Details on Studies

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Genome-wide study of early coronary artery disease

From the article: “A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) Family Heart Study” by Samani NJ, Burton P, Mangino M et al. American Journal of Human Genetics 2005.
Methods: A genome-wide “linkage analysis” looking at areas of the genome that are associated with a high risk of early heart disease. The study involved 1,933 families in the United Kingdom with two or more living siblings with heart disease before age 66 years. This amounted to 4,175 individuals in total available for genotyping.
Results: The authors were able to exclude 99.6% of the genome as having any significant influence on the risk early heart disease. Of the remaining regions of the genome, certain genes on chromosome 2 were strongly associated with increased risk of early heart disease. These genes included the IL-1 gene cluster.
“These findings, taken together, strongly suggest that there is a locus influencing coronary atherosclerosis risk in this region of chromosome 2.” In this region “…there are several attractive potential candidate genes with cardiovascular effects. These include, for example, the interleukins 1A and 1B clusters and protein C. Interleukin 1B polymorphisms have recently been found to associate with risk of premature MI (Iacoviello et al. 2005)”.

IL-1 gene variations associated with early heart attacks in Italian population

From the article: “Polymorphisms of the Interleukin-1β gene affect the risk of myocardial infarction and ischemic stroke at young age and the response of mononuclear cells to stimulation in vitro” by Iacoviello L, Di Castelnuovo A, Gattone M et al. Arterioscler Arteriosclerosis, Thrombosis, and Vascular Biology 2005.
Methods: The study looked at IL-1 gene variations in 406 patients with a heart attack at a young age, compared to 419 healthy controls matched for age and sex, and 134 patients experiencing a stroke at a young age compared to 134 controls and matched accordingly.
Results: Certain IL-1 gene variations were associated with a protective effect, or lower risk of early heart attack or stroke in this population (heart attack odds ratio [OR], 0.36; 95% CI, 0.20-0.64; stroke OR, 0.32 95% CI, 0.13-0.81).

These ‘protective’ IL-1 gene variations are associated with decreased expression of inflammatory mediators; immune (mononuclear) cells sampled from these individuals expressed lower levels of IL-1β and tissue factor (TF). Such findings suggest a muted inflammatory response, and particularly reduced inflammation-activated coagulation.

Further analysis identified a two-fold higher risk of heart attack in people with IL-1 gene variations consistent with IL-1 Risk Patterns. For one gene variation, the heart attack odds ratio [OR] was 2.1; (P = 0.003); for another; it was 1.8 (P = 0.02)
“Our data support a primary role of inflammation-activated coagulation in the development of MI and ischemic stroke at a young age and give the first evidence that the association between IL-1β and ischemic disease at young age is genetically modulated.” “The evidence for an association between IL-1β genetics and the risk of myocardial infarction and ischemic stroke suggests a primary pathogenic role of inflammation in such diseases,”

Mayo clinic study

From an article (unpublished data, Interleukin Genetics) by Berger P, Huttner K, Rogus J, Kornman K, Duff G.
Methods: A study of 504 consecutive patients undergoing coronary artery angiography, primarily due to chest pain, valve disease, or abnormal cardiac test results, at the Mayo Clinic catherization laboratory.
Results: After adjusting for standard risk factors, such as hypertension and blood lipids, three IL-1 genetic patterns were significantly associated with an increased risk for history of a myocardial infarction

Pattern 1 at risk genotypes	Odds ratio	P-value
1a	4.3	0.01
1b	4.1	0.02
1c	7.0	0.003

After full adjustment for age, gender, smoking, family history for MI, hypertension and hyperlipidemia, individuals positive for the CVD test (1a, 1b, 1c) had at least a 2-fold increased risk of heart attack as compared to those in the lowest genetic risk group.

IL-1 gene variations predict levels of inflammation in the body

From the article: “IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1β and C-reactive protein” by Rogus J, Beck JD, Offenbacher S et al. Human Genetics 2008.
Methods: Participants of this study were assessed for IL-1 gene variations. Levels of IL-1β in gingival tissue fluid (fluid between tooth and gum) and CRP in blood were measured in 900 people aged 45-65 years participating in the ‘ARIC’ study. In a separate population of 75 healthy individuals, immune (mononuclear) cells were sampled and IL-1β levels measured following artificial stimulation in the lab.
Results: Gene variations similar to IL-1 Risk Patterns were linked to higher levels of IL-1β in gingival tissue fluid samples, some of which were also linked to higher CRP levels in blood. These same gene variations were found to be linked to higher levels of IL-1β production by stimulated mononuclear cells as well.

Elevated CRP levels are associated with increased risk of heart attack

From the article: “Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events” by Ridker PM, Rifai N, Rose L et al. New England Journal of Medicine 2002.
Methods: Levels of CRP and LDL were measured in 27,939 healthy women who were then monitored for cardiovascular events over an 8-year period.
Results: People with elevated levels of CRP had at least a 2-fold increased chance of a heart attack compared to those with lower levels, after adjusting for age and risk factors. Compared to the 20% of people with the lowest levels of CRP, the OR for heart attack was 2.3 for the 20% with the highest levels of CRP. (P < 0.001) for trend). In people with elevated LDL levels, a known risk factor for heart attacks, prediction of heart attack risk was improved by measuring CRP.
“These data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.”

IL-1 gene variations are associated with higher blood levels of C-reactive protein

From the article: “C-reactive protein levels are influenced by common Il-1 gene variations” by Berger P, McConnell JP, Nunn M et al. Cytokine 2002.
Methods: Levels of CRP and IL-1 gene variations were measured in 454 individuals undergoing coronary angiography.
Results: Levels of CRP were found to be higher in females than males, and in smokers compared to non-smokers. Genetic variations consistent with IL-1 Risk Patterns were linked to a two to three-fold increase in CRP levels in these individuals, compared to gene variations consistent with Non-Risk Patterns. The increase in CRP levels remained significant even after adjusting for standard risk factors (i.e. gender, smoking, age).
“Data from this study indicate that systemic inflammation, as reflected by elevated CRP levels, is strongly and independently influenced by IL-1 genetic polymorphisms that are commonly found in the population. These IL-1 polymorphisms, together with factors such as gender, smoking and age, may explain why some individuals have chronically high CRP levels.”

Certain markers of cardiovascular risk are relevant only in people with IL-1 Risk Patterns

From the article: “Oxidized phospholipids, Lp(a) Lipoprotein, and coronary artery disease” by Tsimikas S, Brilakis ES, Miller ER et al. New England Journal of Medicine 2005 and American College of Cardiology Meeting abstract: “The influence of oxidized phospholipids and Lp(a) lipoprotein on coronary artery disease is conditional upon genotype at the Interleukin-1 region” by Tsimikas S, Duff GW, Berger PB et al. 2007.
Methods: Levels of two novel markers for risk of early heart disease, OxPL and Lp(a), were measured in 504 individuals undergoing coronary angiography (Tsimikas et al., 2005)..The association between OxPL or Lp(a) levels and the presence of coronary artery disease was then determined according to IL-1 Risk Patterns (Tsimikas et al., 2007). Individuals with > 50% blockage (stenosis) of the artery were considered to have coronary artery disease.
Results: People testing positive for IL-1 Risk Patterns who had elevated OxPL levels had a significantly greater risk of coronary artery disease , and particularly of early heart disease, compared to those with the lowest levels [OR = 2.52 (P = 0.01) for all patients and OR = 6.92 (P < 0.001) for patients ≤ 60 years old when comparing highest to lowest quartile]. Such a relationship between OxPL levels and heart disease risk was not found in people who tested negative for I-L1 Risk Patterns. Similar trends were seen when Lp(a) was used as a marker of early heart disease risk.
“The influence of OxPL and Lp(a) on CAD is conditional upon IL-1 genotype status”.

Consumption of certain foods is linked to reduced CRP levels

From the article: “Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in U.S. adults” by Chun OK, Chung S-J, Clycombe KJ, Song WO., The Journal of Nutrition 2008 and the review article: “Impact of C-reactive protein on disease risk and its relation to dietary factors” by Nanri A, Moore MA, Kono S. Asian Pacific Journal of Cancer Prevention 2007.
Methods: The link between dietary flavonoid (ie, plant metabolites with anti-oxidant properties) intake and CRP levels were assessed in a cross-sectional study of 8,335 adults participating in the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2002. Participants’ recall of their dietary intake of flavonoids over a 24-hour period was determined and analyzed with respect to their CRP levels.
Results: People eating higher amounts of apples or vegetables, or who had higher intake of flavonoids such as flavonol, anthocyanidin and isoflavone also had lower CRP levels (P < 0.05). These trends occurred even after adjusting for other variables thought to influence CRP levels (e.g. gender, age, ethnicity, BMI, current smoking, exercise, vitamin C, vitamin E, and carotene intakes).

A general review of dietary factors and their relation to CRP levels can be found in Nanri 2007.

“Daily intake of specific foods and flavonoids have anti-inflammatory potential beyond the benefits of fruit and vegetable consumption and thus may reduce CVD risks” and “Intake of flavonoid-rich foods may thus reduce inflammation-mediated chronic diseases.”

A botanical tablet is linked to reduced CRP levels in people with IL-1 Risk Patterns

From the article: “Interleukin-1 genotype-selective inhibition of inflammatory mediators by a botanical: a nutrigenics proof of concept” by Kornman K, Rogus J, Roh-Schmidt H et al. Nutrition 2007.
Methods: In a prospective clinical trial, IL-1 Risk Patterns were assessed in 79 healthy adults who then received 12 weeks of dosing of a botanical formation including rose hips, a blueberry and blackberry mixture and a grapevine extract.
Results: After 12 weeks of the botanical formulation, levels of IL-1β production by stimulated blood mononuclear cells were reduced in both individuals testing positive and negative for the IL-1 Risk Pattern, but the reduction was much greater in people who tested positive (61% and 44% reduction compared to placebo in people testing positive and negative respectively). More subjects testing positive for the IL-1 Risk Pattern showed a greater than 20% reduction in CRP levels by the end of the 12 week period compared to those testing negative (P = 0.08).
“This nutrigenetics clinical trial demonstrated that a botanical mixture targeting IL-1 production and response was able to significantly reduce IL-1β gene expression and CRP in healthy individuals carrying gene variations that are associated with overexpression of IL-1.”

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