25.05%

14%

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

PPAR-Gamma Gene Prevalence

Study (n=1058)

Control (n=2,245)

Obesity used to be understood in fairly elementary behavioral terms: excess body weight resulting from eating too much and exercising too little, due in large part to a lack of willpower or self-restraint. But as people have increased their dieting and exercise, the rates of obesity continue to rise as the combined prevalence of overweight and obesity in the US has increased from 46% of the adult populations (NHANES II, 1976 to 1980) to over 60% of the adult population in NHANES III (1988-1994). In 1985, obesity was recognized as a chronic medical disease with serious health implications caused by a complex set of factors. Obesity-related medical conditions contribute to 300,000 deaths each year, second only to smoking as a cause of preventable death.1 Obesity has been established as a major risk factor for hypertension, cardiovascular disease, Type 2 diabetes, and some cancers in both men and women. Obesity affects 58 million people across the nation and its prevalence is increasing (source: U.S. Census Bureau). Approximately one-third of American adults are estimated to be obese, and 60% are overweight. In response to this rising epidemic, the medical, food and fitness communities have consistently told Americans to just make behavioral modifications, such as diet and exercise. As scientific advancements have demonstrated in other neurological healthcare conditions such as alcoholism, there are important biological and genetic components that limit the efficacy behavioral adjustments alone.

Sixteen years ago, Blum et al published landmark research suggesting that another prevalent healthcare condition which had been traditionally characterized in behavioral terms like obesity, namely alcoholism, also had a hereditary or genetic component and that genetic information could explain why such a condition could be found to “run in the family”. Blum’s research2, continued to explain how knowing this important genetic information could then caution certain genotypes to adjust their dietary intake and environments to overcome this genetic predisposition. In a recent study of 11,000 Americans, results suggested that more than 75% of obese Americans (n=3,100) say they have healthy eating habits. According to this survey, 40 percent of obese people also said they do “vigorous” exercise at least three times per week. In this survey by Thomson Medstat, a Michigan-based healthcare research firm, obese people reported similar behaviors in snacking, reading nutritional labels, and eating out when compared to normal weight people.3 Weight loss, alone, is difficult, but sustainable weight loss is also exceedingly difficult. Most people regain as much as 2/3rds of weight lost within one year and regain all within five years.

Introduction

 

Genotype Prevalence in the GenoTrim™ D.I.E.T. Study: Insights into Multi-Variant Obesigenics from an Observational Study of Overweight Subjects in The Netherlands

Kenneth Blum, PhD*.1,2,4 Brian Meshkin, B.Sc.2 M –Martinez-Pons, Ph.D.3 Eric Braverman, M.D.4

1Department of Physiology & Pharmacology, Wake Forest University School Of Medicine; 2 Department of Molecular Nutrition & Nutrigenomics, Salugen, Inc. San Diego, California; 3 Department Education, Brooklyn College , CUNY, New York; 4 Path Medical Research Foundation, New York, NY

References

1. Long-term pharmacotherapy in the management of obesity. National Task Force on the Prevention and Treatment of Obesity. JAMA, 1996; 276:1907-1915.

2. Stobbe, Mike. “Survey: Most obese claim to eat healthy,” Yahoo News, http://news.yahoo.com/s/ap/20060802/ap_on_he_me/diet_obesity_survey, August 15, 2006, Atlanta:Associated Press reporting on Thomson MedStat study.

3. Blum, K., Noble, E.P., Sheridan, P.J., Montgomery, A., Ritchie, T., Jagadeeswaran, P., Nogami, H., Briggs, A.H., and Cohn, J.B., Allelic association of human dopamine D2 receptor gene in alcoholism. Journal of the American Medical Association 1990,263: 2055-2060.

4. Blum K, Meshkin B, Downs BW. DNA based customized nutraceutical “gene therapy” utilizing a genoscore: A hypothesized paradigm shift of a novel approach to the diagnosis, stratification, prognosis and treatment of inflammatory process in the human. Med. Hypoth, 66, 1008, 2006.

In this observational study, a total of 1,058 subjects were genotyped in the nutrigenomics laboratory of Salugen, Inc. (San Diego, CA). Each subject self-identified themselves as obese or overweight by selecting GenoTrim as a potential adjunct to their weight loss efforts. Each subject was genotyped based upon the following genetic mutations: Sweet Tooth Gene™ [Dopamine D2 Receptor Gene Taq 1 Alelle (DRD2 A1)], Nervous Eating Gene™ [5-Hydroxytrytamine 2A -1438G/A promoter polymorphism (5-HT2a -1438G/A)], New Cell Gene™ [Methylene Tetrahydrofolate Reductase C677T polymorphism (MTHFR C677T)], Obesity Risk Gene™ [Leptin Genetic Polymorphism - OB1875 < 208-bp alleles (Leptin OB1875)], and the Fat Regulator Gene™ [Peroxisome Proliferator-Activated Receptor-Gamma Gene Pro12Ala polymorphism (PPAR-gamma Pro12Ala Allele)]. The subjects are part of the Dutch Investigation to Evaluate Treatments of DNA-customized nutritional solutions for weight management (D.I.E.T.) Study. The prevalence of these genotypes was measured against literature controls from independent, published clinical studies involving the same genetic mutation in a similar ethnic population. Statistical significance was performed by a biostatistician at Brooklyn College (NY) and determined using the Z-test for two independent proportions (Kanji, G. K. 100 statistical tests. 1997. Thousand Oaks, California: Sage Publications, Inc.).

Methods

The Sweet Tooth Gene single nucleotide polymorphism (SNP) was present in 38.09% of the study subjects (n=1,058) versus 29% of the literature controls (n=3,259). This difference was significant (Z = 8.393, p = 0.0001) [see Figure 1].

The Nervous Eating Gene SNP was present in 64.18% of the study subjects (n=1,058) versus 61% of the literature controls (n=284). This difference was not statistically significant (Z = 0.755, p = 0.23).

The New Cell Gene SNP was present in 69.85% of the study subjects (n=1,058) versus 54% of the literature controls (n=100). This difference was significant (Z* = 2.23, p = 0.01) [see Figure 2].

The Obesity Risk Gene SNP was present in 75.61% of the study subjects (n=1,058) versus 45.6% of the literature controls (n=206). This difference was significant (Z = 5.612, p = 0.0001) [see Figure 3].

The Fat Regulator Gene SNP was present in 25.05% of the study subjects (n=1,058) versus 14% of the literature controls (n=2,245). This difference was significant (Z=17.398, p = 0.001) [see Figure 4].

The prevalence of genetic combinations is also of interest [see Figure 5] as 37.81% had 3 or more gene polymorphisms (PM), 73.91% had 2 or more gene PM. The most common genotypes were Nervous Eating and New Cell Gene PM (13.42%), New Cell Gene PM (11.81%), Sweet Tooth, Nervous Eating and New Cell Gene PM (10.4%) and Nervous Eating Gen PM (7.84%) [see Figure 6].

Results

Figure 1. Sweet Tooth Gene Correlates with Weight ProblemsFigure 1. Sweet Tooth Gene Correlates with Weight Problems

Figure 5. Multi-Gene Prevalence in the D.I.E.T. StudyFigure 5. Multi-Gene Prevalence in the D.I.E.T. Study

Figure 2. New Cell Gene Correlates with Weight ProblemsFigure 2. New Cell Gene Correlates with Weight Problems

No. of Gene PM

No. of Study Subjects Percentage

0 11 1.04%

1 265 25.05%

2 382 36.11%

3 306 28.92%

4 73 6.9%

5 21 1.98%

GenoTrim™ is the world’s first and only DNA-customized nutritional solution for weight and addresses the genetic factors influencing the metabolism and hormones that impact weight. By analyzing a panel of genes, GenoTrim is DNA-customized to provide the consumer with a nutritional supplement to assist in their weight loss efforts.

In the future, our goal as scientists should be to provide the obese individual a tailor made rather than a one-size-fits-all solution. In this regard, we maintain that this evidence underscores a need for further nutrigenomic research to identify various genes associated with obesity. And as those genetic correlates are discovered, we hypothesize using a multi-variant nutrigenomic index for the purposes of customizing or adjusting the formulation of nutritional supplements will result in an improved and novel approach to the diagnosis, stratification, prognosis, and treatment of various healthcare conditions.4GenoTrim™, the world’s first and only DNA-customized nutritional solution for weight management, was test launched in The Netherlands in early 2006. The maker of GenoTrim, Salugen, Inc. anticipates making the product commercially available in the U.S. in Q4 2006. GenoTrim brings together a multivariate genetic analysis of five genes addressing the genetic factors influencing weight. These genes include a serotonin receptor gene 5-HT2a-1438 A>G influencing appetite control, PPAR-Gamma Pro(12)Ala polymorphism influencing fat cell creation and metabolism, Leptin OB gene influencing obesity risk, MTHFR C677T polymorphism influencing folate (Vitamin B9) metabolism and homocysteine, and Dopamine D2 Receptor Taq 1 Allele influencing sugar and carbohydrate cravings.

Based upon a genetic profile derived from this in-depth genetic analysis, a DNA-customized GenoTrim formula is derived to address the genetic predisposition of the subject, as a major contributing underlying factor of their weight problems. The statistical significance of this data suggests that these genes are more prevalent in the obese and overweight populations and underscores their consideration when formulating a nutritional solution to address weight problems. This multi-variant analysis and DNA-customized formulation process is a patented process of Salugen, Inc., San Diego, CA USA.

Discussion

This study is further evidence supporting the role of these various genes and weight management. Specifically, this first phase of the D.I.E.T. Study makes a valuable scientific contribution in identifying specific genotypes of multi-variant genetic analyses that may be more prevalent in obese or overweight populations and thus should be considered as therapeutic targets for complementary and alternative medicines, as well as conventional therapies. With GenoTrim being customized and targeted based upon these various genotypes, GenoTrim is the first solution to address genetic factors that statistically are more common in an overweight and obese population. As these genes have been documented in their involvement in insulin sensitivity, total serum homocysteine, aberrant craving behaviors, anxiety and other healthcare conditions, these genes also illuminate the genetic roles of contributing co-morbidities to the obesity epidemic and shed further light and knowledge on the epidemic of obesigenics.

Conclusion

Figures 3-6

Disclosures: Both Kenneth Blum and Brian Meshkin are stock holders and officers in Salugen, Inc., the makers of GenoTrim – a DNA-customized nutritional solution for weight management. For more information on Salugen or GenoTrim, please visit www.salugen.com and www.genotrim.com.

38.09%

29%

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

35.00%

40.00%

DRD2 Taq 1 Allele Prevalence

Study (n=1058)

Control (n=3,329)

69.85%

54%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

MTHFR C677T Mutation

Study (n=1058)

Control (n=100)

75.61%

46%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

Leptin OB Gene Prevalence

Study (n=1058)

Control (n=206)

Figures 1-2

Figure 3. Obesity Risk Gene Correlates with Weight ProblemsFigure 3. Obesity Risk Gene Correlates with Weight Problems

Figure 4. Fat Regulator Gene Correlates with Weight ProblemsFigure 4. Fat Regulator Gene Correlates with Weight Problems