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 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 Kumar; A Zhernakova; C Wijmenga; L Franke; G Bouma

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 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 Kumar, A Zhernakova, C Wijmenga, L Franke, G Bouma,

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	247-52
Number of pages	6
Journal	Genes and Immunity
Volume	16
Issue number	4
DOIs	https://doi.org/10.1038/gene.2014.82
Publication status	Published - Jun 2015

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10.1038/gene.2014.82

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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. M. J., Vrolijk, J. M., Coenraad, M. J., Kraal, G., Mulder, C. J. J., van Nieuwkerk, C. M. J. (2015). HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes and Immunity, 16(4), 247-52. https://doi.org/10.1038/gene.2014.82

@article{b08257a4e05243ff9edd64d957cf3830,

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.",

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 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 V Kumar and A Zhernakova and C Wijmenga and L Franke and G Bouma",

year = "2015",

month = jun,

doi = "10.1038/gene.2014.82",

language = "English",

volume = "16",

pages = "247--52",

journal = "Genes and Immunity",

issn = "1466-4879",

publisher = "Springer Nature",

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, MMJ, Vrolijk, JM, Coenraad, MJ, Kraal, G, Mulder, CJJ, van Nieuwkerk, CMJ, Bloemena, E, Verspaget, HW, Kumar, V, Zhernakova, A, Wijmenga, C, Franke, L, Bouma, G 2015, 'HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1', Genes and Immunity, vol. 16, no. 4, pp. 247-52. https://doi.org/10.1038/gene.2014.82

TY - JOUR

T1 - HLA-DRB1*03:01 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 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 - Kumar, V

AU - Zhernakova, A

AU - Wijmenga, C

AU - Franke, L

AU - Bouma, 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.

U2 - 10.1038/gene.2014.82

DO - 10.1038/gene.2014.82

M3 - Article

C2 - 25611558

SN - 1466-4879

VL - 16

SP - 247

EP - 252

JO - Genes and Immunity

JF - Genes and Immunity

IS - 4

ER -

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

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