Wednesday, July 30, 2014

Genetic pedigree symbols and legend

The following has been making the rounds on Twitter the past few days. In order to make this useful information available to more viewers and for a longer time, I decided to post this here.

Thursday, April 3, 2014

ARAP1 and type 2 diabetes - a circadian connection?

A new report in the American Journal of Human Genetics shows a variant with association to type 2 diabetes and insulin levels functions within an allele-specific motif for islet cell transcription factors PAX4 and PAX6. Specifically, "measurement of allele-specific mRNA levels in human pancreatic islet samples heterozygous for rs11603334 showed that the T2D-risk and proinsulin-decreasing allele (C) is associated with increased ARAP1 expression (p < 0.02). We evaluated four candidate functional SNPs for allelic effects on transcriptional activity by performing reporter assays in rodent pancreatic beta cell lines. The C allele of rs11603334, located near one of the ARAP1 promoters, exhibited 2-fold higher transcriptional activity than did the T allele (p < 0.0001); three other candidate SNPs showed no allelic differences. Electrophoretic mobility shift assays demonstrated decreased binding of pancreatic beta cell transcriptional regulators PAX6 and PAX4 to the rs11603334 C allele."

Interestingly, Pax4 is abundantly over-represented within cis-regulatory motifs in mouse clock-controlled genes, in liver and muscle, per Table 1, and relative to peak Per2 expression in mice, the Pax4 protein recognizes a motif over-represented in the suprachiasmatic nucleus (SCN, the "master clock" in the brain) at phase 12, per Table 2. These data are from Bozek, Relogio, et al 2009 PLoS One4:e4882. That same study showed similar activity for Pax6: relative to peak Per2 expression in mice, Pax6 protein also recognizes a motif over-represented in the SCN at phase 12, per Table 2 (Bozek Relogio 2009 PLoS One 4:e4882, PMID 19287494).

This makes one wonder about the timing of the food intake that might exacerbate glucose homeostasis in carriers of the risk allele.

Friday, March 14, 2014

APOE, memory impairment, diet and N-3 PUFAs

APOE is a curious gene. It has roles in both lipid/cholesterol homeostasis and memory impairment with its associations with Alzheimer disease. For example, see this entry in OMIM and the section titled "Role of APOE in Abnormalities of Blood Lipids and in Cardiovascular Disease." If you read through that long section, over 2600 words, you'll learn that APOE is an important contributor to the management of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). If LDL and VLDL levels are not in homeostasis, triglyceride levels can become elevated, which increases risk of atherosclerosis.

A recent report in Nature Medicine by Mapstone, et al. entitled "Plasma phospholipids identify antecedent memory impairment in older adults" identified a panel of ten blood-based lipid biomarkers for "detecting preclinical
Alzheimer's disease in a group of cognitively normal older adults." Those ten lipids include two acylcarnitines and eight
phosphatidylcholines (PC), specifically:

3-OH-hexadecenoylcarnitine (C16:1-OH)
phosphatidylcholine diacyl C36:6 (PC aa C36:6) *
lysophosphatidylcholine acyl C18:2 (lysoPC a C18:2)
phosphatidylcholine diacyl C38:0 (PC aa C38:0) *
phosphatidylcholine diacyl C38:6 (PC aa C38:6) *
phosphatidylcholine diacyl C40:1 (PC aa C40:1)
phosphatidylcholine diacyl C40:2 (PC aa C40:2)
phosphatidylcholine diacyl C40:6 (PC aa C40:6) *
phosphatidylcholine acyl-alkyl C40:6 (PC ae C40:6) *

These were noted by the study to be lower in the group of cases compared to controls.

Curiously, this group did not reference the findings from a 2013 study by Rudowska, et al., that characterized the transcriptomic and metabolomic signatures of adding N-3 polyunsaturated fatty acid (N-3 PUFA) to the diet in a Caucasian population. Of their findings, it is most notable that five of the eight above-listed PCs were increased after the six-week N-3 PUFA intervention. These are noted with an asterisk above.

Whether a diet rich in N-3 PUFAs could decrease risk of memory impairment or Alzheimer disease (AD) is a matter for further investigation. Nonetheless, that five of these eight PCs show opposite changes when comparing an N-3 PUFA intervention with the group of cases in the Mapstone, et al. study is highly interesting. Consider also for the moment gene by diet or gene by environment (GxE) interactions. A GxE interaction is an association between a genetic marker and a phenotype that is modified by an environmental factor such as the diet, macronutrient (ie, fat, protein or carbohydrate) intake, physical activity or any of many other lifestyle choices. The risk allele will not show itself as risk until the environmental factor passes a given threshold, say too much saturated fat and now the risk is elevated.

The overlap of the five PCs highlighted here, coupled with the large number of gene-environment interactions we see for the common AD/blood lipid variants of APOE - SNPs rs429358 and rs7412 - strengthen my personal view that lifestyle has a significant role in cognitive decline.

Friday, October 18, 2013

Getting back in gear and tightening the focus

After nearly three weeks of being idle as a result of the government shutdown, I find myself drawing a narrower focus on the activities in which I am engaged. This is a consequence of lost time and of the struggle to get fully re-engaged. The train of thought that is so vital to novel and creative research was severely wounded.

A significant portion of the time in which to accomplish the milestones and achievements for fiscal year 2014, which coincidentally began on 1 Oct, the day the insanity began, is lost. This means that I will be less likely to accept invitations to review manuscripts and more likely to keep many projects on the back burner.

We have a few very important ongoing projects that are at critical stages of either assembling the data into impactful manuscripts or for evaluation of our current and soon to end 5-year research plan. This is where my focus will be for the coming several weeks. This is where the push will be exerted. So many of those little things that add flavor and completeness to the research we do will simply have to wait, hopefully to be squeezed in later.

Friday, June 21, 2013

FTO and memory - connecting the dots

FTO is a well known gene containing variants that have shown rather consistent association to obesity risk and BMI in many different populations. FTO is an efficient oxidative demethylase targeting the abundant N6-methyladenosine (m6A) residues in RNA in vitro and mRNA in the nucleus. This implies that there is a heretofore undescribed, reversible regulatory process in mammalian cells.

Late last year, it was reported that FTO variants can raise susceptibility to decline in verbal memory as detected in middle-aged, community-dwelling adults. A new report released this week has identified an inhibitor of PERK (also known as EIF2AK3) signaling that is rather potent at reversing the effects of EIF2S1 (eIF2alpha) phosphorylation. As EIF2AS1 phosphorylation is implicated in memory consolidation, it was notable that the mice treated with this inhibitor showed significant increases in spatial and fear-associated learning. Thus, the authors conclude, "memory consolidation is inherently limited by the integrated stress response (which involves PERK, PKR (EIF2AK2), GCN2 (EIF2AK4) and HRI (EIF2AK1)), and [the inhibitor] releases this brake."

Here's where things get interesting and the FTO-EIF2AK3 connection tightens. Of 77 mRNAs whose levels are either up- or down-regulated in the liver, skeletal muscle or white adipose tissue of mice homozygous for a nonsynonymous Fto point mutation, as reported by Church, et al. 2009, mRNAs from seven genes, which were all significantly up-regulated in FTO mutants, also contain methyl6A peaks: Acaca, Atf6, Bip, Gcdh, Irs1, Perk, and Xbp1 (Meyer, et al. 2012).

Data mining is fun!