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Read archived newsletters on a range of topics related to genetic testing, genomics and functional medicine by clicking on the links below.

Lifestyle Medicine and Cardiac Health

A Portrait of Genetic Risk Factors

Cardiovascular disease is a leading contributor to morbidity and mortality, with 17.3 million deaths annually worldwide. Partly genetically-inherited, it is a particular risk for adults over age 60. Cardiovascular disease – coronary heart disease, cerebrovascular disease, peripheral artery disease, and atherosclerosis — are heavily influenced by factors such as insulin resistance, hypertension, dyslipidemia, inflammation, and coagulation properties.5 We know many of these factors can be mitigated by lifestyle changes including smoking cessation, increasing aerobic exercise, and eating a well-balanced diet, which can reduce the risk of catastrophic events such as myocardial infarction, or ischemic and hemorrhagic stroke.5 However, in some cases, particularly where family history of cardiovascular disease is prevalent,1 medications are needed to better manage health outcomes. In some patients, lifestyle and medication are still not enough, and greater intervention is necessary.

Knowing a patient’s genetic stasis can help to decrease the chance of developing cardiovascular disease before it even begins. An example of this is the genetic marker 9p21 and the role it plays in the development of atherosclerosis. Recent research has identified that the genetic marker 9p21 is located between two key cell-cycle inhibitors3 (cyclin-dependent kinase inhibitors) and is strongly associated with coronary artery disease. Researchers believe that mutations in this region may affect uncontrolled cell proliferation leading to atherosclerosis, arterial stiffness, and eventually coronary artery disease. Although environmental factors such as diet or smoking play an important role in atherosclerosis development, genetic factors represent consequential determinant of atherosclerotic cardiovascular disease risk.1,2 Carrying one variant allele increases the risk of coronary artery disease by 15 to 35 percent, with the risk doubling in a person with two of these variant alleles.4

Patients with this genetic variant would benefit from increased surveillance by their doctor. Knowing a patients stasis can help the doctor diagnose atherosclerosis sooner and consequently treat the condition more aggressively. The Cardiac Health Panel gives insight into how a patient’s genetic predisposition to cardiac problems can help healthcare providers optimize diagnosis and treatment.

References

  1. Roberts R. Genetics of Coronary Artery Disease. Cir Res. 2014; 114:1890-1903.
  2. The Welcome Trust Case Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447(7145): 661-678.
  3. Genetics Home Reference. Genes: CDKN2A, http://ghr.nlm.nih.gov/gene/CDKN2A
  4. Roberts R and Stewart A. 9p21 and the Genetic Revolution for Coronary Artery Disease. Clinical Chemistry. 2012; 58(1):104-112.
  5. Palomaki, Glenn E., et al. Use of genomic profiling to assess risk for cardiovascular disease and identify individualized prevention strategies- A target evidence based review. Genet Med 2012:12(12): 772-784.

Heart Health, Brain Health and Apolipoprotein E.

The heart and the brain may seem separate at first glance, but doctors know everything is connected. Heart and brain health are important to help patients to both survive, and thrive. One of the key players in the health of these two systems is a protein by the name of Apolipoprotein E (ApoE). ApoE is an important lipid transporting protein whose job is to carry cholesterol from the blood into the cell; it is the principle cholesterol carrier of the brain.1 The gene that encodes for ApoE can produce three different isoforms of the protein depending of which allele is carried. These different isoforms can affect the body differently causing either an increase or decrease in both cardiovascular health as well as plaque formation in the brain.2 So what are the three isoforms of ApoE and how do they affect patients?

The three isoforms: ApoE2, ApoE3, and ApoE42 have different effects on the body. Of the three, ApoE3 is considered the wild type; it neither increases nor decreases the chance of developing cardiovascular disease or Alzheimer’s disease.2 People with this isoform transport cholesterol into cells at a normal rate. However people with the isoform E4 have difficulty with cholesterol transportation which causes a buildup of cholesterol in the vascular system which leads to atherosclerosis.3 Another way in which the Apoe4 isoform can affect the body is by reduced break down of peptide beta amyloid plaques (Aβ) which are seen to be high in patients with Alzheimer’s disease.4-6 Lastly the isoform E2 actually conveys a decreased chance of developing cardiovascular disease and has been shown to increase the breakdown of Aβ plaques in the neural tissue causing a protective effect to the brain.7 However in less than 2% of people with the E2/E2 genotype a condition can develop called type III hyperlipoproteinemia which is characterized by high levels of total cholesterol, LDL and triglycerides. People who have two copies of the E2/E2 allele will benefit greatly from routine lab work checking their cholesterol and triglyceride levels.2,7

Apolipoprotein E may seem like one tiny little player in the lipid transport pathway, but its variation in isoforms can have serious effects on a patient. Prior knowledge of a person’s genotype can be a huge advantage to managing their care. When a patient presents with a family history of either Alzheimer’s Disease or Cardiovascular Disease, it is worth testing the gene to understand the particular risk that patient is facing. Information confers power, knowing the risk can help both you and the patient take proactive steps to maintain health for as long as possible.

References

  1. Puglielli L, Tanzi RE, Kovacs DM (April 2003). “Alzheimer’s disease: the cholesterol connection”. Nature Neuroscience. 6 (4): 345–51. doi:10.1038/nn0403-345. PMID 12658281.
  2. Weisgrabert K., InnerarityT., Mahley R. Abnormal Lipoprotein Receptor-binding Activity of the Human E Apoprotein due to Cysteine-Arginine Interchange at a Single Site. March 10, 1982 Journal of Biological Chemistry. Vol 257. Pp. 2518-2521
  3. Mahley, Robert, Rall SC Apolipoprotein E:far more than a lipid transport protein. Annual Rev Genomics Hum Genet. 200; 1:507-37.
  4. Liu CCI, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013 Feb 9 (2):106-18. Doi: 10.1038/nrneurol. 2012.263.
  5. Liu Y1, Yu JT2, Wang HF3, Han PR4, Tan CC5, Wang C5, Meng XF5, Risacher SL6, Saykin Aj6, Tan L2. APOE genotype and neuroimaging markers of
  6. Alzheimer’s disease: systematic review and meta-analysis. Neurol Neurosurg Psychiatry. 2015 Feb;86(2):127-34. Doi: 10.1136/jnnp-2014-307719.
  7. Haung Wl, Qiu C, von Strauss E, Winblad B, Fratiglioni L. APOE genotype, family history of dementia, and Alzheimer’s disease risk: a 6-year follow-up study. Arch Neurol. 2004 Dec; 61 (12):1930-4.
  8. Mahley, Robert, Hauang, Yadong, Rall C. Stanley Jr. Pathogenesis of type III hyperlipoproteinemia (dsybetalipoporteinemia): questions, quandaries and paradoxes. Journal of Lipid Research. 1999. 40:1933-1949.

Coconut oil the Super Food

Is it Right for Everyone?

Most people who think about healthy foods think about coconut oil. With the surge of interest you can now find it in every store. But the question most people should be asking is if it is right for everyone. FABP2 is a gene that is involved in fat absorption through the digestive tract by encoding for a protein that is crucial for the effective binding of fatty acids2. Some people have an allele that causes them to absorb certain types of fatty acids more easily, this variant is called Ala54Thr2,3,4. These people have a change in the common gene that causes an amino acid conversation to take place in the fatty acid binding protein there by increasing its binding affinity for both long chain saturated fats and unsaturated fatty acids by two-fold2,3,4. It is no surprise that a person with this genetic variation might struggle with maintaining a healthy BMI.

In the past, all foods containing saturated fatty acids were thought to be unhealthy, however research concerning coconut oil has shown that not all these fats contribute to disease. Research has shown that coconut oil contains mostly medium chain triglycerides (MCT) that are formed from fatty acids of chain length 8:0 to 14:05. MCT have been shown in research studies to decrease fat deposits in comparison to consumption of other fats. Because coconut oil contains mostly medium chain triglycerides, its absorption rate is not affected by the variant FABP2.

References

  1. LIU Zhongchen CHEN Daiwen* YU Bing LV Mei MAO Xiangbing HAN Guoquan CHEN Hong MAO Qian(Key. Effects of Different Fat Sources on Growth Performance and Lipid Metabolism in Weened Piglets. www.cnki.com.cn, 2011-09.
  2. Baier Lj et al. An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding increased fat acid binding, increased fat oxidation, and insulin resistance. J Clin Invest.1995;95:1281-1287.
  3. Almeida JC et al. The Ala54Thr polymorphism of the FABP2 gene influences the postprandial fatty acids in patients with type 2 diabetes. J Cin Endocrin Met. 2010;95:3909-3917.
  4. Levy E et al. The polymorphism at codon 54 of the FABP2 gene increases fat absorption in human intestinal explants. J Biol Chem. 2001;276:39679-39684.
  5. Pehowich DJ., Gomes AV., Barnes JA., Fatty acid composition and possible health benefits of coconut oil. The West Indian Medical Journal (2000). 49(2):128-133.

MC4RGene – the Obesity Link

The escalating population prevalence of obesity and its serious implications for public health are now generally accepted. Throughout the last twenty years, the industrialized world has transitioned from low calorie density food to high calorie density food. The ease of resource distribution, the invention of trans-fats which prolonged shelf life of food, the recent unlimited availability of low-cost calorie-dense food, along with increasing sedentary lifestyle, has played a major role in the adult obesity pandemic.

The major driving force behind obesity in modern society is overeating, which is largely coded in genes that are responsible for appetite and satiety regulation. Appetite is the desire to eat, while satiety refers to the sensation of fullness after eating. The Melanocortin4 Receptor (MC4R) refers to a gene found on chromosome 18 and the receptor that this gene creates. The MC4R is located in the hypothalamus, a region of the brain responsible for appetite (among other functions). Mutations in and near the MC4R gene account for up to 6% of severe early-onset obesity cases, suggesting an important role for the central melanocortin system in the maintenance of normal body weight. MCR4 variant has been linked to obesity, diminished insulin response in the brain, altered eating behaviors, and is believed to impair MC4R function.

The MC4R allele results in a tendency for increased appetite and a preference for calorie-dense foods. However, studies in children and teens show that even though carriers of the high risk variant near MC4R are more prone to weight gain, homozygous variant carriers may be even more responsive than non-carriers or heterozygotes to lifestyle modifications. The most effective weight loss strategy for the MC4R variant carriers is calorie restriction through portion control and smart food choice.

The MC4R Variant – Diet and Lifestyle Tips

  • Limit fat in the diet. High fat diets stimulate overeating even after returning to a normal fat diet. Low fat diets reduce the risk of overeating. The ideal allocation of calories is approximately 45% Carbohydrates, 35% Protein, 20% Fat.
  • Control carbohydrate intake and focus on eating low starch carbohydrates such as cruciferous vegetables, fruit with skins, root vegetables with low sugar content such as carrots and rutabagas.
  • Eat a high fiber diet to maintain that feeling of being full for a longer period of time.
  • Eat 5+ small meals a day. MC4R genotype can have an increase tendency to snack so it is better to plan for these tendencies and spread out calories over many small meals.
  • Exercise daily. 50 minutes daily at 65-75% maximum heart rate reduces the influence of the allele. 50-60 minutes may be too large of a time frame for some people to set aside to exercise. It is okay to break this amount into 2-6 smaller intervals over the course of the day but it is important to get the full 50-60 minutes into the daily schedule. Research has shown that there is some benefit to smaller intervals of exercise more frequently in the day, but the most important thing is that the body moves for at least an hour a day to best reduce the effects of the MC4R variant on weight loss efforts.

Email us at to request the Patient Info Sheet on the MC4R Variant. Request the Poster on The Weight Management Panel – 25% discount on testing runs through the end of February, 2017.

A Leptin Resistance Solution?

Leptin is a hormone that signals the very important message, “I am not hungry”. In a culture that has easy access to tempting foods, why would anyone ever want to stop eating? The answer to this question lies in the body’s ability to feel full. Leptin is produced primarily by adipose tissue and, when the systems works the way it should, the body increases leptin levels which triggers a decrease in appetite1. At first glance this may seem like a perfect system, but just as with insulin, when the levels of leptin are high for an extended period of time, resistance to the signal develops 2. The consequence of this is called leptin resistance and it leads to an increased feeling of hunger, decreased feelings of satiety, and more eating action resulting in weight gain. This is an important survival mechanism when there is only seasonal supply of food, and when it is important to build up energy stores to be burned when less food is available. However, in modern times, when food is available all year round, leptin resistance increases the risk of a patient becoming obese.

As incidence of leptin resistance is increasing in the obese population, providers are looking for ways to improve the leptin signaling process and decrease resistance. Since leptin is a key link between nutrition and many physiologic systems, understanding leptin resistance, and possibly finding a way to intervene between insulin and leptin signaling, has become a major goal3,4. Any diet which is high in sugar, particularly fructose,5 leads to excess insulin being secreted by the body 6. Chronically elevated insulin levels help to block leptin’s negative feedback signal.7 The moral of the story here is to significantly reduce carbohydrate, especially refined, simple carbohydrate.

Genetics can also play an important role in the way the hypothalamus processes the signal leptin. Research established a gene called SH2B1 which encodes for a protein that is a positive regulator of both insulin and leptin action8. Deletion of the SH2B1 gene entirely can very easily lead to severe obesity, insulin resistance, and leptin resistance8. Some people possess a single nucleotide polymorphism (SNP) in SH2B1 called rs7498665 which has been associated with an alteration to the protein product. The SNP rs7498665 has also been strongly correlated to an increased BMI in people who possess the variant.9 Because leptin resistance is associated with receptor signaling in the hypothalamus, researchers are starting to look at the connection between this SNP in the gene SH2B1 and obesity. Understanding the influence genes have on patient presentation can help the practitioner to focus their treatment. When treating patients with the SNP rs7498665 it is important to optimize the body’s response to leptin.

As leptin resistance is better understood, treatment of this condition is becoming more important to clinicians. Some research shows that a long-term exercise strategy can be a valuable tool for gradually decreasing leptin resistance by reducing both insulin and leptin levels; however changing diet away from simple carbohydrates and saturated fats and portion control can have the greatest long term effect. Genetic testing can be a valuable tool for identifying patients that maybe at risk for leptin resistance, and can help the practitioner target their treatment protocol to each specific patient.

References

  1. Kam, Katherine. Reviewed by Martin, Laura MD (01/2010). WebMD. The Facts on Leptin: FAQ. http://www.webmd.com/diet/obesity/features/the-facts-on-leptin-faq#1
  2. Munzberg Heike, Flier Jeffrey, Bjorbaek, Christian. “Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice”. Endocrinology 145 (11) (2004) 4880-4889.
  3. Ozcan L, Ergin AS, Lu A, et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9(1):35-51.
  4. Mancour LV, Daghestani HN, Dutta S, et al. Ligand-induced architecture of the leptin receptor signaling complex. Mol Cell. 2012;48(4):655-61.
  5. Merat S, Casanada F, Sutphin M, Palinski W, Reaven PD. Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. Arterioscler Thromb Vasc Biol. 1999;19(5):1223-30.
  6. Aijälä M, Malo E, Ukkola O, et al. Long-term fructose feeding changes the expression of leptin receptors and autophagy genes in the adipose tissue and liver of male rats: a possible link to elevated triglycerides. Genes Nutr. 2013;8(6):623-35.
  7. Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of insulin-glucose axis. Front Neurosci. 2013;7:51.
  8. Maures Tj. Et al. SH2B1 (SH2-B) and JAK2: a muiltifunctional adaptor protein and kinase made for each other. Trends Endocrinol Metab. 2007; 18: 38-45.
  9. WillerCj et al. Six new loci associated with body mass index highlight a neuronal influence on bodyweight regulation. Nature Genetics. 2009:25-34.

Leptin Resistance

Goldilocks: “like porridge, leptin needs to be juuuuust right.”

Leptin is a hormone secreted primarily in white adipose fat cells and plays a role in regulating energy balance by curbing or stimulating hunger. Often referred to as the “satiety hormone,” leptin works by signaling the need to start or stop eating. In the short term, as fat supplies are reduced, leptin levels drop to signal when enough food has been consumed per meal.

Leptin levels vary exponentially, not linearly, with fat mass.1,2” White fat, or white adipose tissue, is traditionally linked to the development of obesity, heart disease and diabetes, because it stores up calories, in contrast to brown fat which burns calories to generate heat.

Leptin also works on a more seasonal basis. Leptin is released from the body’s fat base and is a longer term signaling mechanism to indicate when it is time to build more fat supplies to ensure survival. If fat supplies are adequate, then leptin levels will be high. If fat supplies are low, then the corresponding lower leptin levels will signal that it is time to eat carbohydrates to rebuild fat supplies. This is a natural metabolic feedback mechanism that plays out for multiple species.

It is possible however for the body to become leptin resistant, just as it is possible to become insulin resistant. High circulating levels of leptin can result in downregulation of leptin receptors. As a result, the elevated levels of leptin fail to signal the need to stop eating. Over eating and the associated incremental weight gain is common with leptin resistance.

The SH2B adapter protein 1 (SH2B1) has been identified as a positive regulator of insulin, IGF–1 and leptin action.4-7 It is well known that insulin’s primary role is to regulate glucose and lipid metabolism. SH2B1 deletion results in marked insulin and leptin resistance, obesity, and type 2 diabetes in mice as well as humans, indicating that SH2B1is required for the maintenance of normal body weight, insulin sensitivity, and glucose metabolism.7-12 In addition, it has been consistently demonstrated that SNPs in the SH2B1 gene are associated with obesity and/or BMI. The rs7498665 SNP of the SH2B1 gene, which is included in the Kashi Health Weight Management Genetic Panel, results in the non-synonymous amino acid exchange Thr484Ala in a splice variant-independent position with low conservation. The association of increased BMI with SH2B1 SNP (rs7498665 and/or rs7359397) risk alleles has been robustly replicated in a study of 249,796 individuals of European ancestry,13 and in 34,416 subjects of various ethnicities14. Another study, conducted in 1,700 Dutch women, 15 demonstrated that the risk allele at rs7498665 was associated with increased intake of total fat (per allele effect: 1.08 g/d), saturated fat (per allele effect: 0.60 g/d) and monounsaturated fat (per allele effect: 0.37 g/d). These results suggest that consumption of a diet high in fat, and particularly a diet high in saturated fat, places people who possess the SH2B1 risk allele at a greater risk of obesity.

The Kashi Health Weight Management Panel provides valuable genetic data so you can offer the best guidance to each of your patients on their ideal diet approaches for individualized weight loss goals. The lifestyle recommendations support the work you are doing by identifying key eating and exercise strategies. Call 877-879-1815 to order the free Weight Management Poster, request patient education brochures, and begin using this informative tool in your practice.

References

  1. Lönnqvist F, Arner P, Nordfors L, Schalling M (1995). “Overexpression of the obese (ob) gene in adipose tissue of human obese subjects”. Nat. Med. 1 (9): 950–3. doi:10.1038/nm0995-950. PMID 7585223.
  2. Madej T (1998). “Considerations in the use of lipid-based drug products”. J Intraven Nurs. 21 (6): 326. PMID 10392096.
  3. J Clin Endocrinol Metab. 2000 Aug;85(8):2685-91. Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake. Chin-Chance C1, Polonsky KS, Schoeller DA.
  4. Kotani K et al. SH2-B alpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase. Biochem. J. 1998;335:103–109
  5. Maures TJ et al. SH2B1(SH2–B) and JAK2: a multifunctional adaptor protein and kinase made for each other. Trends Endocrinol Metab. 2007;18: 38–45
  6. Morris DL et al. SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes. 2009;58:2039-2047
  7. Ren D et al. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J Clin Invest 2007;117:397–406
  8. Duan C et al. Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Mol Cell Biol 2004;24:7435–7443
  9. Ren D et al. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metabolism. 2005;2:95–104
  10. Li M et al. Differential role of SH2-B and APS in regulating energy and glucose homeostasis. Endocrinology. 2006;147: 2163–2170
  11. Bochukova EG et al. Large, rare chromosomal deletions associated with severe early onset obesity. Nature. 2010;463:666–670
  12. Walters RG et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature. 2010;463:671–675
  13. Speliotes EK et al. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nat Genet. 2010;42:937–948
  14. Thorleifsson G et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet. 2009;41:18–24
  15. Bauer F et al. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am J Clin Nutr. 2009;90:951–959