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/β-adrenergic pathway loci

Jennifer Wessel, Guillermo Moratorio, Fangwen Rao, Manjula Mahata, Lian Zhang, William Greene, Brinda K. Rana, Brian P. Kennedy, Srikrishna Khandrika, Pauline Huang, Elizabeth O. Lillie, Pei An Betty Shih, Douglas W. Smith, Gen Wen, Bruce A. Hamilton, Michael G. Ziegler, Joseph L. Witztum, Nicholas J. Schork, Geert W. Schmid-Schönbein, Daniel T. O'Connor

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: 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. METHODS: 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 (h). 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. RESULTS: MZ and DZ twin variance components indicated substantial h for CRP, at ∼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/β-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (β1-adrenergic receptor) and ADRB2 (β2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to ∼6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted ∼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). CONCLUSIONS: 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/β-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.

Original languageEnglish (US)
Pages (from-to)329-343
Number of pages15
JournalJournal of Hypertension
Volume25
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

Fingerprint

Twin Studies
Adrenergic Agents
C-Reactive Protein
Blood Pressure
Inflammation
Phenotype
Tyrosine 3-Monooxygenase
Triglycerides
Body Mass Index
Leptin
Genetic Pleiotropy
Dizygotic Twins
Monozygotic Twins
Biosynthetic Pathways
Hypertension
Adrenergic Receptors
Haplotypes
Single Nucleotide Polymorphism
Genotype
Heredity

Keywords

  • Adrenergic
  • Catecholamine
  • Hypertension
  • Inflammation
  • Metabolic
  • Receptor
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology

Cite this

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/β-adrenergic pathway loci. / Wessel, Jennifer; Moratorio, Guillermo; Rao, Fangwen; Mahata, Manjula; Zhang, Lian; Greene, William; Rana, Brinda K.; Kennedy, Brian P.; Khandrika, Srikrishna; Huang, Pauline; Lillie, Elizabeth O.; Shih, Pei An Betty; Smith, Douglas W.; Wen, Gen; Hamilton, Bruce A.; Ziegler, Michael G.; Witztum, Joseph L.; Schork, Nicholas J.; Schmid-Schönbein, Geert W.; O'Connor, Daniel T.

In: Journal of Hypertension, Vol. 25, No. 2, 02.2007, p. 329-343.

Research output: Contribution to journalArticle

Wessel, J, Moratorio, G, Rao, F, Mahata, M, Zhang, L, Greene, W, Rana, BK, Kennedy, BP, Khandrika, S, Huang, P, Lillie, EO, Shih, PAB, Smith, DW, Wen, G, Hamilton, BA, Ziegler, MG, Witztum, JL, Schork, NJ, Schmid-Schönbein, GW & O'Connor, DT 2007, '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/β-adrenergic pathway loci', Journal of Hypertension, vol. 25, no. 2, pp. 329-343. https://doi.org/10.1097/HJH.0b013e328011753e
Wessel, Jennifer ; Moratorio, Guillermo ; Rao, Fangwen ; Mahata, Manjula ; Zhang, Lian ; Greene, William ; Rana, Brinda K. ; Kennedy, Brian P. ; Khandrika, Srikrishna ; Huang, Pauline ; Lillie, Elizabeth O. ; Shih, Pei An Betty ; Smith, Douglas W. ; Wen, Gen ; Hamilton, Bruce A. ; Ziegler, Michael G. ; Witztum, Joseph L. ; Schork, Nicholas J. ; Schmid-Schönbein, Geert W. ; O'Connor, Daniel T. / 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/β-adrenergic pathway loci. In: Journal of Hypertension. 2007 ; Vol. 25, No. 2. pp. 329-343.
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abstract = "BACKGROUND: 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. METHODS: 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 (h). 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. RESULTS: MZ and DZ twin variance components indicated substantial h for CRP, at ∼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/β-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (β1-adrenergic receptor) and ADRB2 (β2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to ∼6.6{\%} of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted ∼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). CONCLUSIONS: 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/β-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.",
keywords = "Adrenergic, Catecholamine, Hypertension, Inflammation, Metabolic, Receptor, Tyrosine hydroxylase",
author = "Jennifer Wessel and Guillermo Moratorio and Fangwen Rao and Manjula Mahata and Lian Zhang and William Greene and Rana, {Brinda K.} and Kennedy, {Brian P.} and Srikrishna Khandrika and Pauline Huang and Lillie, {Elizabeth O.} and Shih, {Pei An Betty} and Smith, {Douglas W.} and Gen Wen and Hamilton, {Bruce A.} and Ziegler, {Michael G.} and Witztum, {Joseph L.} and Schork, {Nicholas J.} and Schmid-Sch{\"o}nbein, {Geert W.} and O'Connor, {Daniel T.}",
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language = "English (US)",
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pages = "329--343",
journal = "Journal of Hypertension",
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TY - JOUR

T1 - C-reactive protein, an 'intermediate phenotype' for inflammation

T2 - Human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/β-adrenergic pathway loci

AU - Wessel, Jennifer

AU - Moratorio, Guillermo

AU - Rao, Fangwen

AU - Mahata, Manjula

AU - Zhang, Lian

AU - Greene, William

AU - Rana, Brinda K.

AU - Kennedy, Brian P.

AU - Khandrika, Srikrishna

AU - Huang, Pauline

AU - Lillie, Elizabeth O.

AU - Shih, Pei An Betty

AU - Smith, Douglas W.

AU - Wen, Gen

AU - Hamilton, Bruce A.

AU - Ziegler, Michael G.

AU - Witztum, Joseph L.

AU - Schork, Nicholas J.

AU - Schmid-Schönbein, Geert W.

AU - O'Connor, Daniel T.

PY - 2007/2

Y1 - 2007/2

N2 - BACKGROUND: 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. METHODS: 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 (h). 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. RESULTS: MZ and DZ twin variance components indicated substantial h for CRP, at ∼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/β-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (β1-adrenergic receptor) and ADRB2 (β2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to ∼6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted ∼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). CONCLUSIONS: 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/β-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.

AB - BACKGROUND: 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. METHODS: 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 (h). 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. RESULTS: MZ and DZ twin variance components indicated substantial h for CRP, at ∼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/β-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (β1-adrenergic receptor) and ADRB2 (β2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to ∼6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted ∼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). CONCLUSIONS: 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/β-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.

KW - Adrenergic

KW - Catecholamine

KW - Hypertension

KW - Inflammation

KW - Metabolic

KW - Receptor

KW - Tyrosine hydroxylase

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