C-reactive protein, an 'intermediate phenotype' for inflammation: human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/beta-adrenergic pathway loci
C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to understand the role of heredity in determining CRP secretion. CRP, as well as multiple facets of the metabolic syndrome, were measured in a series o...
Saved in:
Published in | Journal of hypertension Vol. 25; no. 2; p. 329 |
---|---|
Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.02.2007
|
Subjects | |
Online Access | Get more information |
Cover
Loading…
Abstract | C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to understand the role of heredity in determining CRP secretion.
CRP, as well as multiple facets of the metabolic syndrome, were measured in a series of 229 twins, both monozygotic (MZ) and dizygotic (DZ), to estimate trait heritability (h2). Single nucleotide polymorphism (SNP) genotyping was done at adrenergic pathway loci. Haplotypes were inferred from genotypes by likelihood methods. Association of CRP with hypertension and the metabolic syndrome was studied in a larger series of 732 individuals, including 79 with hypertension.
MZ and DZ twin variance components indicated substantial h2 for CRP, at approximately 56 +/- 7% (P < 0.001). CRP was significantly associated (P < 0.05) with multiple features of the metabolic syndrome in twins, including body mass index (BMI), blood pressure (BP), leptin and lipids. In established hypertension, elevated CRP was associated with increased BP, BMI, insulin, HOMA (index of insulin resistance), leptin, triglycerides and norepinephrine. Twin correlations indicated pleiotropy (shared genetic determination) for CRP with BMI (P = 0.0002), leptin (P < 0.001), triglycerides (P = 0.002) and systolic blood pressure (SBP) (P = 0.042). Approximately 9800 genotypes (43 genetic variants at 17 loci) were scored within catecholaminergic pathways: biosynthetic, receptor and signal transduction. Plasma CRP concentration in twins was predicted by polymorphisms at three loci in physiological series within the catecholamine biosynthetic/beta-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (beta1-adrenergic receptor) and ADRB2 (beta2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to approximately 6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted approximately 2.8% of CRP, while ADRB2 promoter variants T-47C and T-20C also contributed. Particular haplotypes and diplotypes at TH and ADRB1 also predicted CRP, though typically no better than single SNPs alone. Epistasis (gene-by-gene interaction) was demonstrated for particular combinations of TH and ADRB2 alleles, consistent with their actions in a pathway in series. In an illustration of pleiotropy, not only CRP but also plasma triglycerides were predicted by polymorphisms at TH (P = 0.0053) and ADRB2 (P = 0.027).
CRP secretion is substantially heritable in humans, demonstrating pleiotropy (shared genetic determination) with other features of the metabolic syndrome, such as BMI, triglycerides or BP. Multiple, common genetic variants in the catecholaminergic/beta-adrenergic pathway contribute to CRP, and these variants (especially at TH and ADRB2) seem to interact (epistasis) to influence the trait. The results uncover novel pathophysiological links between the adrenergic system and inflammation, and suggest new strategies to probe the role and actions of inflammation within this setting. |
---|---|
AbstractList | C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to understand the role of heredity in determining CRP secretion.
CRP, as well as multiple facets of the metabolic syndrome, were measured in a series of 229 twins, both monozygotic (MZ) and dizygotic (DZ), to estimate trait heritability (h2). Single nucleotide polymorphism (SNP) genotyping was done at adrenergic pathway loci. Haplotypes were inferred from genotypes by likelihood methods. Association of CRP with hypertension and the metabolic syndrome was studied in a larger series of 732 individuals, including 79 with hypertension.
MZ and DZ twin variance components indicated substantial h2 for CRP, at approximately 56 +/- 7% (P < 0.001). CRP was significantly associated (P < 0.05) with multiple features of the metabolic syndrome in twins, including body mass index (BMI), blood pressure (BP), leptin and lipids. In established hypertension, elevated CRP was associated with increased BP, BMI, insulin, HOMA (index of insulin resistance), leptin, triglycerides and norepinephrine. Twin correlations indicated pleiotropy (shared genetic determination) for CRP with BMI (P = 0.0002), leptin (P < 0.001), triglycerides (P = 0.002) and systolic blood pressure (SBP) (P = 0.042). Approximately 9800 genotypes (43 genetic variants at 17 loci) were scored within catecholaminergic pathways: biosynthetic, receptor and signal transduction. Plasma CRP concentration in twins was predicted by polymorphisms at three loci in physiological series within the catecholamine biosynthetic/beta-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (beta1-adrenergic receptor) and ADRB2 (beta2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to approximately 6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted approximately 2.8% of CRP, while ADRB2 promoter variants T-47C and T-20C also contributed. Particular haplotypes and diplotypes at TH and ADRB1 also predicted CRP, though typically no better than single SNPs alone. Epistasis (gene-by-gene interaction) was demonstrated for particular combinations of TH and ADRB2 alleles, consistent with their actions in a pathway in series. In an illustration of pleiotropy, not only CRP but also plasma triglycerides were predicted by polymorphisms at TH (P = 0.0053) and ADRB2 (P = 0.027).
CRP secretion is substantially heritable in humans, demonstrating pleiotropy (shared genetic determination) with other features of the metabolic syndrome, such as BMI, triglycerides or BP. Multiple, common genetic variants in the catecholaminergic/beta-adrenergic pathway contribute to CRP, and these variants (especially at TH and ADRB2) seem to interact (epistasis) to influence the trait. The results uncover novel pathophysiological links between the adrenergic system and inflammation, and suggest new strategies to probe the role and actions of inflammation within this setting. |
Author | Zhang, Lian Smith, Douglas W Hamilton, Bruce A Khandrika, Srikrishna Rana, Brinda K Kennedy, Brian P Moratorio, Guillermo Wessel, Jennifer Ziegler, Michael G Rao, Fangwen Wen, Gen Schmid-Schönbein, Geert W Greene, William Shih, Pei-An Betty Lillie, Elizabeth O Witztum, Joseph L Mahata, Manjula Schork, Nicholas J O'Connor, Daniel T Huang, Pauline |
Author_xml | – sequence: 1 givenname: Jennifer surname: Wessel fullname: Wessel, Jennifer organization: Department of Medicine, University of California at San Diego, California 92093-0838, USA – sequence: 2 givenname: Guillermo surname: Moratorio fullname: Moratorio, Guillermo – sequence: 3 givenname: Fangwen surname: Rao fullname: Rao, Fangwen – sequence: 4 givenname: Manjula surname: Mahata fullname: Mahata, Manjula – sequence: 5 givenname: Lian surname: Zhang fullname: Zhang, Lian – sequence: 6 givenname: William surname: Greene fullname: Greene, William – sequence: 7 givenname: Brinda K surname: Rana fullname: Rana, Brinda K – sequence: 8 givenname: Brian P surname: Kennedy fullname: Kennedy, Brian P – sequence: 9 givenname: Srikrishna surname: Khandrika fullname: Khandrika, Srikrishna – sequence: 10 givenname: Pauline surname: Huang fullname: Huang, Pauline – sequence: 11 givenname: Elizabeth O surname: Lillie fullname: Lillie, Elizabeth O – sequence: 12 givenname: Pei-An Betty surname: Shih fullname: Shih, Pei-An Betty – sequence: 13 givenname: Douglas W surname: Smith fullname: Smith, Douglas W – sequence: 14 givenname: Gen surname: Wen fullname: Wen, Gen – sequence: 15 givenname: Bruce A surname: Hamilton fullname: Hamilton, Bruce A – sequence: 16 givenname: Michael G surname: Ziegler fullname: Ziegler, Michael G – sequence: 17 givenname: Joseph L surname: Witztum fullname: Witztum, Joseph L – sequence: 18 givenname: Nicholas J surname: Schork fullname: Schork, Nicholas J – sequence: 19 givenname: Geert W surname: Schmid-Schönbein fullname: Schmid-Schönbein, Geert W – sequence: 20 givenname: Daniel T surname: O'Connor fullname: O'Connor, Daniel T |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17211240$$D View this record in MEDLINE/PubMed |
BookMark | eNo9kUtv1TAQhY1U1Bf9BwjNrpumtZ3XDTt0BVxQJTawrhx7TAbFdmQ7vcq_r9sCq9FodL5zdOaCnfjgkbH3gt8KPvR3h--HWz5yUWMtd1yIvq3xhJ1z2dVVV7fyjF2k9Idzvhv6-pSdiV4KIRt-_obtq4hKZ3pEWGLISP4GlIdr8hmjQ0Mql8uEPuRtwWuwIQJ5OyvnVKbgP8K0uiLIR_KQ8moIE0R8RDXDhJGyGmmmvBVqSkHTiwiOlCcY5xBMccWU1ojF1UCeEBwWTZhJQ9q8icHhzf_bs_OKXiMECzo4V1hLmDcX4jJRcqAy6JJYT6EkJI_xN-m7sRArZSK-7rCoPB3VBnPJ8469tWpOePV3XrJfXz7_3B-q-x9fv-0_3Ve6Kb1WjWkk7kZhrVF6ELzVXA7ScjvWaLTSPe9sJ9pWCNv1Q6trLRsx8kHLQe-06eQl-_DKXdax1PqwRHIqbg__XiGfABpklGo |
CitedBy_id | crossref_primary_10_1007_s11906_008_0083_1 crossref_primary_10_1016_j_intimp_2007_07_015 crossref_primary_10_1111_j_1469_1809_2008_00444_x crossref_primary_10_1053_j_gastro_2010_06_009 crossref_primary_10_1161_HYPERTENSIONAHA_107_090480 crossref_primary_10_1097_PSY_0b013e318245d762 crossref_primary_10_1186_s40345_021_00220_w crossref_primary_10_1016_j_biopsych_2008_04_023 crossref_primary_10_1016_j_ymgme_2011_08_035 crossref_primary_10_1111_jnc_12346 crossref_primary_10_1182_blood_2010_10_311969 crossref_primary_10_1161_CIRCGENETICS_113_000173 crossref_primary_10_1186_s13098_017_0295_0 crossref_primary_10_1097_HJH_0b013e328332bc87 crossref_primary_10_1210_jc_2011_0590 crossref_primary_10_1007_s12041_019_1065_6 crossref_primary_10_1038_sj_gene_6364395 crossref_primary_10_1375_twin_12_3_286 crossref_primary_10_1007_s00439_013_1307_2 crossref_primary_10_1186_1755_8794_2_2 crossref_primary_10_3109_00365513_2011_568123 crossref_primary_10_1038_s41598_017_08696_2 crossref_primary_10_3892_br_2015_519 crossref_primary_10_1161_ATVBAHA_112_300251 crossref_primary_10_1210_jc_2008_2428 crossref_primary_10_3389_fimmu_2020_604000 crossref_primary_10_1038_ajh_2010_210 crossref_primary_10_1016_j_jnutbio_2016_11_013 crossref_primary_10_1016_j_nut_2015_07_015 crossref_primary_10_1016_j_amjcard_2009_07_063 crossref_primary_10_1038_oby_2008_465 crossref_primary_10_1097_HJH_0b013e328337f6bc crossref_primary_10_1016_j_jacc_2010_03_092 crossref_primary_10_1161_CIRCRESAHA_116_302888 crossref_primary_10_1038_ajh_2011_163 crossref_primary_10_1016_j_bbi_2010_02_009 crossref_primary_10_1016_j_atherosclerosis_2009_03_030 crossref_primary_10_2337_dc07_1525 crossref_primary_10_3892_mmr_2016_5495 crossref_primary_10_1194_jlr_P900033_JLR200 crossref_primary_10_1016_j_bbi_2011_07_239 crossref_primary_10_1371_journal_pgen_1007021 crossref_primary_10_3390_jcm10050986 crossref_primary_10_1007_s00439_012_1230_y crossref_primary_10_1179_1743132815Y_0000000053 crossref_primary_10_1373_clinchem_2008_117754 crossref_primary_10_1161_CIRCULATIONAHA_107_745737 crossref_primary_10_1016_j_jacc_2008_07_047 crossref_primary_10_1186_s40695_020_00051_2 crossref_primary_10_1016_j_hlc_2013_03_075 crossref_primary_10_1097_HJH_0b013e3283110402 crossref_primary_10_1371_journal_pone_0117007 crossref_primary_10_1002_ajhb_22842 crossref_primary_10_1146_annurev_biodatasci_102022_120818 crossref_primary_10_1097_HJH_0b013e32835b053d crossref_primary_10_1093_humrep_des416 crossref_primary_10_1007_s40292_021_00466_6 crossref_primary_10_1016_j_gene_2015_05_052 crossref_primary_10_1016_j_metabol_2010_05_015 crossref_primary_10_1038_nrrheum_2011_37 crossref_primary_10_1111_odi_14009 crossref_primary_10_1038_ng_271 crossref_primary_10_1093_hmg_ddy211 crossref_primary_10_1016_j_atherosclerosis_2017_08_008 crossref_primary_10_1016_j_jacc_2009_11_064 crossref_primary_10_1097_MNH_0b013e3283406ecf crossref_primary_10_1007_s10519_023_10165_8 crossref_primary_10_1017_thg_2013_58 crossref_primary_10_1007_s11325_009_0268_0 crossref_primary_10_1016_j_regpep_2008_11_001 crossref_primary_10_1097_HJH_0b013e328013dc13 crossref_primary_10_1038_ki_2008_113 crossref_primary_10_1007_s00439_008_0517_5 crossref_primary_10_1016_j_bbi_2007_11_008 crossref_primary_10_1038_sj_gene_6364459 crossref_primary_10_1586_1744666X_4_3_379 crossref_primary_10_1016_j_neuropharm_2011_02_027 crossref_primary_10_1089_met_2012_0154 |
ContentType | Journal Article |
DBID | CGR CUY CVF ECM EIF NPM |
DOI | 10.1097/HJH.0b013e328011753e |
DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed |
DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) |
DatabaseTitleList | MEDLINE |
Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
DeliveryMethod | no_fulltext_linktorsrc |
Discipline | Medicine |
ExternalDocumentID | 17211240 |
Genre | Research Support, U.S. Gov't, Non-P.H.S Twin Study Journal Article Research Support, N.I.H., Extramural |
GrantInformation_xml | – fundername: NCRR NIH HHS grantid: RR00827 – fundername: NHLBI NIH HHS grantid: P01 HL058120 |
GroupedDBID | --- .-D .55 .GJ .XZ .Z2 01R 0R~ 1J1 40H 4Q1 4Q2 4Q3 53G 5GY 5RE 5VS 71W 77Y 7O~ AAAAV AAAXR AAGIX AAHPQ AAIQE AAJCS AAMOA AAMTA AAQKA AARTV AASCR AASOK AAUEB AAWTL AAXQO AAYEP ABASU ABBUW ABDIG ABJNI ABOCM ABVCZ ABXVJ ABZAD ACCJW ACDDN ACEWG ACGFO ACGFS ACILI ACLDA ACWDW ACWRI ACXJB ACXNZ ADFPA ADGGA ADHPY ADNKB AE3 AE6 AEBDS AEETU AENEX AFDTB AFEXH AFFNX AFSOK AFUWQ AGINI AHOMT AHQNM AHRYX AHVBC AI. AIJEX AINUH AJIOK AJNWD AJNYG AJZMW AKULP ALMA_UNASSIGNED_HOLDINGS ALMTX AMJPA AMKUR AMNEI AOHHW AWKKM BOYCO BQLVK BS7 C45 CAG CGR COF CS3 CUY CVF DIWNM DU5 DUNZO E.X EBS ECM EEVPB EIF EJD ERAAH EX3 F2K F2L F2M F2N F5P FCALG FL- FW0 GNXGY GQDEL H0~ HLJTE HZ~ IKREB IKYAY IN~ IPNFZ JF9 JG8 JK3 JK8 K8S KD2 KMI L-C L7B N9A NPM N~7 N~B N~M O9- OAG OAH OCUKA ODA ODMTH OHYEH OJAPA OL1 OLG OLH OLU OLV OLW OLY OLZ OPUJH ORVUJ OUVQU OVD OVDNE OVIDH OVLEI OVOZU OWU OWV OWW OWX OWY OWZ OXXIT P-K P2P R58 RIG RLZ S4R S4S T8P TEORI TSPGW V2I VH1 VVN W3M WOQ WOW X3V X3W X7M XXN XYM YFH YYP ZFV ZGI ZXP ZZMQN |
ID | FETCH-LOGICAL-c4013-4d42e8b1ffdac9105c0292f0fb3edcac706f615511f6795c3c241b09c29c8cd62 |
ISSN | 0263-6352 |
IngestDate | Tue Oct 15 23:33:26 EDT 2024 |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 2 |
Language | English |
LinkModel | OpenURL |
MergedId | FETCHMERGED-LOGICAL-c4013-4d42e8b1ffdac9105c0292f0fb3edcac706f615511f6795c3c241b09c29c8cd62 |
PMID | 17211240 |
ParticipantIDs | pubmed_primary_17211240 |
PublicationCentury | 2000 |
PublicationDate | 2007-Feb |
PublicationDateYYYYMMDD | 2007-02-01 |
PublicationDate_xml | – month: 02 year: 2007 text: 2007-Feb |
PublicationDecade | 2000 |
PublicationPlace | England |
PublicationPlace_xml | – name: England |
PublicationTitle | Journal of hypertension |
PublicationTitleAlternate | J Hypertens |
PublicationYear | 2007 |
References | 17211232 - J Hypertens. 2007 Feb;25(2):281-3 |
References_xml | |
SSID | ssj0008973 |
Score | 2.2334986 |
Snippet | C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to... |
SourceID | pubmed |
SourceType | Index Database |
StartPage | 329 |
SubjectTerms | Adult Body Mass Index C-Reactive Protein - analysis C-Reactive Protein - genetics C-Reactive Protein - immunology Catecholamines - analysis Catecholamines - metabolism Coronary Artery Disease - genetics Coronary Artery Disease - immunology Epistasis, Genetic Female Humans Hypertension - blood Hypertension - genetics Inflammation - genetics Inflammation - physiopathology Inheritance Patterns Male Metabolic Syndrome - blood Metabolic Syndrome - genetics Metabolic Syndrome - immunology Microsatellite Repeats Polymorphism, Single Nucleotide Receptors, Adrenergic, beta - genetics Tyrosine 3-Monooxygenase - genetics |
Title | C-reactive protein, an 'intermediate phenotype' for inflammation: human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/beta-adrenergic pathway loci |
URI | https://www.ncbi.nlm.nih.gov/pubmed/17211240 |
Volume | 25 |
hasFullText | |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnZ3Lb9NAEIeXBiTUC-JNeWkOSD2kpn7FD8QFVZSoUnpqRW_Ver3bBGG7qhxF5a9nZtavpC0CLla0Gzux5_N6dvybWSE-6MQkkySPnVwmkRNmqedkoec5OT4cXTcLdcox3dlxND0Nj84mZ1ujzwPV0rLOPqpft-aV_I9VsQ3tSlmy_2DZ7qDYgJ_RvrhFC-P2r2x84KDLxwPWmOst2HoAkuwZUx2IK84LqbF3rsuKoq0kmTAsQTeIQtFJO-xSffVqUXLBWZw-U1KL5kRJCh-whJbtIXt72iAuS9_HrKdtX0aQM1to3IuKDndFEVqhKPUu2rVRGlk7XjJaL-K6qNDuvG5HPSatFk-9C05QXCi8UBke1ZGUfc4tVBZ2vpLXY3wkL-7ws-d42les0-8VB9-pYvqauqcDr2LdwYIjyN-WnClZVP3bMG4_lOXFqs-hm8m5tE74TJY_lj_lWiglbtXX3YjrR4GDHtja48HmZTe3gT8Y6wMbqrnxDLK1jadH0zbI7Ce2IKoefh1te1kwlzwJ923Rqj_3blQGb7tGYhQntGzJMUWqGi8kSa26oj2lNm00jfdv-2tUPLc53MYEix2tk8fiUWM5-GJxfyK2dPlUPJw1GpBn90RPPTTU74EsYXdIPHTE7wLyDkPePwHTDkQ7NLSDpR2GtONRe9aBWAdmHVrW8VdzQJqhYx1a1ve6vo50qAxY0mFIOsgabpC-v8E5NJwDcf5cnB5-PTmYOs06Jo6i6IUT5qGvk8wzJpcK3fOJcv3UN67JAp0rqWI3MiQP8DwTxelEBQrd6sxNlZ-qROWR_0LcL6tSvxKgjQl1IN2AJkI4ecukH-VZFGntyRD33BEvre3OL22xmvPWqq_v7Hkjtvub4a14YHB01O_Q1a6z98zUb7nr4Cw |
link.rule.ids | 780 |
linkProvider | National Library of Medicine |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=C-reactive+protein%2C+an+%27intermediate+phenotype%27+for+inflammation%3A+human+twin+studies+reveal+heritability%2C+association+with+blood+pressure+and+the+metabolic+syndrome%2C+and+the+influence+of+common+polymorphism+at+catecholaminergic%2Fbeta-adrenergic+pathway+loci&rft.jtitle=Journal+of+hypertension&rft.au=Wessel%2C+Jennifer&rft.au=Moratorio%2C+Guillermo&rft.au=Rao%2C+Fangwen&rft.au=Mahata%2C+Manjula&rft.date=2007-02-01&rft.issn=0263-6352&rft.volume=25&rft.issue=2&rft.spage=329&rft_id=info:doi/10.1097%2FHJH.0b013e328011753e&rft_id=info%3Apmid%2F17211240&rft_id=info%3Apmid%2F17211240&rft.externalDocID=17211240 |
thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0263-6352&client=summon |
thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0263-6352&client=summon |
thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0263-6352&client=summon |