Fine mapping of Xq28

Both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups

Kenneth M. Kaufman, Jian Zhao, Jennifer A. Kelly, Travis Hughes, Adam Adler, Elena Sanchez, Joshua O. Ojwang, Carl D. Langefeld, Julie T. Ziegler, Adrienne H. Williams, Mary E. Comeau, Miranda C. Marion, Stuart B. Glenn, Rita M. Cantor, Jennifer M. Grossman, Bevra H. Hahn, Yeong Wook Song, Chack Yung Yu, Judith A. James, Joel M. Guthridge & 30 others Elizabeth E. Brown, Graciela S. Alarcón, Robert P. Kimberly, Jeffrey C. Edberg, Rosalind Ramsey-Goldman, Michelle Petri, John D. Reveille, Luis M. Vilá, Juan Manuel Anaya, Susan A. Boackle, Anne M. Stevens, Barry I. Freedman, Lindsey A. Criswell, Bernardo A. Pons-Este, Joo Hyun Lee, Ji Seon Lee, Deh Ming Chang, R. Hal A Scofield, Gary S. Gilkeson, Joan T. Merrill, Timothy B. Niewold, Timothy James Vyse, Sang Cheol Bae, Marta E. Alarcón-Riquelme, Chaim O. Jacob, Kathy Moser Sivils, Patrick M. Gaffney, John B. Harley, Amr H. Sawalha, Betty P. Tsao

Research output: Contribution to journalArticle

Abstract

Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant (s) conferring risk of SLE. Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. Results: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p-8 with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p meta=1.3×10-27, OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-KB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064). Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

Original languageEnglish (US)
Pages (from-to)437-444
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume72
Issue number3
DOIs
StatePublished - Mar 2013

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Systemic Lupus Erythematosus
Association reactions
Single Nucleotide Polymorphism
Genes
Neural Cell Adhesion Molecule L1
Asian Americans
Linkage Disequilibrium
Genetic Association Studies
Amino Acid Substitution
Hispanic Americans
Substitution reactions
Haplotypes
Meta-Analysis
Amino Acids
Alleles
Messenger RNA
Genotype
Testing

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Fine mapping of Xq28 : Both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. / Kaufman, Kenneth M.; Zhao, Jian; Kelly, Jennifer A.; Hughes, Travis; Adler, Adam; Sanchez, Elena; Ojwang, Joshua O.; Langefeld, Carl D.; Ziegler, Julie T.; Williams, Adrienne H.; Comeau, Mary E.; Marion, Miranda C.; Glenn, Stuart B.; Cantor, Rita M.; Grossman, Jennifer M.; Hahn, Bevra H.; Song, Yeong Wook; Yu, Chack Yung; James, Judith A.; Guthridge, Joel M.; Brown, Elizabeth E.; Alarcón, Graciela S.; Kimberly, Robert P.; Edberg, Jeffrey C.; Ramsey-Goldman, Rosalind; Petri, Michelle; Reveille, John D.; Vilá, Luis M.; Anaya, Juan Manuel; Boackle, Susan A.; Stevens, Anne M.; Freedman, Barry I.; Criswell, Lindsey A.; Pons-Este, Bernardo A.; Lee, Joo Hyun; Lee, Ji Seon; Chang, Deh Ming; Scofield, R. Hal A; Gilkeson, Gary S.; Merrill, Joan T.; Niewold, Timothy B.; Vyse, Timothy James; Bae, Sang Cheol; Alarcón-Riquelme, Marta E.; Jacob, Chaim O.; Sivils, Kathy Moser; Gaffney, Patrick M.; Harley, John B.; Sawalha, Amr H.; Tsao, Betty P.

In: Annals of the Rheumatic Diseases, Vol. 72, No. 3, 03.2013, p. 437-444.

Research output: Contribution to journalArticle

Kaufman, KM, Zhao, J, Kelly, JA, Hughes, T, Adler, A, Sanchez, E, Ojwang, JO, Langefeld, CD, Ziegler, JT, Williams, AH, Comeau, ME, Marion, MC, Glenn, SB, Cantor, RM, Grossman, JM, Hahn, BH, Song, YW, Yu, CY, James, JA, Guthridge, JM, Brown, EE, Alarcón, GS, Kimberly, RP, Edberg, JC, Ramsey-Goldman, R, Petri, M, Reveille, JD, Vilá, LM, Anaya, JM, Boackle, SA, Stevens, AM, Freedman, BI, Criswell, LA, Pons-Este, BA, Lee, JH, Lee, JS, Chang, DM, Scofield, RHA, Gilkeson, GS, Merrill, JT, Niewold, TB, Vyse, TJ, Bae, SC, Alarcón-Riquelme, ME, Jacob, CO, Sivils, KM, Gaffney, PM, Harley, JB, Sawalha, AH & Tsao, BP 2013, 'Fine mapping of Xq28: Both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups', Annals of the Rheumatic Diseases, vol. 72, no. 3, pp. 437-444. https://doi.org/10.1136/annrheumdis-2012-201851
Kaufman, Kenneth M. ; Zhao, Jian ; Kelly, Jennifer A. ; Hughes, Travis ; Adler, Adam ; Sanchez, Elena ; Ojwang, Joshua O. ; Langefeld, Carl D. ; Ziegler, Julie T. ; Williams, Adrienne H. ; Comeau, Mary E. ; Marion, Miranda C. ; Glenn, Stuart B. ; Cantor, Rita M. ; Grossman, Jennifer M. ; Hahn, Bevra H. ; Song, Yeong Wook ; Yu, Chack Yung ; James, Judith A. ; Guthridge, Joel M. ; Brown, Elizabeth E. ; Alarcón, Graciela S. ; Kimberly, Robert P. ; Edberg, Jeffrey C. ; Ramsey-Goldman, Rosalind ; Petri, Michelle ; Reveille, John D. ; Vilá, Luis M. ; Anaya, Juan Manuel ; Boackle, Susan A. ; Stevens, Anne M. ; Freedman, Barry I. ; Criswell, Lindsey A. ; Pons-Este, Bernardo A. ; Lee, Joo Hyun ; Lee, Ji Seon ; Chang, Deh Ming ; Scofield, R. Hal A ; Gilkeson, Gary S. ; Merrill, Joan T. ; Niewold, Timothy B. ; Vyse, Timothy James ; Bae, Sang Cheol ; Alarcón-Riquelme, Marta E. ; Jacob, Chaim O. ; Sivils, Kathy Moser ; Gaffney, Patrick M. ; Harley, John B. ; Sawalha, Amr H. ; Tsao, Betty P. / Fine mapping of Xq28 : Both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. In: Annals of the Rheumatic Diseases. 2013 ; Vol. 72, No. 3. pp. 437-444.
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title = "Fine mapping of Xq28: Both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups",
abstract = "Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant (s) conferring risk of SLE. Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. Results: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p-8 with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p meta=1.3×10-27, OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-KB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064). Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.",
author = "Kaufman, {Kenneth M.} and Jian Zhao and Kelly, {Jennifer A.} and Travis Hughes and Adam Adler and Elena Sanchez and Ojwang, {Joshua O.} and Langefeld, {Carl D.} and Ziegler, {Julie T.} and Williams, {Adrienne H.} and Comeau, {Mary E.} and Marion, {Miranda C.} and Glenn, {Stuart B.} and Cantor, {Rita M.} and Grossman, {Jennifer M.} and Hahn, {Bevra H.} and Song, {Yeong Wook} and Yu, {Chack Yung} and James, {Judith A.} and Guthridge, {Joel M.} and Brown, {Elizabeth E.} and Alarc{\'o}n, {Graciela S.} and Kimberly, {Robert P.} and Edberg, {Jeffrey C.} and Rosalind Ramsey-Goldman and Michelle Petri and Reveille, {John D.} and Vil{\'a}, {Luis M.} and Anaya, {Juan Manuel} and Boackle, {Susan A.} and Stevens, {Anne M.} and Freedman, {Barry I.} and Criswell, {Lindsey A.} and Pons-Este, {Bernardo A.} and Lee, {Joo Hyun} and Lee, {Ji Seon} and Chang, {Deh Ming} and Scofield, {R. Hal A} and Gilkeson, {Gary S.} and Merrill, {Joan T.} and Niewold, {Timothy B.} and Vyse, {Timothy James} and Bae, {Sang Cheol} and Alarc{\'o}n-Riquelme, {Marta E.} and Jacob, {Chaim O.} and Sivils, {Kathy Moser} and Gaffney, {Patrick M.} and Harley, {John B.} and Sawalha, {Amr H.} and Tsao, {Betty P.}",
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TY - JOUR

T1 - Fine mapping of Xq28

T2 - Both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups

AU - Kaufman, Kenneth M.

AU - Zhao, Jian

AU - Kelly, Jennifer A.

AU - Hughes, Travis

AU - Adler, Adam

AU - Sanchez, Elena

AU - Ojwang, Joshua O.

AU - Langefeld, Carl D.

AU - Ziegler, Julie T.

AU - Williams, Adrienne H.

AU - Comeau, Mary E.

AU - Marion, Miranda C.

AU - Glenn, Stuart B.

AU - Cantor, Rita M.

AU - Grossman, Jennifer M.

AU - Hahn, Bevra H.

AU - Song, Yeong Wook

AU - Yu, Chack Yung

AU - James, Judith A.

AU - Guthridge, Joel M.

AU - Brown, Elizabeth E.

AU - Alarcón, Graciela S.

AU - Kimberly, Robert P.

AU - Edberg, Jeffrey C.

AU - Ramsey-Goldman, Rosalind

AU - Petri, Michelle

AU - Reveille, John D.

AU - Vilá, Luis M.

AU - Anaya, Juan Manuel

AU - Boackle, Susan A.

AU - Stevens, Anne M.

AU - Freedman, Barry I.

AU - Criswell, Lindsey A.

AU - Pons-Este, Bernardo A.

AU - Lee, Joo Hyun

AU - Lee, Ji Seon

AU - Chang, Deh Ming

AU - Scofield, R. Hal A

AU - Gilkeson, Gary S.

AU - Merrill, Joan T.

AU - Niewold, Timothy B.

AU - Vyse, Timothy James

AU - Bae, Sang Cheol

AU - Alarcón-Riquelme, Marta E.

AU - Jacob, Chaim O.

AU - Sivils, Kathy Moser

AU - Gaffney, Patrick M.

AU - Harley, John B.

AU - Sawalha, Amr H.

AU - Tsao, Betty P.

PY - 2013/3

Y1 - 2013/3

N2 - Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant (s) conferring risk of SLE. Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. Results: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p-8 with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p meta=1.3×10-27, OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-KB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064). Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

AB - Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant (s) conferring risk of SLE. Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. Results: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p-8 with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p meta=1.3×10-27, OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-KB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064). Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

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