The impact of our genomes on metabolic health
Torben Hansen, Copenhagen University
Part 1: human genetic studies of common forms of obesity.
Several Features of obesity, which all lead to type 2 diabetes and vascular diabetes. Triggers: overeating and lack of physical activity, but what about genetics?
Eighteen risk loci associate with obesity or increased BMI with genome-wide significance. Eight are common, but only increase risk of obesity with 8-33%. Most of them were discovered in 2009 or later. The most important was discovered in 2007: FTO.
Most of obesity genes are expressed in the brain. Seems to be a brain disease. A more recent analysis (Speliotes-EK et al. 2010) found 18 additional loci, over 249,796 individuals in the study.
Can also consider distribution of the fat, which are determined by another 13 genes.
Knowing all of this, how do we apply this to clinical settings?
Cumulative effect and predictive value of 32 loci was tested on 8,120 individuals. There is a correlation between the number of risk loci carried and the BMI, which supports their contribution to human health analysis. Thus, they should be used for predictive analysis to focus our attention on populations at highest risk.
ROC graph shown (Specificity vs Sensitivity). [It looks Terrible!] It’s not particularly sensitive or specific, so it can not be used yet. (No value given, unfortunately.) There is obviously more in play than just the risk loci.
Is an imbalance in gut bacteria in part to blame for obesity?
Human colon bacteria are collectively about 1.5kg of bacteria, mainly made up of baacteriodetes and Fimicutes (90%). Protect against pathogens, control epithelial cell proliferation, etc.
Obese mice have more Firmicutes (Ley RE et all, PNAS 102). Firmicutes have a higher capacity for fermentation of non-digestible polysaccharides than bacteriodetes. This is also transferrable, when flora from obese mice were moved into skinny mice, they became obese.
80% of human gut bacteria can not be cultured.
Major aim of MetaHIT project is to identify the gut microbiome at the gene level, and to study the role of the gut bacterial genes and species.
Massively parallel shotgun sequencing of genes from distal gut bacteria of 86 Danes and 38 from Spain. Sequencing done at BGI. Published in Nature, 2010.
3.3 million genes from distal gut identified. Human gut gene set is at least 150 times larger than the gene set of the thuman genome. 99% are bacterial. 160 gut bacterial species with 530k genes.
64/160 bacterial species are shared by more 90% of individuals.
High variabilit in abundance of shared species, up to 5000-fold
Do any of these species associate with obesity?
Danish population study undertaken, started in 1999, updated in 2004 and now added to again in 2009. (Study metrics show, with controls methods, including “no yogurt for 5 days prior to collection”.
Genes of the obese cohort.
177 danish individuals had their gene presence assessed by illumina sequencing. 30M PET per individual. Sequencing again done at BGI.
How many genes do indiduals actually have. Distribution of obese people is in two sets: a low gene count, and a high gene count. Over weights and normals only show the high gene count distributions.
Those with low gene counts and obese phenotype are more insulin resistant that those with high gene count and obese phenotype. This is not apparently affected by gender.
The differences in metabolic profile, however were most pronounced in obese women.
Those obese women with low gene counts also show other issues, such as dyslipidemia. [did I spell that right?]
Food questionaire was inspected. Those with low gene counts had a higher incident of fat in their food.
Looking back over the study from the earliest control, there are other trends. Over time low gene count obese women increase their BMI and waist circumferenece more than high gene count obese women. Insulin levels also increase over time.
Bimodal distribution of gut bacterial genes seen in both French and Danish groups. Distribution of genes is different between high and low gene counts, however.. Some are only found in one group or the other.
Phenotpyes of low-gene count obese people include other issues such as increased inflamatory parameters, found in the French data set. However, the Danish study did not include these parameters.
Is low grade inflamation associated with low gene count obesity?
Four meta-species are diagnostic for low and high gene individuals. AUC 0.99 for ROC. (Tested on 99 Danes.)
Models may have prognostic value for identifying people at higher risk of cardiovascular genes.
Searching for species associated with BMI. 33 species associate significantly with obesity. ROC AUC is 0.85.
The same meta-species discriminate micro-obese individuals.
Which molecular mediators are involved in the metabolic dysfunctions?
Could microbiome based interventions work? Fecal transplants? Could we customize treatments based on genomic gut profiles?
We must consider gut microbiome as an integral part of the human health equation.