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Towards a better understanding of genetic associations in the major histocompatibility complex

Projectomschrijving

Dat erfelijke factoren een belangrijke rol kunnen spelen bij ziekten is al lange tijd duidelijk. Door middel van moderne technieken om het DNA van patiënten op grote schaal uit te lezen en te analyseren is het nu mogelijk om specifieke genetische varianten aan te wijzen die een sleutelrol spelen bij verschillende ziekten. Dit kan dan beter inzicht verschaffen in het onderliggende biologische mechanisme, wat relevant is bijvoorbeeld voor het ontwikkelen van nieuwe geneesmiddelen. In dit Vidi project hebben wij computationele methoden ontwikkeld om een belangrijk regio van het humane genoom, namelijk het HLA, te bestuderen. We hebben deze methoden toegepast op een groot aantal immuun-gerelateerde aandoeningen zoals reumatoïde arthritis en type 1 diabetes. Ons onderzoek bevestigt de rol van specifieke aminozuren in de HLA-eiwitten en de aard van de moleculaire interactie tussen HLA en T-celreceptoren. In een vervolgtraject van dit Vidi project hebben wij de nieuwste sequencing-technieken (waaronder de Oxford Nanopore) gebruikt om nog meer dergelijke complexe regio’s in ons DNA uit te lezen.

Big Data

Wij hebben een methode ontwikkeld om aan de hand van Big Data van genetische studies verzameld in grote aantallen patiënten beter te begrijpen hoe dit precies in elkaar zit. Deze methode maakt slim gebruik van de samenhang tussen dichtbijgelegen varianten in ons DNA, waardoor we precies kunnen zien waar een causaal verband bestaat tussen onze erfelijke genen en het risico op bijvoorbeeld diabetes.

Producten

Titel: Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis.
Auteur: Invernizzi P, Ransom M, Raychaudhuri S, Kosoy R, Lleo A, Shigeta R, Franke A, Bossa F, Amos CI, Gregersen PK, Siminovitch KA, Cusi D, de Bakker PIW, Podda M, Gershwin ME, Seldin MF; Italian PBC Genetics Study Group.
Magazine: Genes and Immunity
Titel: Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity.
Auteur: Ombrello MJ, Kirino Y, de Bakker PI, Gül A, Kastner DL, Remmers EF.
Magazine: Proceedings of the National Academy of Sciences USA
Titel: Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role?
Auteur: Smit LA, Strachan DP, Vermeulen R, de Bakker PI, Demenais F, Dumas O, Carsin AE, Cullinan P, Curjuric I, Ghosh RE, Heederik D, Imboden M, Jarvis D, Lathrop M, Le Moual N, Mehta A, Miedinger D, Sigsgaard T, Siroux V, Vernez D, Zock JP, Kauffmann F, Probst-Hensch N, Kogevinas M, Bouzigon E.
Magazine: European Respiratory Journal
Titel: Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08
Auteur: Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, Simpfendorfer KR, Pirskanen-Matell R, Piehl F, Pan-Hammarstrom Q, Verschuuren JJ, Titulaer MJ, Niks EH, Marx A, Ströbel P, Tackenberg B, Pütz M, Maniaol A, Elsais A, Tallaksen C, Harbo HF, Lie BA, Raychaudhuri S, de Bakker PIW, Melms A, Garchon HJ, Willcox N, Hammarstrom L, Seldin MF
Magazine: Annals of Neurology
Titel: Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk
Auteur: Foo JN, Smedby KE, Akers NK, Berglund M, Irwan ID, Jia X, Li Y, Conde L, Darabi H, Bracci PM, Melbye M, Adami HO, Glimelius B, Khor CC, Hjalgrim H, Padyukov L, Humphreys K, Enblad G, Skibola CF, de Bakker PIW, Liu J
Magazine: American Journal of Human Genetics
Titel: Association of Granulomatosis With Polyangiitis (Wegener's) With HLA-DPB1*04 and SEMA6A Gene Variants: Evidence From Genome-Wide Analysis
Auteur: Xie G, Roshandel D, Sherva R, Monach PA, Lu EY, Kung T, Carrington K, Zhang SS, Pulit SL, Ripke S, Carette S, Dellaripa PF, Edberg JC, Hoffman GS, Khalidi N, Langford CA, Mahr AD, St Clair EW, Seo P, Specks U, Spiera RF, Stone JH, Ytterberg SR, Raychaudhuri S, de Bakker PIW, Farrer LA, Amos CI, Merkel PA, Siminovitch KA
Magazine: Arthritis and Rheumatism
Titel: Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.
Auteur: Skibola CF, Berndt SI, Vijai J, Conde L, Wang Z, Yeager M, de Bakker PI, Birmann BM, Vajdic CM, Foo JN, Bracci PM, Vermeulen RC, Slager SL, de Sanjose S, Wang SS, Linet MS, Salles G, Lan Q, Severi G, Hjalgrim H, Lightfoot T, Melbye M, Gu J, Ghesquières H, Link BK, Morton LM, Holly EA, Smith A, Tinker LF, Teras LR, Kricker A, Becker N, Purdue MP, Spinelli JJ, Zhang Y, Giles GG, Vineis P, Monnereau A, Bertrand KA, Albanes D, Zeleniuch-Jacquotte A, Gabbas A, Chung CC, Burdett L, Hutchinson A, Lawr
Magazine: American Journal of Human Genetics
Titel: Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls.
Auteur: McLaren PJ, Coulonges C, Ripke S, van den Berg L, Buchbinder S, Carrington M, Cossarizza A, Dalmau J, Deeks SG, Delaneau O, De Luca A, Goedert JJ, Haas D, Herbeck JT, Kathiresan S, Kirk GD, Lambotte O, Luo M, Mallal S, van Manen D, Martinez-Picado J, Meyer L, Miro JM, Mullins JI, Obel N, O'Brien SJ, Pereyra F, Plummer FA, Poli G, Qi Y, Rucart P, Sandhu MS, Shea PR, Schuitemaker H, Theodorou I, Vannberg F, Veldink J, Walker BD, Weintrob A, Winkler CA, Wolinsky S, Telenti A, Goldstein DB, de Bakke
Magazine: PLoS Pathogens
Titel: A genome-wide association study of marginal zone lymphoma shows association to the HLA region.
Auteur: Vijai J, Wang Z, Berndt SI, Skibola CF, Slager SL, de Sanjose S, Melbye M, Glimelius B, Bracci PM, Conde L, Birmann BM, Wang SS, Brooks-Wilson AR, Lan Q, de Bakker PI, Vermeulen RC, Portlock C, Ansell SM, Link BK, Riby J, North KE, Gu J, Hjalgrim H, Cozen W, Becker N, Teras LR, Spinelli JJ, Turner J, Zhang Y, Purdue MP, Giles GG, Kelly RS, Zeleniuch-Jacquotte A, Ennas MG, Monnereau A, Bertrand KA, Albanes D, Lightfoot T, Yeager M, Chung CC, Burdett L, Hutchinson A, Lawrence C, Montalvan R, Liang
Magazine: Nature Communications
Titel: GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers.
Auteur: Li S, Qian J, Yang Y, Zhao W, Dai J, Bei JX, Foo JN, McLaren PJ, Li Z, Yang J, Shen F, Liu L, Yang J, Li S, Pan S, Wang Y, Li W, Zhai X, Zhou B, Shi L, Chen X, Chu M, Yan Y, Wang J, Cheng S, Shen J, Jia W, Liu J, Yang J, Wen Z, Li A, Zhang Y, Zhang G, Luo X, Qin H, Chen M, Wang H, Jin L, Lin D, Shen H, He L, de Bakker PIW, Wang H, Zeng YX, Wu M, Hu Z, Shi Y, Liu J, Zhou W
Magazine: PLoS Genetics
Titel: Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
Auteur: Okada Y, Han B, Tsoi LC, Stuart PE, Ellinghaus E, Tejasvi T, Chandran V, Pellett F, Pollock R, Bowcock AM, Krueger GG, Weichenthal M, Voorhees JJ, Rahman P, Gregersen PK, Franke A, Nair RP, Abecasis GR, Gladman DD, Elder JT, de Bakker PI, Raychaudhuri S.
Magazine: American Journal of Human Genetics
Titel: Variation at HLA-DRB1 is associated with resistance to enteric fever.
Auteur: Dunstan SJ, Hue NT, Han B, Li Z, Tram TT, Sim KS, Parry CM, Chinh NT, Vinh H, Lan NP, Thieu NT, Vinh PV, Koirala S, Dongol S, Arjyal A, Karkey A, Shilpakar O, Dolecek C, Foo JN, Phuong le T, Lanh MN, Do T, Aung T, Hon do N, Teo YY, Hibberd ML, Anders KL, Okada Y, Raychaudhuri S, Simmons CP, Baker S, de Bakker PI, Basnyat B, Hien TT, Farrar JJ, Khor CC.
Magazine: Nature Genetics
Titel: Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.
Auteur: Yin X, Low HQ, Wang L, Li Y, Ellinghaus E, Han J, Estivill X, Sun L, Zuo X, Shen C, Zhu C, Zhang A, Sanchez F, Padyukov L, Catanese JJ, Krueger GG, Duffin KC, Mucha S, Weichenthal M, Weidinger S, Lieb W, Foo JN, Li Y, Sim K, Liany H, Irwan I, Teo Y, Theng CT, Gupta R, Bowcock A, De Jager PL, Qureshi AA, de Bakker PI, Seielstad M, Liao W, Ståhle M, Franke A, Zhang X, Liu J.
Magazine: Nature Communications
Titel: Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations.
Auteur: Okada Y, Kim K, Han B, Pillai NE, Ong RT, Saw WY, Luo M, Jiang L, Yin J, Bang SY, Lee HS, Brown MA, Bae SC, Xu H, Teo YY, de Bakker PI, Raychaudhuri S.
Magazine: Human Molecular Genetics
Titel: High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
Auteur: Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, Amos CI, Padyukov L, Toes RE, Huizinga TW, Wijmenga C, Trynka G, Franke L, Westra HJ, Alfredsson L, Hu X, Sandor C, de Bakker PI, Davila S, Khor CC, Heng KK, Andrews R, Edkins S, Hunt SE, Langford C, Symmons D; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate; Wellcome Trust Case Control Consortium, Concannon P, Onengut-Gumuscu S, Rich SS, Deloukas P, Gonzalez-Gay MA, Rodrig
Magazine: Nature Genetics
Titel: HLA-B*13:01 and the dapsone hypersensitivity syndrome.
Auteur: Zhang FR, Liu H, Irwanto A, Fu XA, Li Y, Yu GQ, Yu YX, Chen MF, Low HQ, Li JH, Bao FF, Foo JN, Bei JX, Jia XM, Liu J, Liany H, Wang N, Niu GY, Wang ZZ, Shi BQ, Tian HQ, Liu HX, Ma SS, Zhou Y, You JB, Yang Q, Wang C, Chu TS, Liu DC, Yu XL, Sun YH, Ning Y, Wei ZH, Chen SL, Chen XC, Zhang ZX, Liu YX, Pulit SL, Wu WB, Zheng ZY, Yang RD, Long H, Liu ZS, Wang JQ, Li M, Zhang LH, Wang H, Wang LM, Xiao P, Li JL, Huang ZM, Huang JX, Li Z, Liu J, Xiong L, Yang J, Wang XD, Yu DB, Lu XM, Zhou GZ, Yan LB, Sh
Magazine: New England Journal of Medicine
Titel: Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations.
Auteur: Pillai NE, Okada Y, Saw WY, Ong RT, Wang X, Tantoso E, Xu W, Peterson TA, Bielawny T, Ali M, Tay KY, Poh WT, Tan LW, Koo SH, Lim WY, Soong R, Wenk M, Raychaudhuri S, Little P, Plummer FA, Lee EJ, Chia KS, Luo M, De Bakker PI, Teo YY.
Magazine: Human Molecular Genetics
Titel: Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.
Auteur: Hu X, Deutsch AJ, Lenz TL, Onengut-Gumuscu S, Han B, Chen WM, Howson JM, Todd JA, de Bakker PIW, Rich SS, Raychaudhuri S.
Magazine: Nature Genetics
Titel: A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.
Auteur: Carmona FD, Mackie SL, Martín JE, Taylor JC, Vaglio A, Eyre S, Bossini-Castillo L, Castañeda S, Cid MC, Hernández-Rodríguez J, Prieto-González S, Solans R, Ramentol-Sintas M, González-Escribano MF, Ortiz-Fernández L, Morado IC, Narváez J, Miranda-Filloy JA; Spanish GCA Group, Beretta L, Lunardi C, Cimmino MA, Gianfreda D, Santilli D, Ramirez GA, Soriano A, Muratore F, Pazzola G, Addimanda O, Wijmenga C, Witte T, Schirmer JH, Moosig F, Schönau V, Franke A, Palm Ø, Molberg Ø, Diamantopo
Magazine: American Journal of Human Genetics
Titel: Interrogating the major histocompatibility complex with high-throughput genomics
Auteur: de Bakker PIW, Raychaudhuri S
Magazine: Human Molecular Genetics
Titel: Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load
Auteur: McLaren PJ, Coulonges C, Bartha I, Lenz TL, Deutsch AJ, Bashirova A, Buchbinder S, Carrington MN, Cossarizza A, Dalmau J, De Luca A, Goedert JJ, Gurdasani D, Haas DW, Herbeck JT, Johnson EO, Kirk GD, Lambotte O, Luo M, Mallal S, van Manen D, Martinez-Picado J, Meyer L, Miro JM, Mullins JI, Obel N, Poli G, Sandhu MS, Schuitemaker H, Shea PR, Theodorou I, Walker BD, Weintrob AC, Winkler CA, Wolinsky SM, Raychaudhuri S, Goldstein DB, Telenti A, de Bakker PIW, Zagury JF, Fellay J.
Magazine: Proceedings of the National Academy of Sciences USA
Titel: Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.
Auteur: Cortes A, Pulit SL, Leo PJ, Pointon JJ, Robinson PC, Weisman MH, Ward M, Gensler LS, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, Førre Ø, Tuomilehto J, Laiho K, Bradbury LA, Elewaut D, Burgos-Vargas R, Stebbings S, Appleton L, Farrah C, Lau J, Haroon N, Mulero J, Blanco FJ, Gonzalez-Gay MA, Lopez-Larrea C, Bowness P, Gaffney K, Gaston H, Gladman DD, Rahman P, Maksymowych WP, Crusius JB, van der Horst-Bruinsma IE, Valle-Oñate R, Romero-Sánchez C, Hansen IM, Pimentel-Santos FM, Inman R
Magazine: Nature Communications
Titel: A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.
Auteur: Kuiper JJ, Van Setten J, Ripke S, Van 'T Slot R, Mulder F, Missotten T, Baarsma GS, Francioli LC, Pulit SL, De Kovel CG, Ten Dam-Van Loon N, Den Hollander AI, Huis in het Veld P, Hoyng CB, Cordero-Coma M, Martín J, Llorenç V, Arya B, Thomas D, Bakker SC, Ophoff RA, Rothova A, De Bakker PI, Mutis T, Koeleman BP.
Magazine: Human Molecular Genetics
Titel: Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity.
Auteur: Han B, Diogo D, Eyre S, Kallberg H, Zhernakova A, Bowes J, Padyukov L, Okada Y, González-Gay MA, Rantapää-Dahlqvist S, Martin J, Huizinga TW, Plenge RM, Worthington J, Gregersen PK, Klareskog L, de Bakker PI, Raychaudhuri S.
Magazine: American Journal of Human Genetics
Titel: Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.
Auteur: Lenz TL, Deutsch AJ, Han B, Hu X, Okada Y, Eyre S, Knapp M, Zhernakova A, Huizinga TW, Abecasis G, Becker J, Boeckxstaens GE, Chen WM, Franke A, Gladman DD, Gockel I, Gutierrez-Achury J, Martin J, Nair RP, Nöthen MM, Onengut-Gumuscu S, Rahman P, Rantapää-Dahlqvist S, Stuart PE, Tsoi LC, van Heel DA, Worthington J, Wouters MM, Klareskog L, Elder JT, Gregersen PK, Schumacher J, Rich SS, Wijmenga C, Sunyaev SR, de Bakker PIW, Raychaudhuri S
Magazine: Nature Genetics
Titel: Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.
Auteur: Betz RC, Petukhova L, Ripke S, Huang H, Menelaou A, Redler S, Becker T, Heilmann S, Yamany T, Duvic M, Hordinsky M, Norris D, Price VH, Mackay-Wiggan J, de Jong A, DeStefano GM, Moebus S, Böhm M, Blume-Peytavi U, Wolff H, Lutz G, Kruse R, Bian L, Amos CI, Lee A, Gregersen PK, Blaumeiser B, Altshuler D, Clynes R, de Bakker PI, Nöthen MM, Daly MJ, Christiano AM.
Magazine: Nature Communications
Titel: Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma.
Auteur: Cerhan JR, Berndt SI, Vijai J, Ghesquières H, McKay J, Wang SS, Wang Z, Yeager M, Conde L, de Bakker PI, Nieters A, Cox D, Burdett L, Monnereau A, Flowers CR, De Roos AJ, Brooks-Wilson AR, Lan Q, Severi G, Melbye M, Gu J, Jackson RD, Kane E, Teras LR, Purdue MP, Vajdic CM, Spinelli JJ, Giles GG, Albanes D, Kelly RS, Zucca M, Bertrand KA, Zeleniuch-Jacquotte A, Lawrence C, Hutchinson A, Zhi D, Habermann TM, Link BK, Novak AJ, Dogan A, Asmann YW, Liebow M, Thompson CA, Ansell SM, Witzig TE, Weine
Magazine: Nature Genetics
Titel: Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease.
Auteur: Gutierrez-Achury J, Zhernakova A, Pulit SL, Trynka G, Hunt KA, Romanos J, Raychaudhuri S, van Heel DA, Wijmenga C, de Bakker PIW.
Magazine: Nature Genetics
Titel: Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.
Auteur: Patsopoulos NA, Barcellos LF, Hintzen RQ, Schaefer C, van Duijn CM, Noble JA, Raj T; IMSGC; ANZgene, Gourraud PA, Stranger BE, Oksenberg J, Olsson T, Taylor BV, Sawcer S, Hafler DA, Carrington M, De Jager PL, de Bakker PI.
Magazine: PLoS Genetics
Titel: Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia.
Auteur: Gockel I, Becker J, Wouters MM, Niebisch S, Gockel HR, Hess T, Ramonet D, Zimmermann J, Vigo AG, Trynka G, de León AR, de la Serna JP, Urcelay E, Kumar V, Franke L, Westra HJ, Drescher D, Kneist W, Marquardt JU, Galle PR, Mattheisen M, Annese V, Latiano A, Fumagalli U, Laghi L, Cuomo R, Sarnelli G, Müller M, Eckardt AJ, Tack J, Hoffmann P, Herms S, Mangold E, Heilmann S, Kiesslich R, von Rahden BH, Allescher HD, Schulz HG, Wijmenga C, Heneka MT, Lang H, Hopfner KP, Nöthen MM, Boeckxstaens GE,
Magazine: Nature Genetics
Titel: Imputing amino acid polymorphisms in human leukocyte antigens
Auteur: Jia X, Han B, Onengut-Gumuscu S, Chen WM, Concannon PJ, Rich SS, Raychaudhuri S, de Bakker PIW
Magazine: PLoS ONE
Titel: Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans
Auteur: McLaren PJ, Ripke S, Pelak K, Weintrob AC, Patsopoulos NA, Jia X, Erlich RL, Lennon NJ, Kadie CM, Heckerman D, Gupta N, Haas DW, Deeks SG, Pereyra F, Walker BD, de Bakker PIW; International HIV Controllers Study.
Magazine: Human Molecular Genetics
Titel: Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans
Auteur: Morris DL, Taylor KE, Fernando MM, Nititham J, Alarcón-Riquelme ME, Barcellos LF, Behrens TW, Cotsapas C, Gaffney PM, Graham RR, Pons-Estel BA, Gregersen PK, Harley JB, Hauser SL, Hom G; International MHC and Autoimmunity Genetics Network, Langefeld CD, Noble JA, Rioux JD, Seldin MF; Systemic Lupus Erythematosus Genetics Consortium, Criswell LA, Vyse TJ
Magazine: American Journal of Human Genetics

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Samenvatting van de aanvraag

Common diseases affect many millions of people across the world. Unfortunately, for most diseases, therapies are usually inadequate and rarely result in a cure. Human genetic studies offer a valuable approach to gain important insights into the underlying mechanisms involved in disease. Across all chromosomes of the human genome, there is one particular region, called the major histocompatibility complex (MHC), which harbours the largest number of validated associations to a wide range of diseases, including autoimmune disorders, infectious disease, cancer and schizophrenia. Yet the biological basis for most of these associations is poorly understood, in part because of the difficulty to pinpoint functional variants and causal genes in the MHC. In this proposal, we develop two complementary approaches that will enable comprehensive interrogation of DNA sequence variation across the MHC. Leveraging available whole-genome sequencing data in 250 trios from the ongoing Genome of the Netherlands Project, we will build a haplotype panel with near-complete coverage of genetic variation across the MHC observed in at least 1000 unrelated (haploid) genomes. With this MHC-wide panel, we will reanalyze existing genome-wide data sets collected by collaborators. Through imputation of variants observed in the MHC panel, we will fine-map initial MHC associations from genome-wide association studies and identify potentially causal variants. By combining state-of-the-art sequencing and a novel imputation technique pioneered by the applicant, the ultimate goal is to provide novel biological insight into which genes (and which variants) in the MHC are involved in human diseases with a known MHC component. In the long term, this may help us design better therapies and cures for a wide range of common diseases.

Onderwerpen

Kenmerken

Projectnummer:
91712354
Looptijd: 100%
Looptijd: 100 %
2012
2018
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. P.I.W. de Bakker PhD
Verantwoordelijke organisatie:
Universitair Medisch Centrum Utrecht