Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2013-01-01
|
Series: | PLoS Genetics |
Online Access: | http://europepmc.org/articles/PMC3575474?pdf=render |
id |
doaj-74744baacd384c39998a0eac8019495c |
---|---|
record_format |
Article |
spelling |
doaj-74744baacd384c39998a0eac8019495c2020-11-25T02:06:26ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-01-0192e100322210.1371/journal.pgen.1003222Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.Julio E MolinerosAmit K MaitiCeli SunLoren L LoogerShizhong HanXana Kim-HowardStuart GlennAdam AdlerJennifer A KellyTimothy B NiewoldGary S GilkesonElizabeth E BrownGraciela S AlarcónJeffrey C EdbergMichelle PetriRosalind Ramsey-GoldmanJohn D ReveilleLuis M ViláBarry I FreedmanBetty P TsaoLindsey A CriswellChaim O JacobJason H MooreTimothy J VyseCarl L LangefeldJoel M GuthridgePatrick M GaffneyKathy L MoserR Hal ScofieldMarta E Alarcón-RiquelmeBIOLUPUS NetworkScott M WilliamsJoan T MerrillJudith A JamesKenneth M KaufmanRobert P KimberlyJohn B HarleySwapan K NathSystemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.http://europepmc.org/articles/PMC3575474?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Julio E Molineros Amit K Maiti Celi Sun Loren L Looger Shizhong Han Xana Kim-Howard Stuart Glenn Adam Adler Jennifer A Kelly Timothy B Niewold Gary S Gilkeson Elizabeth E Brown Graciela S Alarcón Jeffrey C Edberg Michelle Petri Rosalind Ramsey-Goldman John D Reveille Luis M Vilá Barry I Freedman Betty P Tsao Lindsey A Criswell Chaim O Jacob Jason H Moore Timothy J Vyse Carl L Langefeld Joel M Guthridge Patrick M Gaffney Kathy L Moser R Hal Scofield Marta E Alarcón-Riquelme BIOLUPUS Network Scott M Williams Joan T Merrill Judith A James Kenneth M Kaufman Robert P Kimberly John B Harley Swapan K Nath |
spellingShingle |
Julio E Molineros Amit K Maiti Celi Sun Loren L Looger Shizhong Han Xana Kim-Howard Stuart Glenn Adam Adler Jennifer A Kelly Timothy B Niewold Gary S Gilkeson Elizabeth E Brown Graciela S Alarcón Jeffrey C Edberg Michelle Petri Rosalind Ramsey-Goldman John D Reveille Luis M Vilá Barry I Freedman Betty P Tsao Lindsey A Criswell Chaim O Jacob Jason H Moore Timothy J Vyse Carl L Langefeld Joel M Guthridge Patrick M Gaffney Kathy L Moser R Hal Scofield Marta E Alarcón-Riquelme BIOLUPUS Network Scott M Williams Joan T Merrill Judith A James Kenneth M Kaufman Robert P Kimberly John B Harley Swapan K Nath Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. PLoS Genetics |
author_facet |
Julio E Molineros Amit K Maiti Celi Sun Loren L Looger Shizhong Han Xana Kim-Howard Stuart Glenn Adam Adler Jennifer A Kelly Timothy B Niewold Gary S Gilkeson Elizabeth E Brown Graciela S Alarcón Jeffrey C Edberg Michelle Petri Rosalind Ramsey-Goldman John D Reveille Luis M Vilá Barry I Freedman Betty P Tsao Lindsey A Criswell Chaim O Jacob Jason H Moore Timothy J Vyse Carl L Langefeld Joel M Guthridge Patrick M Gaffney Kathy L Moser R Hal Scofield Marta E Alarcón-Riquelme BIOLUPUS Network Scott M Williams Joan T Merrill Judith A James Kenneth M Kaufman Robert P Kimberly John B Harley Swapan K Nath |
author_sort |
Julio E Molineros |
title |
Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. |
title_short |
Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. |
title_full |
Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. |
title_fullStr |
Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. |
title_full_unstemmed |
Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. |
title_sort |
admixture mapping in lupus identifies multiple functional variants within ifih1 associated with apoptosis, inflammation, and autoantibody production. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2013-01-01 |
description |
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis. |
url |
http://europepmc.org/articles/PMC3575474?pdf=render |
work_keys_str_mv |
AT julioemolineros admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT amitkmaiti admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT celisun admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT lorenllooger admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT shizhonghan admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT xanakimhoward admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT stuartglenn admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT adamadler admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT jenniferakelly admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT timothybniewold admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT garysgilkeson admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT elizabethebrown admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT gracielasalarcon admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT jeffreycedberg admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT michellepetri admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT rosalindramseygoldman admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT johndreveille admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT luismvila admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT barryifreedman admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT bettyptsao admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT lindseyacriswell admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT chaimojacob admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT jasonhmoore admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT timothyjvyse admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT carlllangefeld admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT joelmguthridge admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT patrickmgaffney admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT kathylmoser admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT rhalscofield admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT martaealarconriquelme admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT biolupusnetwork admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT scottmwilliams admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT joantmerrill admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT judithajames admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT kennethmkaufman admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT robertpkimberly admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT johnbharley admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction AT swapanknath admixturemappinginlupusidentifiesmultiplefunctionalvariantswithinifih1associatedwithapoptosisinflammationandautoantibodyproduction |
_version_ |
1724933960125906944 |