Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associa...
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-05-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3102741?pdf=render |
| _version_ | 1818197090353807360 |
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| author | Jian Zhao Hui Wu Melanie Khosravi Huijuan Cui Xiaoxia Qian Jennifer A Kelly Kenneth M Kaufman Carl D Langefeld Adrienne H Williams Mary E Comeau Julie T Ziegler Miranda C Marion Adam Adler Stuart B Glenn Marta E Alarcón-Riquelme BIOLUPUS Network GENLES Network Bernardo A Pons-Estel John B Harley Sang-Cheol Bae So-Young Bang Soo-Kyung Cho Chaim O Jacob Timothy J Vyse Timothy B Niewold Patrick M Gaffney Kathy L Moser Robert P Kimberly Jeffrey C Edberg Elizabeth E Brown Graciela S Alarcon Michelle A Petri Rosalind Ramsey-Goldman Luis M Vilá John D Reveille Judith A James Gary S Gilkeson Diane L Kamen Barry I Freedman Juan-Manuel Anaya Joan T Merrill Lindsey A Criswell R Hal Scofield Anne M Stevens Joel M Guthridge Deh-Ming Chang Yeong Wook Song Ji Ah Park Eun Young Lee Susan A Boackle Jennifer M Grossman Bevra H Hahn Timothy H J Goodship Rita M Cantor Chack-Yung Yu Nan Shen Betty P Tsao |
| author_facet | Jian Zhao Hui Wu Melanie Khosravi Huijuan Cui Xiaoxia Qian Jennifer A Kelly Kenneth M Kaufman Carl D Langefeld Adrienne H Williams Mary E Comeau Julie T Ziegler Miranda C Marion Adam Adler Stuart B Glenn Marta E Alarcón-Riquelme BIOLUPUS Network GENLES Network Bernardo A Pons-Estel John B Harley Sang-Cheol Bae So-Young Bang Soo-Kyung Cho Chaim O Jacob Timothy J Vyse Timothy B Niewold Patrick M Gaffney Kathy L Moser Robert P Kimberly Jeffrey C Edberg Elizabeth E Brown Graciela S Alarcon Michelle A Petri Rosalind Ramsey-Goldman Luis M Vilá John D Reveille Judith A James Gary S Gilkeson Diane L Kamen Barry I Freedman Juan-Manuel Anaya Joan T Merrill Lindsey A Criswell R Hal Scofield Anne M Stevens Joel M Guthridge Deh-Ming Chang Yeong Wook Song Ji Ah Park Eun Young Lee Susan A Boackle Jennifer M Grossman Bevra H Hahn Timothy H J Goodship Rita M Cantor Chack-Yung Yu Nan Shen Betty P Tsao |
| author_sort | Jian Zhao |
| collection | DOAJ |
| description | Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE. |
| first_indexed | 2024-12-12T01:44:27Z |
| format | Article |
| id | doaj.art-714680860d754c02ba45e9b2d825dcfd |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-12T01:44:27Z |
| publishDate | 2011-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-714680860d754c02ba45e9b2d825dcfd2022-12-22T00:42:37ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-05-0175e100207910.1371/journal.pgen.1002079Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.Jian ZhaoHui WuMelanie KhosraviHuijuan CuiXiaoxia QianJennifer A KellyKenneth M KaufmanCarl D LangefeldAdrienne H WilliamsMary E ComeauJulie T ZieglerMiranda C MarionAdam AdlerStuart B GlennMarta E Alarcón-RiquelmeBIOLUPUS NetworkGENLES NetworkBernardo A Pons-EstelJohn B HarleySang-Cheol BaeSo-Young BangSoo-Kyung ChoChaim O JacobTimothy J VyseTimothy B NiewoldPatrick M GaffneyKathy L MoserRobert P KimberlyJeffrey C EdbergElizabeth E BrownGraciela S AlarconMichelle A PetriRosalind Ramsey-GoldmanLuis M ViláJohn D ReveilleJudith A JamesGary S GilkesonDiane L KamenBarry I FreedmanJuan-Manuel AnayaJoan T MerrillLindsey A CriswellR Hal ScofieldAnne M StevensJoel M GuthridgeDeh-Ming ChangYeong Wook SongJi Ah ParkEun Young LeeSusan A BoackleJennifer M GrossmanBevra H HahnTimothy H J GoodshipRita M CantorChack-Yung YuNan ShenBetty P TsaoSystemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.http://europepmc.org/articles/PMC3102741?pdf=render |
| spellingShingle | Jian Zhao Hui Wu Melanie Khosravi Huijuan Cui Xiaoxia Qian Jennifer A Kelly Kenneth M Kaufman Carl D Langefeld Adrienne H Williams Mary E Comeau Julie T Ziegler Miranda C Marion Adam Adler Stuart B Glenn Marta E Alarcón-Riquelme BIOLUPUS Network GENLES Network Bernardo A Pons-Estel John B Harley Sang-Cheol Bae So-Young Bang Soo-Kyung Cho Chaim O Jacob Timothy J Vyse Timothy B Niewold Patrick M Gaffney Kathy L Moser Robert P Kimberly Jeffrey C Edberg Elizabeth E Brown Graciela S Alarcon Michelle A Petri Rosalind Ramsey-Goldman Luis M Vilá John D Reveille Judith A James Gary S Gilkeson Diane L Kamen Barry I Freedman Juan-Manuel Anaya Joan T Merrill Lindsey A Criswell R Hal Scofield Anne M Stevens Joel M Guthridge Deh-Ming Chang Yeong Wook Song Ji Ah Park Eun Young Lee Susan A Boackle Jennifer M Grossman Bevra H Hahn Timothy H J Goodship Rita M Cantor Chack-Yung Yu Nan Shen Betty P Tsao Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. PLoS Genetics |
| title | Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. |
| title_full | Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. |
| title_fullStr | Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. |
| title_full_unstemmed | Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. |
| title_short | Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. |
| title_sort | association of genetic variants in complement factor h and factor h related genes with systemic lupus erythematosus susceptibility |
| url | http://europepmc.org/articles/PMC3102741?pdf=render |
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