Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease

Natalie J. Prescott, Katherine M. Dominy, Michiaki Kubo, Cathryn M. Lewis, Sheila A. Fisher, Richard Redon, Ni Huang, Barbara E. Stranger, Katarzyna Blaszczyk, Barry Hudspith, Gareth Parkes, Naoya Hosono, Keiko Yamazaki, Clive M. Onnie, Alastair Forbes, Emmanouil T. Dermitzakis, Yusuke Nakamura, John C. Mansfield, Jeremy Sanderson, Matthew E. HurlesRoland G. Roberts, Christopher G. Mathew

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Abstract

DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstreamof IRGM was recently shown to be in strong linkage disequilibrium(LD)withtheCD-associated single nucleotide polymorphisms and is itself associatedwithCD (P < 0.01). The deletionwas correlatedwith increased or reduced expression of IRGMin transformed cells in a cell line-dependentmanner, and has been proposed as a likely causal variant.We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10 -5 to 1.40 × 10 -9 ), and that the CNV and the 5′-untranslated region variant -308(GTTT) 5 contribute independently to CD susceptibility (P = 2.6 × 10 -7 and P = 2 × 10 -5 , respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10 -12 ) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.

Original languageEnglish
Article numberddq041
Pages (from-to)1828-1839
Number of pages12
JournalHuman molecular genetics
Volume19
Issue number9
DOIs
Publication statusPublished - 27-01-2010

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Minor Lymphocyte Stimulatory Loci
GTP Phosphohydrolases
Crohn Disease
Immunity
Population
5' Untranslated Regions
Haplotypes
DNA Copy Number Variations
HapMap Project
Genes
Gene-Environment Interaction
Disease Susceptibility
Zinc Fingers
Linkage Disequilibrium
Single Nucleotide Polymorphism
Chromosomes
Alleles
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Prescott, N. J., Dominy, K. M., Kubo, M., Lewis, C. M., Fisher, S. A., Redon, R., ... Mathew, C. G. (2010). Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease. Human molecular genetics, 19(9), 1828-1839. [ddq041]. https://doi.org/10.1093/hmg/ddq041
Prescott, Natalie J. ; Dominy, Katherine M. ; Kubo, Michiaki ; Lewis, Cathryn M. ; Fisher, Sheila A. ; Redon, Richard ; Huang, Ni ; Stranger, Barbara E. ; Blaszczyk, Katarzyna ; Hudspith, Barry ; Parkes, Gareth ; Hosono, Naoya ; Yamazaki, Keiko ; Onnie, Clive M. ; Forbes, Alastair ; Dermitzakis, Emmanouil T. ; Nakamura, Yusuke ; Mansfield, John C. ; Sanderson, Jeremy ; Hurles, Matthew E. ; Roberts, Roland G. ; Mathew, Christopher G. / Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease. In: Human molecular genetics. 2010 ; Vol. 19, No. 9. pp. 1828-1839.
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abstract = "DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstreamof IRGM was recently shown to be in strong linkage disequilibrium(LD)withtheCD-associated single nucleotide polymorphisms and is itself associatedwithCD (P < 0.01). The deletionwas correlatedwith increased or reduced expression of IRGMin transformed cells in a cell line-dependentmanner, and has been proposed as a likely causal variant.We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10 -5 to 1.40 × 10 -9 ), and that the CNV and the 5′-untranslated region variant -308(GTTT) 5 contribute independently to CD susceptibility (P = 2.6 × 10 -7 and P = 2 × 10 -5 , respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10 -12 ) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.",
author = "Prescott, {Natalie J.} and Dominy, {Katherine M.} and Michiaki Kubo and Lewis, {Cathryn M.} and Fisher, {Sheila A.} and Richard Redon and Ni Huang and Stranger, {Barbara E.} and Katarzyna Blaszczyk and Barry Hudspith and Gareth Parkes and Naoya Hosono and Keiko Yamazaki and Onnie, {Clive M.} and Alastair Forbes and Dermitzakis, {Emmanouil T.} and Yusuke Nakamura and Mansfield, {John C.} and Jeremy Sanderson and Hurles, {Matthew E.} and Roberts, {Roland G.} and Mathew, {Christopher G.}",
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Prescott, NJ, Dominy, KM, Kubo, M, Lewis, CM, Fisher, SA, Redon, R, Huang, N, Stranger, BE, Blaszczyk, K, Hudspith, B, Parkes, G, Hosono, N, Yamazaki, K, Onnie, CM, Forbes, A, Dermitzakis, ET, Nakamura, Y, Mansfield, JC, Sanderson, J, Hurles, ME, Roberts, RG & Mathew, CG 2010, 'Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease', Human molecular genetics, vol. 19, no. 9, ddq041, pp. 1828-1839. https://doi.org/10.1093/hmg/ddq041

Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease. / Prescott, Natalie J.; Dominy, Katherine M.; Kubo, Michiaki; Lewis, Cathryn M.; Fisher, Sheila A.; Redon, Richard; Huang, Ni; Stranger, Barbara E.; Blaszczyk, Katarzyna; Hudspith, Barry; Parkes, Gareth; Hosono, Naoya; Yamazaki, Keiko; Onnie, Clive M.; Forbes, Alastair; Dermitzakis, Emmanouil T.; Nakamura, Yusuke; Mansfield, John C.; Sanderson, Jeremy; Hurles, Matthew E.; Roberts, Roland G.; Mathew, Christopher G.

In: Human molecular genetics, Vol. 19, No. 9, ddq041, 27.01.2010, p. 1828-1839.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease

AU - Prescott, Natalie J.

AU - Dominy, Katherine M.

AU - Kubo, Michiaki

AU - Lewis, Cathryn M.

AU - Fisher, Sheila A.

AU - Redon, Richard

AU - Huang, Ni

AU - Stranger, Barbara E.

AU - Blaszczyk, Katarzyna

AU - Hudspith, Barry

AU - Parkes, Gareth

AU - Hosono, Naoya

AU - Yamazaki, Keiko

AU - Onnie, Clive M.

AU - Forbes, Alastair

AU - Dermitzakis, Emmanouil T.

AU - Nakamura, Yusuke

AU - Mansfield, John C.

AU - Sanderson, Jeremy

AU - Hurles, Matthew E.

AU - Roberts, Roland G.

AU - Mathew, Christopher G.

PY - 2010/1/27

Y1 - 2010/1/27

N2 - DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstreamof IRGM was recently shown to be in strong linkage disequilibrium(LD)withtheCD-associated single nucleotide polymorphisms and is itself associatedwithCD (P < 0.01). The deletionwas correlatedwith increased or reduced expression of IRGMin transformed cells in a cell line-dependentmanner, and has been proposed as a likely causal variant.We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10 -5 to 1.40 × 10 -9 ), and that the CNV and the 5′-untranslated region variant -308(GTTT) 5 contribute independently to CD susceptibility (P = 2.6 × 10 -7 and P = 2 × 10 -5 , respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10 -12 ) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.

AB - DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstreamof IRGM was recently shown to be in strong linkage disequilibrium(LD)withtheCD-associated single nucleotide polymorphisms and is itself associatedwithCD (P < 0.01). The deletionwas correlatedwith increased or reduced expression of IRGMin transformed cells in a cell line-dependentmanner, and has been proposed as a likely causal variant.We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10 -5 to 1.40 × 10 -9 ), and that the CNV and the 5′-untranslated region variant -308(GTTT) 5 contribute independently to CD susceptibility (P = 2.6 × 10 -7 and P = 2 × 10 -5 , respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10 -12 ) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.

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