Inflammation & Treatment



Inflammation Is Critical To Many Chronic Diseases

Inflammation is the overt expression of the body’s protective mechanism in response to a challenge. Individuals with different IL-1 genetic variations have different clinical trajectories of certain diseases. The critical question relative to genetics of complex diseases is whether gene variations have sufficient biological effects to alter clinically measurable outcomes. IL-1 expression is a characteristic of the pathogenesis of several diseases, including rheumatoid arthritis, inflammatory bowel disease, cardiovascular disease, chronic periodontitis, and osteoporosis.

IL-1 genetic variations do not cause the disease, but rather modify the course of disease development. Individuals with certain IL-1 gene variations appear to develop several chronic diseases earlier. Some disease initiator, i.e. the challenge to the body’s tissues, must be present. For example in heart disease certain types of cholesterol appear to be the disease initiator and some level of this challenge must be present for the biological changes to occur that lead over time to clinical signs of disease. If the disease challenge is present, there are various modifiers that determine how the body reacts to the challenge. This may mean that a) lower levels of cholesterol in certain individuals produce the same disease as in other individuals with higher cholesterol, or b) at the same level of cholesterol, the disease progresses faster in certain individuals than in other individuals. Those disease modifiers include “acquired” factors, such as smoking and diabetes, and genetic factors. The modifiers work by producing different biochemical responses in different individuals. The more powerful the modifying factor, and the more it is at the head of multiple cascades, the greater the demonstrable influence on downstream biochemical factors. If the biochemical changes attributable to the modifying factors are important to disease expression, individuals will show different patterns of disease development over time.

In the past ten years specific IL-1 gene variations have been associated with earlier onset or more severe disease expression of Alzheimer’s disease, cardiovascular disease, osteoporosis, periodontal disease, and others. Intellectual property patents have been issued to ILGN on many of these conditions. Some studies, however, have failed to show any such correlations. The interpretation of studies of associations between candidate gene variations and clinical disease is complicated, often due to the use of SNPs that do not adequately represent the variation in the candidate gene and the use of imprecise clinical endpoints.

Alzheimer’s Disease
IL-1 has been implicated as a key molecule in Alzheimer’s disease (AD). IL-1 is markedly over-expressed in the Alzheimer brain and is directly involved in the pathogenesis of the disease. Genetic studies evaluating IL-1 genetic variations in both Alzheimer and control patients show that specific homozygous genotypes confer an increased risk for the development of AD at an earlier age of onset. This risk is further increased when the specific variations are put into a composite genotype including multiple variations.

Asthma and Pulmonary Fibrosis
Asthma is a chronic lung disease due to a reversible obstruction of airflow resulting from inflammation and hyper-responsiveness of the airways. Interleukin Genetics has demonstrated that certain variations (SNPs) in the IL-1 and IL-13 genes produce lifelong tendencies to have more inflammation or qualitative differences in inflammatory mechanisms. The patent was based on studies by ILGN and collaborators that show specific gene variations may be used as part of a medical assessment to predict an individual’s response to different asthma drugs (pharmacogenetics), and to identify individuals who are likely to develop more severe asthma. One major characteristic of those that do develop the more severe disease state is the development of persistent inflammation in the airway wall. Tests based on genetic variations, such as those described in the Interleukin patent, should be useful in identifying individuals at risk for more severe cases of Obstructive Airway Disease and for selection of the best drug therapy to assist in the early management of asthma.

Cardiovascular Disease
Inflammation is a crucial factor in the process that leads to heart disease and subsequent heart attacks. Studies conducted by ILGN have demonstrated that certain variations in the IL-1 gene can amplify inflammation in the arteries, and make an individual at least two times more likely to develop clinically significant heart disease prior to age 60.

Approximately one-half of all first heart attacks cannot be predicted. Because the victims do not smoke, are not obese, do not have high cholesterol, and do not have a family history of heart disease, their heart attacks are unexpected. But prior knowledge of the IL-1 genetic risk factor may ultimately prompt many individuals to better manage their cardiovascular health.

Diabetic Complications
Chronic inflammation is now a well-recognized risk factor in the development of diabetes mellitus and its complications. ILGN was awarded a patent for a method that uses specific genetic markers to identify those persons with diabetes who are at an increased risk of sight-threatening retinopathy. Studies conducted by ILGN have demonstrated that certain variations (SNPs) in the IL-1 genes produce lifelong tendencies to have more inflammation or qualitative differences in inflammation mechanisms.

The patent is based on the discovery that individuals with diabetes who have certain common variations in the IL-1 genes have an increased risk for diabetic retinopathy and an increased risk of blindness. This knowledge can provide new targets for development of drugs to better manage the risk in persons with diabetes who have these gene variations.

Gastric Cancer
IL-1 genetic variations are associated with gastric cancer. The gastrointestinal disorders of chronic gastritis, peptic ulcers, and gastric cancer are initiated by Helicobacter pylori, a Gram-negative microorganism. Although H. pylorus is an essential requirement for development of gastric cancer, disease appears to require a susceptible host. Between 2000 and mid-2005, 26 studies on the association of IL-1 genetics and gastric cancer have been published, of which twenty-one found significant positive associations with IL-1 genotype, although the specific genotypes differed somewhat in Caucasians and Asians. Most of the studies have evaluated the influence of IL-1 genetics in individuals with documented H. pylori infection and have shown individuals with specific IL-1 genotypes had a three-fold increased risk for cancer. In general, current studies in both Asian and Caucasian populations indicate that SNPs that are part of the IL-1 haplotype #2 are involved in the increased host susceptibility to gastric cancer in individuals infected with H. pylori.

Intestinal Diseases and Conditions
A genetic predisposition to suffer from chronic inflammatory bowel diseases (IBD) _ Crohns disease (CD) and ulcerative colitis (UC) _ is well recognized. Both CD and UC patients can be sub-divided into a number of subgroups based on the course of the disease, clinical markers, and pathology. These differences are to a certain extent genetically determined. In the patho-physiology of IBD, IL-1 is a central element in the regulation of inflammation both systemically and at the mucosal level of the gastrointestinal tract. In healthy individuals the inter-individual variations found in in vitro production of IL-1 protein appear to be genetically determined. Two bi-allelic base-exchange polymorphisms described in the IL-1 beta gene (IL1B) influence IL-1b production. One is in the promoter region, at position _511(IL1B-511), the other is in exon 5 at position c3953 (IL1Bc3953).

Menopause (Early-onset)
Studies conducted by ILGN demonstrate how certain variations (SNPs) in the IL-1 genes produce lifelong tendencies to have more inflammation or qualitative differences in inflammatory mechanisms. Chronic inflammation is now a well-recognized biological mechanism that influences numerous conditions, including a variety of hormonally regulated processes, such as early-onset menopause, also known as premature ovarian failure. Typically, menopause occurs in a woman’s late 40s or early 50s. However, premature ovarian failure occurs in up to one percent of women before age 40. But up to 30 percent of women with premature ovarian failure have at least one female relative with the same condition, strongly suggesting that many cases are influenced by genetic predisposition. Early menopause is an important risk factor for osteoporosis, so the ability to identify women who are at increased risk for early menopause may provide new opportunities to reduce the risk for or delay the onset of osteoporosis in those individuals.

ILGN has patented the discovery that certain common variations in the IL-1 (IL-1) genes are associated with an increased risk for osteoporosis. The IL-1 SNPs being analyzed for osteoporosis are used to differentiate certain IL-1 genotypes with varying inflammatory responses and to identify individuals at risk for adverse clinical events, e.g., vertebral fractures. Inflammation leads to accelerated osteoclastic (bone degradation) activity resulting in accelerated bone loss and osteoporosis. Simply stated, evidence supports that IL-1 is at the critical control point for levels of inflammation. Individuals with specific IL-1 genetic patterns vary the level of IL-1 expression and inflammatory response that, in specific IL-1 genotypes, leads to an over-expression of inflammation and increased bone degradation. Individuals with these IL-1 genotypes have an increased risk for vertebral fractures.

Periodontal Disease
ILGN’s first genetic susceptibility test, PST, identifies patients at risk for rapid progression of periodontitis. Periodontitis is a bacterial induced chronic inflammation that destroys the collagen fibers and bone that surround and support the teeth. Untreated, periodontitis will eventually result in tooth loss.

PST was the result of the discovery of an association between specific IL-1 SNPs and severe periodontal disease. Prevention or therapeutic intervention aimed at reducing the bacterial challenge should decrease the stimulus for IL-1 production and could thereby protect the patient against the potentially destructive effects of this genotype. Based on clinical trials and commercial testing, approximately 30% of the population will test positive for this genotype.

Pregnancy Complications (Low Birth Weight)
Chronic inflammation is now a well-recognized biological mechanism that influences numerous conditions, including low birth weight, pre-term infants. Studies conducted by ILGN discovered that certain common variations in the IL-1 genes are associated with increased risk for pregnancy complications. Depending on an individual’s exact pattern of genetic variations, these variations (SNPs) in the IL-1 genes produce lifelong tendencies to have more inflammation or qualitative differences in inflammatory mechanisms that identify which pregnant women are more likely to have a pre-term, low birth weight infants.
Approximately one in every 13 babies born each year in the United States is a pre-term, low birth weight infant. In addition to being a factor in 65 percent of infant deaths, low birth weight increases the risk that babies will have serious health problems as newborns. It also is associated with an increased risk of long-term disabilities.

Investigators from the Deutsches Herzzentrum in Munich, the Mayo Clinic, and the University of Sheffield participating in a collaborative study published results of a large clinical trial showing that patients with a commonly occurring variation in a gene in the IL-1 (IL-1) gene cluster on chromosome 2 have less restenosis (artery blockage) than do persons lacking the variation after stent placement to open coronary arteries. The study included 1850 consecutive patients who underwent angioplasty and stent placement of which 84% were reexamined by angiography six months after the procedure. The investigators found that patients who had a common variation (present in at least one copy in about 48% of Caucasians) in the IL-1 receptor antagonist (IL-1ra) gene had a 22% lower risk of restenosis than those who lacked the variation. This protective effect was even more pronounced among patients under 60 in whom the risk of restenosis was 37% lower (p<. 001). The IL-1 receptor antagonist codes for a protein that suppresses inflammation by blocking the action of IL-1

Rheumatoid Arthritis
Rheumatoid Arthritis (RA) is a chronic disease of unknown cause characterized by prolonged inflammation, swelling and pain of multiple joints. ILGN has conducted preliminary studies of genetic susceptibility to Rheumatoid Arthritis. A retrospective, pharmacogenetic study to determine the association between cytokine polymorphisms and the response to anti-TNF-a therapy, specifically Enbrel was performed. The study population was selected from the United Health Group (UHG) Center for Healthcare Policy’s database with a diagnosis of rheumatoid arthritis (by code) and evidence of at least one pharmacy claim for Enbrel_ during the previous 12 months. Using criteria defined by the American College of Rheumatology, the UHG patient population comprises 300 responders to Enbrel_ (90%) and 33 non-responders (10%). For the purpose of identifying a group with potentially elevated rates of response to rheumatoid arthritis treatment, IL-1 positive (+) consisted of individuals meeting one of three conditions: 1) genotype 2.2 at IL-1A (+4845), genotype 1.1 at IL-1B (-511) and 1.1 genotype at IL-1RN (+2018), 2) genotype 2.2 at IL-1B (-511) and 2.2 genotype at IL-1RN (+2018), or 3) genotype 2.2 at IL-1B (-511) and 1.2 genotype at IL-1RN (+2018). Thirteen percent of the study population was scored as IL-1 positive and response to treatment in this group was 97% compared to 88% in the non-IL-1 positive group (statistically significant). For the purpose of identifying a group with potentially decreased rates of response to rheumatoid arthritis treatment, IL-1 negative consisted of individuals who have genotype 1.2 at IL-1B (-511) and genotype 1.2 at IL-1B (-3737). Thirty-two percent of the study population was scored as IL-1 negative and response to treatment in this group was 79% compared to 94% in the non-IL-1 negative group (statistically significant).

Each year in the United States, tens of thousands of patients develop sepsis, often after severe trauma, burns or surgery. Such patients face a high risk of mortality. In response to bacterial infection, the individual mounts an inflammatory response, a defensive strategy in which the IL-1A and IL-1B genes play a key role. Research conducted by the company indicates that common variations that are in linkage disequilibrium with a particular SNP (single nucleotide polymorphism) called IL-1B (-511) confer increased risk for dying if patients develop sepsis. In the clinical study upon which the patent application was based 31 of 128 (24%) persons diagnosed with sepsis died. In contrast, 57% of the sepsis patients who were homozygous for the IL-1B polymorphism died. That is, patients with two copies of this common polymorphism who developed sepsis were more than twice as likely to die than were those who developed sepsis but did not have the predisposing variants. ILGN has filed a patent for the discovery that common variations in the human IL-1B gene are associated with a significantly increased risk of death from sepsis (a bacterial infection of the blood).

April 1, 2005
Journal of Strength and Conditioning
Scientific Bibliography

Aug 5, 2003 (published in Journal of Rheumatology)
The Effects of a Cetylated Fatty Acid Topical Cream on Functional Mobility and Performance in Patients with Osteoarthritis

Feb 14, 2002 (published in Journal of Rheumatology)
Cetylated Fatty Acids Improve Knee Function in Patients with Osteoarthritis