The WHO's report on noncommunicable diseases

The World Health Organization of the United Nations has released a report titled "Global status report on noncommunicable diseases." Access to the report and its individual chapters is at this link. I was particularly interested in Chapter 1 and the major contributing factors to noncommunicable diseases (NCD).

According to the above report and others from the WHO, the four primary contributors to global increases in NCDs, such as type 2 diabetes, cancer, and cardiovascular diseases, are:

tobacco

harmful use of alcohol

unhealthy diet

physical inactivity

While such a list is really not surprising, what I do take from this, with respect to my own research on the genetic basis for the differential response to the diet as it pertains to metabolic diseases, is these are our key environmental factors used to assess gene by environment, or GxE, interactions. In other words, while these factors are strong contributors to NCD onset and progression, genetic differences exert different influences on the disease risk, onset and progression in different individuals. That influence could be negative - increasing risk - or positive - being more protective.

Thus, the importance of GxE identification cannot be overlooked, and ought really to be emphasized in genetic association studies.

POTW: Uncovering the function of an intergenic SNP

My choice for Paper Of The Week this week is a report from a few weeks back (digging through the pile...) in which a polymorphism conferring increased risk of renal cell carcinoma is investigated for allele-specific functions. The paper is "Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression" by Schödel, et al. (Nature Genetics 44:420-425).

Although the authors had several clues that the risk SNPs would (likely) affect expression of CCND1 (cyclin D1) in a manner regulated by hypoxia-induced factors - namely, that HIFs were known to regulate CCND1 but from an unknown binding site and that CCND1 is an established oncogene, among others - they accumulated much new data to nail down the role of EPAS1 (HIF-2) in regulating CCND1 expression.

One nice aspect of this work is the authors' taking advantage of signals seen in a renal carcinoma cell line and not in a breast cancer cell line (serving then as control). For example, they looked at the epigenetic enhancer marks at the 11q13.3 susceptibility locus with FAIRE (ormaldehyde-assisted isolation of regulatory elements to identify regions of nucleosome occupancy), and EPAS1 binding as assessed by ChIP-qPCR. The use of pVHL-defective RCC cell lines verified the role of VHL (von Hippel–Lindau tumor suppressor) in this cancer and consequence of allele-specific expression of CCND1.

Taken together, the data presented show that the haplotype associating with reduced renal cell cancer risk hinders EPAS1 binding, "resulting in an allelic imbalance in cyclin D1 expression, thus affecting a link between hypoxia pathways and cell cycle control." This is nice work and a fine example of the approaches needed to develop a clear understanding of polymorphism and disease risk from a functional perspective.

POTW: January, 2012 choices

Three papers published last month that I found to be of interest are listed here. These are:

The mystery of missing heritability: Genetic interactions create phantom heritability, by Zuk, et al. This addresses the missing heritability question, suggesting that "the total heritability may be much smaller and thus the proportion of heritability explained much larger."

Characterisation and discovery of novel miRNAs and moRNAs in JAK2V617F mutated SET2 cells, by Botoluzzi, et al. What interested me in this article was the generation of novel microRNAs that were induced by the cancerous state triggered by this JAK2 variant. This indicates to me that the microRNA realm is broad and rich with many as yet undiscovered relationships.

The PLoS One paper entitled "Genetic signatures of exceptional longevity in humans," by Sebastiani, et al. We here were very curious how this was different from the version retracted from Science and what findings are now reported. TOMM40 near APOE is indeed interesting.

Paper of the Week: cis-eQTL between normal and cancer tissue

My choice for Paper of the Week this week is "cis-Expression QTL Analysis of Established Colorectal Cancer Risk Variants in Colon Tumors and Adjacent Normal Tissue," by Loo, Cheng, Tiirikainen, Lum-Jones, Seifried, et al. (2012) appearing in PLoS One.

I find this article of interest because I feel that many GWAS hits for disease risk will serve to alter expression of a near or distant gene(s) in an allele-specific manner. This group looked at gene expression differences between tissues that were either colorectal tumors or their paired, adjacent normal tissue, and then associated those gene expression differences with allelic variation. Assaying 40 individuals was sufficient to identify 3 SNPs affecting expression of 4 genes: ATP5C1, DLGAP5, NOL3 and DDX28.

A link to this paper is here.

Citation:
Loo LWM, Cheng I, Tiirikainen M, Lum-Jones A, Seifried A, et al. (2012) cis-Expression QTL Analysis of Established Colorectal Cancer Risk Variants in Colon Tumors and Adjacent Normal Tissue. PLoS ONE 7(2): e30477.

Olive oil and cancer

Could a diet where olive oil is the primary source of fat assist in delaying or preventing the onset of cancer? That's a tempting question and certainly a good one for nutrigenomics. As one might expect, the answer is both a yes and a no.

Yes. A recent study by Hirsch, Struhl, et al. used two isogenic cancer models to uncover the transcript profile and gene signature linking cancer with inflammatory and metabolic diseases. This group identified 345 genes whose expression signature is also involved in inflammation and metabolic diseases such as type 2 diabetes and cardiovascular disease. In fact, within these 345 genes are genes identified by GWAS (and other types of studies) for HDL-cholesterol (ABCA1 and GALNT2), obesity (NPC1), stroke (AIM1), and celiac disease (PTPN2, PTPRK, SCHIP1 and ZMIZ1), among others. Curiously, there is substantial sharing of genes between those upregulated in this cancer set and those that we identified as downregulated after acute intake of phenol-rich olive oil. Ten genes are shared. This is a 4.2-fold enrichment over what one would expect by chance given the size of the two gene sets. That sounds quite strong and the genes look mighty interesting:

ANXA3 - annexin A3
CXCL3 - chemokine (C-X-C motif) ligand 3
DUSP1 - dual specificity phosphatase 1
EREG - epiregulin
IER2 - immediate early response 2
IL1B - interleukin 1, beta
IL6 - interleukin 6 (interferon, beta 2)
JUNB - jun B proto-oncogene
SOCS3 - suppressor of cytokine signaling 3
SOD2 - superoxide dismutase 2, mitochondrial

These are some big players and so perhaps there is an olive oil-cancer prevention link.

However...

No. Because not everyone living in countries with heavy use of olive oil in the diet, countries such as Spain and Italy, adheres to a typical or Mediterranean diet, population data on cancer rates are not really an accurate way to assess that an olive oil-rich or Mediterranean diet lowers one's risk of cancer. Besides, cancer is too general a term - risk of specific types of cancer should be measured. For example, adherence to the traditional Mediterranean diet is associated with reduced risk of upper aerodigestive tract cancers and reduced risk of colorectal cancer has been observed in those who follow a diet higher in fruits/vegetables, lower in fat and more toward a Mediterranean diet.

The list of common cancer pathway genes is much greater than 10. Some 240 genes are upregulated and 105 are downregulated. Thus, while the 10 cancer pathway, olive oil-sensitive genes listed above are a highly interesting list, this is by no means sufficient to unequivocally state that a diet high in phenol-rich olive oil will prevent cancer.

Furthermore, many of the genes in this list of 10 are common to several important pathways. IL1B is a pro-inflammatory mediator and is also involved in the postprandial response of triglyderides. The floxed Socs3 gene in mouse gives an animal that is resistant to diet-induced obesity and this gene has been assigned to an insulin resistance inflammation network. One major point of our olive oil paper was the anti-inflammation nature of the response to the phenol-rich olive oil on gene expression in PBMCs. A recent paper essentially confirms this finding. Hence, the dual assignment of many genes to a cancer pathway and something else like inflammation is highly intriguing, but caution is, as always, warranted in condensing the complexities of metabolism, inflammation and cancer to a single kernel of dietary advice.