEPTIBILITY, HLA, ASSOCIATION, POLYMORPHISMS, HAPLOTYPES, ANTIBODIES, DIAGNOSIS",

author = "{van Gerven}, {N. M. F.} and {de Boer}, {Y. S.} and A. Zwiers and Verwer, {B. J.} and Drenth, {J. P. H.} and {van Hoek}, B. and {van Erpecum}, {K. J.} and U. Beuers and {van Buuren}, {H. R.} and {den Ouden}, {J. W.} and Verdonk, {R. C.} and Koek, {G. H.} and Brouwer, {J. T.} and Guichelaar, {M. J.} and Vrolijk, {J. M.} and Coenraad, {M. J.} and G. Kraal and Mulder, {C. J. J.} and {van Nieuwkerk}, {C. M. J.} and E. Bloemena and Verspaget, {H. W.} and {Magadi Gopalaiah}, V. and A. Zhernakova and C. Wijmenga and L. Franke and G. Bouma and {Dutch Autoimmune Hepatitis Study G}",

year = "2015",

month = jun,

doi = "10.1038/gene.2014.82",

language = "English",

volume = "16",

pages = "247--252",

journal = "Genes & Immunity",

issn = "1466-4879",

publisher = "Nature Publishing Group",

number = "4",

}

van Gerven, NMF, de Boer, YS, Zwiers, A, Verwer, BJ, Drenth, JPH, van Hoek, B, van Erpecum, KJ, Beuers, U, van Buuren, HR, den Ouden, JW, Verdonk, RC, Koek, GH, Brouwer, JT, Guichelaar, MJ, Vrolijk, JM, Coenraad, MJ, Kraal, G, Mulder, CJJ, van Nieuwkerk, CMJ, Bloemena, E, Verspaget, HW, Magadi Gopalaiah, V , Zhernakova, A , Wijmenga, C , Franke, L, Bouma, G & Dutch Autoimmune Hepatitis Study G 2015, 'HLA-DRB1*03: 01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1', Genes & Immunity, vol. 16, nr. 4, blz. 247-252. https://doi.org/10.1038/gene.2014.82

TY - JOUR

T1 - HLA-DRB1*03

T2 - 01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1

AU - van Gerven, N. M. F.

AU - de Boer, Y. S.

AU - Zwiers, A.

AU - Verwer, B. J.

AU - Drenth, J. P. H.

AU - van Hoek, B.

AU - van Erpecum, K. J.

AU - Beuers, U.

AU - van Buuren, H. R.

AU - den Ouden, J. W.

AU - Verdonk, R. C.

AU - Koek, G. H.

AU - Brouwer, J. T.

AU - Guichelaar, M. J.

AU - Vrolijk, J. M.

AU - Coenraad, M. J.

AU - Kraal, G.

AU - Mulder, C. J. J.

AU - van Nieuwkerk, C. M. J.

AU - Bloemena, E.

AU - Verspaget, H. W.

AU - Magadi Gopalaiah, V.

AU - Zhernakova, A.

AU - Wijmenga, C.

AU - Franke, L.

AU - Bouma, G.

AU - Dutch Autoimmune Hepatitis Study G

PY - 2015/6

Y1 - 2015/6

N2 - The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P <0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P = 0.2; HLA-DRB1*04:01; P = 0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P = 0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P = 0.03) and a female predominance (P = 0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

AB - The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P <0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P = 0.2; HLA-DRB1*04:01; P = 0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P = 0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P = 0.03) and a female predominance (P = 0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

KW - LIVER-DISEASE

KW - SUSCEPTIBILITY

KW - HLA

KW - ASSOCIATION

KW - POLYMORPHISMS

KW - HAPLOTYPES

KW - ANTIBODIES

KW - DIAGNOSIS

U2 - 10.1038/gene.2014.82

DO - 10.1038/gene.2014.82

M3 - Article

SN - 1466-4879

VL - 16

SP - 247

EP - 252

JO - Genes & Immunity

JF - Genes & Immunity

IS - 4

ER -