Obesity and Ordinary Weight Gain Linked To Guess What? Not Simply Junk Food But A Gene Called Niemann Pick Type C.

The first genetic map of obesity has been constructed using DNA microarray technology and guess what gene obesity is linked to?  The Niemann Pick Type C gene on Chromosome 18 that is mutated in Addi and Cassi and which is causing their deadly cholesterol metabolism disorder.   I have now found out that the NPC gene that is involved in all people’s cholesterol metabolism is liked to the HIV/AIDs viruses ability to assembly itself in the body of infected persons, Cystic Fibrosis, Muscular Dystrophy and now Obesity!

Would the NIH please provide more funding into studying the NPC gene — the NPC cholesterol gene dates back 500 million years to worms, flies and plants and obviously is involved in many critical processes in the human body.

The obesity report was publsihed in Nature Genetics by a research group led by CNRS researcher Philippe Froguel and Inserm researcher David Meyre.  This study led to the discovery of three new genes that increase the risk not only of severe obesity but also ordinary weight gain in the population.  It underlines that there is no difference between being overweight and other forms of obesity (mild, severe or massive).

Even though the increase in the number of obese people over the two last decades is partially due to social causes (inactivity, junk food, etc.), heredity plays an important part in determining body weight (70% hereditary) and the occurrence of obesity, especially when this is severe and appears early in life, according to researchers.

Froguel’s team has been working for 15 years to better understand the molecular basis of type 2 diabetes and the obesity found in 80% of diabetics.  Their work has revealed several genes responsible for monogenic forms of obesity and has demonstrated the essential role these genes play in appetite control.   The scientists first confirmed that the genes FTO and MC4R(4) played a major role in susceptibility to common obesity and weight gain in the population as a whole.  These two genes work by controlling eating behavior.

The researchers also found variations in the DNA close to the genes MAF and PTER(5), and directly in the coding sequence of the NPC1 gene.  Mutations associated with obesity could therefore directly induce an increase in the function of the NPC1 protein, such that it would work too well if the gene had mutated.

As for the MAF gene, it codes for a particular protein involved in the differentiation of adipose tissue (tissue responsible for fat storage) and in the production of a digestive hormone involved in satiety and insulin secretion.  The last gene (PRL) is more particularly associated with obesity and weight gain in adults.  PRL produces prolactin, a hormone well known for its effect in stimulating lactation in women.  Prolactin also plays a role in controlling the amount of food we consume.

Apo E Gene and Diet

All afternoon, I have been thinking about the Apo E cholesterol-related gene and what combination of Apo E genes each person in our family inherited.  The Apo E gene provides instructions for making a protein called apolipoprotein E and it is located on Chromosome 19.   This protein combines with fats (lipids) in the body to form molecules called lipoproteins.   Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream.

Some research suggests there is a connection between the Apo E gene and Alzheimer’s and dementia.   I found out that Addi and Cassi have Apo E gene is 3/3, which is considered "neutral" so this doesn’t explain their dementia.  I think their problems have more to do with insulin factors (they have a glucose metabolism problem in frontal lobe of their brains), oxidative stress, and inflammation and the interaction between genes and nutrients/vitamins.

Research suggests that Apo E genes can influence your predisposition to certain illnesses from Alzheimer’s disease, Parkinson’s disease, heart disease and cancer.   I read that persons with the Apo E 4/4 genotype could have up to a 90 percent chance of developing a chronic illness such as Alzheimer’s.   The Apo E gene occurs as three variations in your body: Apo E 2, Apo E 3, and Apo E 4.  Since genes come in matching pairs, we inherit one from each parent.  There are six possible combinations of Apo E gene pairs: 2/2, 2/3, 3/3, 4/2, 4/3, and 4/4.

The Apo E gene could be a factor affecting how your body uses different types of foods and nutrients and different Apo E genotypes likely process foods differently.  There is an interesting book on this topic called The Apo E Diet.

Over the next few weeks, I will be working to have personal genetic testing done on our entire family and we will find out how our Apo E combinations might play a role in our health.

Understanding Genetic Testing & Sequencing – It’s Greek To Me

We have recently learned from the Mayo Clinic that our twins Addi and Cassi have one Niemann Pick Type C gene mutation that has been identified in their bodies — it’s called Exon 12 DNA Change 1920delG.   This DNA sequence change (or deletion) is a “known pathogenic mutation in the sterol-sensing domain.”   The 1920delG mutation leads to a premature stop in the synthesis of the protein after 655 residues, instead of the normal 1278 residues.  We were told that because of the position of Addi and Cassi’s mutation, the lab at Mayo could only get clean DNA sequencing in the forward direction.  We are still trying to figure out what all of this means.

The second mutation in the twins have so far has proved elusive to Mayo Clinic researchers.  At this point, Hugh and I need to have our Niemann Pick Type C genes on Chromosome 18 sequenced in order to try identify our family’s second mutation.  Next week, we will have our blood drawn and sent to Mayo for analysis and hope to find the second mutation.  By finding our genetic mutations, we can learn clues about Niemann Pick Type C disease.  We have also found out that Addi and Cassi do not have a common NPC mutation — that mutation is called I1061C.  It gets more complicated for us and the mystery deepens.

I wonder if I have the Exon 12 DNA Change 1920delG in my body?  Or is Hugh the carrier of this faulty gene?   Which one of us has the gene that is proving elusive and hiding?   How did this even happen to us and our family?  This mystery goes back thousands of years and is so bizarre and so complicated that I simply don’t want to think about it anymore tonight.   God only knows what will happen in my dreams.  Each night, I am afraid to close my eyes for fear as to how my unconscious mind will take over  — my nightmares are beyond comprehension.

The National Chemical Genomics Center, Rockville, Maryland

We are leaving tomorrow, Nov. 26, 2008, for a special meeting to discuss accelerating research into Niemann Pick Type C disease at the National Chemical Genomics Center (NCGC) located in Rockville, Maryland.

The National Institutes of Health (NIH) established the NCGC to create a national resource for the study of protein and cell functions so they can learn more about the biology of diseases and genetics.

We are going to get a tour of the state-of-the-art high throughput screening robotic operation and we can’t wait to learn more.  The NCGC is one component of the NIH’s Roadmap Initiatives, an innovate project to create research centers, teams and technologies to accelerate new discoveries in biomedical research.

You can read more about the entire NIH project here.