CRP-gone with the Century

C-reactive Protein ─ Gone with the Century 

  • Elevated plasma  level of high- sensitive C-reactive protein (hs-CRP) is  an inflamatory marker that is closely associated with  obesity, metabolic syndrome, diabetes, and  cardiovascular disease (CVD) events  such as heart attack.1 Circulating CRP level has been proposed as biomarker for CVD risk prediction and as a selection marker for initiating statin treatment.2
  • Obesity and hs-CRP levels are inextricably intertwined with more than 70% of obese women and more than 50% of obese men having elevated levels and vice versa.3-5  More than two thirds of Americans and Indians are overweight or obese and obesity was the strongest predictor of hs-CRP levels.6 CRP is just one of the several biomarkers in the vascular biology of obesity.3  Likewise smokers have 38% higher CRP levels than nonsmokers.
  • CRP is an acute phase reactant synthesized by the liver and therefore unspecific for local processes such as coronary stenosis. There is currently controversy over whether CRP plays a causal role in atherosclerosis with more evidence are against than for a causal role. Transgenic rabbits that express high amounts of human CRP have no evidence of aortic or coronary atherosclerosis, despite evidence of CRP in the vessel wall.7
  • Evidence from animal models and human genetic studies (using the Mendelian randomization principle) also refute the causative role for CRP.8-14  Genotype combinations of the four CRP polymorphisms were associated with a lifelong 64% increase in CRP level but no increase in CVD in a large population –based sample.14, 15
  • An analysis of genetic data on 82,725 subjects from 25 studies identified 18 genetic loci that are associated with serum CRP levels. However, these single-nucleotide polymorphisms were not associated with incident heart attacks or CAD, either individually or in combination.  Specifically the study found no association between genetically elevated CRP and risk of CAD.16
  • Recent meta-analysis shows that CRP concentration has continuous associations with not only the risk of CVD, but also with several cancers and lung disease that are each of broadly similar size and questions the value of its clinical use.8
  • CRP levels vary markedly by ethnicity, even after adjustments for age, body-mass index, smoking, and polymorphisms in the CRP gene. African Americans had the highest CRP levels, with an average of 2.6 mg/L, followed by Hispanics (2.51 mg/L), South Asians (2.34 mg/L), and whites (2.03 mg/L). East Asians had the lowest CRP levels, at 1.01 mg/L.9  Based on these figures, more than half of all Americans would likely exceed the 2-mg/L CRP threshold at 50 years of age.9
  • Women have 30% higher CRP than men. Among the 3154 women enrolled in the Study of Women’s Health Across the Nation (SWAN), CRP levels varied with ethnicity. African-American women had the highest median CRP concentrations (3.2 mg/L), followed by Hispanic (2.3 mg/L), white (1.5 mg/L), Chinese (0.7 mg/L), and Japanese (0.5 mg/L) women. Body mass index (BMI) markedly attenuated the association between ethnicity and CRP.17
  • Several studies the UK, US, and Canada have demonstrated higher levels high sensitivity CRP (hs-CRP) in Asian Indians in than in Europids.18-22 This is due to greater abdominal obesity and insulin resistance.5, 18, 19, 23 Differences in CRP levels between south Asians and other ethnic groups have been found in children as young as 10 years of age.24
  • A large body of recent literature suggests minimal clinical utility of CRP levels in risk assessment and decision making for lipid-lowering therapy. Although environmental factors such as obesity, smoking, and hormone therapy influence levels of serum CRP, genes play an important role in determining serum CRP levels. Adding hs CRP do not add to CAD risk prediction on top of FRS and CAC.25, 26
  • A new analysis of the data from ASCOT─ a primary prevention trial and Heart Protection Study─ a secondary prevention trial showed outcome benefit of similar magnitude in people with low, medium and high CRP levels. In the Heart Protection Study, the significant benefit was observed in people with low LDL-C (<125mg/dl) and the lowest CRP concentrations.27
  • In the MESA study, hsCRP as defined by JUPITER (>2mg/dl) was weakly associated with silent heart disease as evidenced by high CACS. In contrast obesity was associated with increased atherosclerosis independent of hsCRP status.3  There was no multiplicative interaction between hs CRP and obesity.3
  • A new analysis of the MESA Study that evaluated 1451 “JUPITER-like” subjects (LDL-C <130mg/dl, no lipid-lowering therapy, no diabetes and hsCRP >2 mg/dl) has also demonstrated the futility of measuring CRP levels to identify high risk individuals. In this presumably high risk subgroup, the CVD events rate was less than 1 per 1000 person-years.3
  • In this analysis, coronary artery calcium score (CACS) was the major determinant of CVD events, conferring a 10-fold increased risk of a CVD event with the presence of any calcium. Approximately 2/3 of all events occurred in the 15% of patients with CACS >100 (a rate of 19 per 1000 person-years).  The number needed to treat (NNT) was 714 among those with zero CAC which decreased to 25 among those with CAC >100. 3
  • The recommended LDL-C is <100mg/dl for primary prevention for Asian Indians because of the heightened risk of malignant CAD in this population.28 Mounting evidence indicates that the  principal villain for the malignant heart CAD in young Asian Indians is the genetically determined high levels of Lp(a).29 The adverse effects of all lifestyle related modifiable risk factors are markedly magnified in people with high Lp(a) levels.30
  • These data highlight the futility of measuring CRP and the usefulness of CACS measurement in identifying patients with low LDL-C for statin therapy (see heart scan).

Sources

1. Ridker PM, Wilson PW, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation. Jun 15 2004;109(23):2818-2825.

2. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. Nov 20 2008;359(21):2195-2207.

3. Blaha MJ, Rivera JJ, Budoff MJ, et al. Association Between Obesity, High-Sensitivity C-Reactive Protein >=2 mg/L, and Subclinical Atherosclerosis: Implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. Jun 2011;31(6):1430-1438.

4. Meng KC, Sairazi S, Taslim S, et al. Ethnicity Modifies the Relationships of Insulin Resistance, Inflammation, and Adiponectin With Obesity in a Multi-Ethnic Asian Population. Diabetes Care. Apr 4 2011.

5. Jeemon P, Prabhakaran D, Ramakrishnan L, et al. Association of high sensitive C-reactive protein (hsCRP) with established cardiovascular risk factors in the Indian population. Nutrition & metabolism. Mar 28 2011;8(1):19.

6. Cushman M, McClure LA, Howard VJ, Jenny NS, Lakoski SG, Howard G. Implications of increased C-reactive protein for cardiovascular risk stratification in black and white men and women in the US. Clinical chemistry. Sep 2009;55(9):1627-1636.

7. Koike T, Kitajima S, Yu Y, et al. Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation. Nov 24 2009;120(21):2088-2094.

8. Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. Jan 9 2010;375(9709):132-140.

9. Shah T, Newcombe P, Smeeth L, et al. Ancestry as a determinant of mean population C-reactive protein values: implications for cardiovascular risk prediction. Circ Cardiovasc Genet. Oct 1 2010;3(5):436-444.

10. Trion A, de Maat MP, Jukema JW, et al. No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-leiden/human C-reactive protein transgenic mice. Arteriosclerosis, thrombosis, and vascular biology. Aug 2005;25(8):1635-1640.

11. Kovacs A, Tornvall P, Nilsson R, Tegner J, Hamsten A, Bjorkegren J. Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia. Proceedings of the National Academy of Sciences of the United States of America. Aug 21 2007;104(34):13768-13773.

12. Casas J P, Shah T, Cooper J, et al. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol. Aug 2006;35(4):922-931.

13. Lawlor DA, Harbord RM, Timpson NJ, et al. The association of C-reactive protein and CRP genotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants. PLoS ONE. 2008;3(8):e3011.

14. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med. Oct 30 2008;359(18):1897-1908.

15. Elliott P, Chambers JC, Zhang W, et al. Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. Jul 1 2009;302(1):37-48.

16. Dehghan A, Dupuis J, Barbalic M, et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple Loci for C-reactive protein levels. Circulation. Feb 22 2011;123(7):731-738.

17. Kelley-Hedgepeth A, Lloyd-Jones DM, Colvin A, et al. Ethnic differences in C-reactive protein concentrations. Clinical chemistry. Jun 2008;54(6):1027-1037.

18. Chambers JC, Eda S, Bassett P, et al. C-reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European Whites. Circulation. 2001;104(2):145-150.

19. Anand SS, Razak F, Yi Q, et al. C-reactive protein as a screening test for cardiovascular risk in a multiethnic population. Arteriosclerosis, thrombosis, and vascular biology. Aug 2004;24(8):1509-1515.

20. Forouhi NG, Sattar N, McKeigue PM. Relation of C-reactive protein to body fat distribution and features of the metabolic syndrome in Europeans and South Asians. Int J Obes Relat Metab Disord. 2001;25(9):1327-1331.

21. Chandalia M, Cabo-Chan AV, Jr., Devaraj S, Jialal I, Grundy SM, Abate N. Elevated plasma high-sensitivity C-reactive protein concentrations in Asian Indians living in the United States. The Journal of clinical endocrinology and metabolism. Aug 2003;88(8):3773-3776.

22. Chandalia M, Abate N, Cabo-Chan AV, Jr., Devaraj S, Jialal I, Grundy SM. Hyperhomocysteinemia in Asian Indians living in the United States. The Journal of clinical endocrinology and metabolism. 2003;88(3):1089-1095.

23. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. 1998;97(20):2007-2011.

24. Cook D G, Mendall MA, Whincup PH, et al. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factors. Atherosclerosis. Mar 2000;149(1):139-150.

25. Mohlenkamp S, Lehmann N, Moebus S, et al. Quantification of coronary atherosclerosis and inflammation to predict coronary events and all-cause mortality. J Am Coll Cardiol. Mar 29 2011;57(13):1455-1464.

26. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol. Jul 5 2005;46(1):158-165.

27. Heart Protection Study Collaborative G. C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20 536 patients in the Heart Protection Study. Lancet. Feb 5 2011;377(9764):469-476.

28. Enas  EA, Singh V, Gupta R, Patel R, et al. Recommendations of the Second Indo-US Health Summit for the prevention and control of cardiovascular disease among Asian Indians. Indian heart journal. 2009;61:265-74.

29. Enas EA. Lipoprotein(a) is an important genetic risk factor for coronary artery disease in Asian Indians. Am  J  Cardiol. 2001;88:201-202.

30. Enas EA, Chacko V, Senthilkumar A, Puthumana N, Mohan V. Elevated lipoprotein(a)–a genetic risk factor for premature vascular disease in people with and without standard risk factors: a review. Dis Mon. Jan 2006;52(1):5-50.

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