Monday, 31 March 2014

Apolipoprotein E - genealogy and picking grapes

This is part 3 of my little ApoE series. I'm making an attempt to put them in some logical order, so see parts 1, part 2 to make some sense of this one. 

The next few posts will outline some population observations, particularly in regard to E4. I realise that this sort of information can only provide clues as to what mischief your particular ApoE gets up to, but they're at least something to start with.

You may notice I don't pay equal attention to E2, which is partly for selfish reasons, but also because E2 is even rarer than E4 and the only unpleasant condition that I'm aware of that is associated with E2/E2 is something called Type 3 hyperlipoproteinemia. "Only" is probably a poor choice of word, because it's a particularly nasty condition, but it's a lot less common than something like Alzheimer's and dementia.

ApoE Geographic distribution.
In a general global sense, the different Apolipoprotein E alleles are encountered as follows: 
ApoE allele
Mean average frequency
E2
6.4%
E3
78.3%
E4
14.5%

Of course it depends on where you live and where your descendants are from. It seems that, in Europe at least, the further you travel north, the more people with E4 you will meet. 
The table above is from the ApoEurope Project and they found that the number of people with E4 near the Mediterranean (Greece, Portugal, Spain) was lower when compared with more northern populations in Ireland, Finland and France. 

E4 is also fairly prevalent in places where skin colour is naturally dark. For example: 
Population
Approximate E4 %
Central African Pygmies
40.7%
Tutsi (East Africa)
38.5%
Papuans
36.8%
Australian Aboriginals
26%

If you go digging for papers on this topic, you'll generally find that E4 is less common in certain populations and locations and while the geographical distribution is an interesting observation, it doesn't really tell us anything by itself. So we'll move on to the next observation:

Vitamin D status

People with E4 tend to have higher circulating levels of Vitamin D. Again, interesting, but what does it mean?

Well, if you are in to putting several associations together and jumping to a conclusion, and I definitely am when it suits my argument, then you may speculate that evolution had a hand in giving E4 (and therefore a smaller chance of suffering Vitamin D deficiency) to those who were less likely to get a sun tan. Or put another way, E3 evolved in those populations getting more Vitamin D while picking grapes in places like Rome or Cyprus.

The skin colour observation above, may also play a part here as people with dark skin will synthesise less Vitamin D from the sun than those with fair skin. Sound logical? Good. If it doesn't, you obviously don't belong here because I hate being contradicted.

Of course I'm kidding, I don't really gain any benefit from investing my beliefs in this relationship. While it might be a nice thing to naturally have decent Vitamin D levels, I'm a white man living in the tropics, so it's not exactly a massive bonus for me. I couldn't avoid the sun if I wanted to.

Summary

The list of ApoE observations is not exactly a short one, so these two are just a start. We're obviously dealing with a lot of associations rather than any definitive facts, but in the world of ApoE research, that is mainly what we have to go with. It is theorized by certain experts that E4 is the 'ancestral' gene and that E3 and E2 evolved over time in response to agriculture and a greater nutritional reliance on grains. Whether that is true, I doubt we'll ever find out, but I s'pose it's fun to play these guessing games.

My descendants are from Great Britain and Northern Germany, so I loosely fit the typical E4 profile detailed in this post, but that's not really useful in understanding how Mrs Evolution thinks I should be living my life to maximise health and longevity in a modern society. 

Which is the whole point of researching this topic.

Trust me, the story gets more interesting. More to come. 

References:
Eisenberg et al - Worldwide Allele Frequencies of the Human Apolipoprotein E Gene: Climate, Local Adaptations, and Evolutionary History 2010
Haddy et al, The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe, 2002.
Schiele et al, Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project, 1999.
Huebbe et al, APOE 4 is associated with higher vitamin D levels in targeted replacement mice and humans, 2011.
Hollick and Chen, Vitamin D deficiency: a worldwide problem with health consequences, 2008.





Tuesday, 18 March 2014

My low fat, super healthy dinner

The lighting in my kitchen is crap and I feel an overwhelming sense of twatiness when photographing my food, but this is an example of what I'd cook maybe once every 1-2 weeks. 

It's not really low fat, I just have a stupid sense of humour. If it were low fat, I wouldn't be wasting my time cooking it.

Ingredients - wine and butter were a bit camera-shy
piece of salmon, skin on
eggs, preferably recently popped from  a happy hen's vagina
fat tallow/dripping or fat of your choice
zucchini
sauerkraut
onion
garlic, chilli - chopped
Japanese mayo (kewpie), chilli sauce.

I don't know if anyone has successfully made sauerkraut in the tropics, but I'm not a fan of pointless exercises in frustration, or risking botulism, so I buy a jar. This one comes from Poland so it must be good. I hear it's no where near the equator.

The sauerkraut takes the longest, so that goes on first. Onions fried in tallow until soft, garlic, chilli added and cooked a further few minutes. Add a dash of dry white wine and the jar of sauerkraut. Cook through. Add caraway seeds near the end if you can be bothered.
I know, Germans reading this are probably shaking their head and rolling their eyes.
Meanwhile, the zucchini is cut in flat strips using a knife or mandolin. Mayo and chilli sauce mixed together. 
chilli + kewpie mayo = sausome

The fish is in now a hot pan of tallow, skin first to make it crispy, eggs are being fried slowly in butter and a grill pan is putting nice black stripes on the zucchini:
Wife says I use too many pans. So I leave one burner free.

And it all comes together to form a plate fit for a greedy pig. Of course if you're a food (s)nob like me, you send it back if the salmon isn't pink in the middle, the eggs don't have runny yolks or you're just in the mood for being a dick.
At this point I realise one egg would have been plenty

I'm not one for dissecting meals into micro-nutrients, but I'm guessing this is what the experts should be talking about when they speak of a 'balanced' meal. Plenty of vitamins and minerals and plenty of delicious fat to transport that goodness to your body's cells. 



Sunday, 16 March 2014

Thor and Porsches

I tend to blabber on about lots of stuff that annoys me. Things that give me the shits and that I find particularly illogical or downright stupid. Although how I'm seen by random strangers isn't that important, I'd still rather not come across as an angry, bitter person. I've read those blogs, and they become tiring very quickly.

Of course I understand that I'm incredibly lucky and have very little to complain about. The random chain of events that has led me to where I am today is probably verging on the statistically impossible. That I even made it through puberty with all limbs and brain function in tact is a damn miracle. 

But here I am. I'm healthy, I have money to buy nice food and pay for comfortable shelter. I have people who care about me and healthy children who look up to me. I also live in a wonderful city where the only thing our rulers really punish us with is their stupidity
and the sunsets aren't too shabby
The fact that I don't drive a Porsche Panamera or holiday every 6 months in the south of France is, quite frankly, pretty low on my care factor register. And so is the fact that I'm not 6 foot 5 and I don't look anything like Chris Hemsworth.
It's unnatural for a man to be this hot
I don't speak more than one language and can't play a musical instrument. I can't sing or dance with any modicum of talent and if you asked me to build anything with my hands I'd ask what drugs you were on.

The list of things that I can't do or don't have is long. The list of things that I do have may be much shorter, but the sum value is immeasurable.


pretty, but no room for an esky 
Despite the tone of some posts here, I enjoy a good laugh, particularly at myself. Life is too short to get worked up about shit you can't control. I choose to focus on what I have, rather than what the internet tells me I should be like or possess. 

Life is good.

Wednesday, 12 March 2014

NHMRC says unicorns are real, Heart Foundation says "we're totally ok with that"

It sometimes amazes me that the Australian Heart Foundation holds sway over public opinion and are not widely ridiculed. 

But then I remember that public opinion is invariably idiotic and my internal sense of calm returns. 

The Heart Foundation website is a surreal place to visit. It's kind of like when you stop and actually pay attention to the TV shows your kids are watching and realise it's some messed up shit. 


Funny, but in a completely different way to the HF.

But back to the HF, they certainly pack in maximum hilarity per page. Apart from their current war on salt, it seems sugar is not important unless you don't brush your teeth:

"The NHMRC (National Health and Medical Research Council) recently reviewed all available evidence to update the Australian dietary guidelines and concluded that sugar as an individual nutrient was only important in relation to dental caries."

At this point I get the same sensation I had when my work colleague was butchering a South African accent and I thought I was having an aneurysm and/or stroke because I couldn't understand a word he was saying. That is to say - rising panic and dizziness. 

Regarding the NHMRC's outstanding guidelines, I've already had a splash around in the waters of insanity here, but I press on regardless:

"There is no scientific consensus that sugar as a nutrient causes heart disease. We believe that while overall kilojoule intake is important, other factors such as levels of sodium, fibre and saturated fat and trans fat are more important in preventing cardiovascular disease.

The advice of the National Heart Foundation of Australia is based on sound science. And we will continue to review new scientific evidence as it becomes available."


Now the debate in my head is heating up as my brain's rational voice is convinced they have been hacked by someone with a half-decent sense of humour, while the panicky voice is certain they are serious and society is on the brink of collapse.

Scientific consensus? Since when did they wait for scientific consensus before damning a macro-nutrient to hell? 

"If we were to consider only sugars in a food, it would mean foods like breakfast cereals, yoghurts and even fresh and dried fruit would appear to be poor choices as they can be higher in sugars than other foods despite providing vital nutrients for good health."

The website hacking scenario is out, because it's not even funny any more. Breakfast cereals only appear to be poor food choices if you're not on acid or don't have a severe learning disorder.


"The Heart Foundation encourages people to look at the total make-up of a food, not just one element, such as sugar, to determine if it is a healthier choice."

Because that is not what they do with fat or salt. At all.

"Healthy heart tip - Rather than making choices based on sugar content alone see what else a food offers nutritionally. Look for high fibre and calcium and foods low in saturated fat and sodium."

Brilliant. So it seems it is okey dokey to eat 3 bowls of Froot Loops for breakfast as long as you eat it with skim milk and dump a few tablespoons of psyllium husks in there. It's called the Froot Loop loophole and you heard it here first.

"Guides, policies & position statements - The Heart Foundation produces an extensive range of evidence-based position papers and guidelines for dieticians and other health professionals working in the area of nutrition and cardiovascular health." 

Yes, well, I don't really have the energy to go there at the moment, so instead I'll just point out that even their nutbag cousins in the US are a little less gung-ho when it comes to hopping on the sugar train to Diabetes Central.

And that the beacon of nutritional nonsense, the World Health Organisation, has just recently cut their daily sugar recommendation by half. Mind you, it's just a draft, so they may change their mind after consulting with 'experts' to see how much money is at stake. 

And finally links below to a few studies that the NHMRC had trouble finding when they said "sugar as an individual nutrient was only important in relation to dental caries." Some disclaimers before you take a look (1) I haven't read them all in detail (2) I cheated and took a few from Jenny's excellent website, and (3) in linking to some, I'm taking a monumental leap of faith that sugar intake is most likely leading to the type 2 diabetes or high blood sugar of the subjects. 

Look, just like any other nutrient, the perfect study is yet to be conducted. Regardless, some still think that fat is the key to all modern ills. I choose sugar. I know that makes me a hypocrite, but considering I'm selfish and only really care about me and my family, my care factor is, y'know.... 

It took me maybe 15 minutes to find them all and they seem rather adamant that your internal organs think you're a c*nt if you feed them lots of sugar. 

I am Jack's complete lack of surprise. I am Jack's pancreas...and I'm bloody pissed off!*

Fung et al, 2009
Sharma et al, 2008 
Welsh et al, 2011
Cavalot et al, 2011
Kay-Tee Khaw et al, 2004
This is a new one, but I figure they'll ignore it too - Yang et al, 2014

*that will probably make sense if you've seen Fight Club at least 15 times like i have.

,



Monday, 10 March 2014

I foresee compulsory internal searches

All in the name of security, of course.

Malaysia Airlines Flight MH370 has been missing a couple of days now, with the 239 passengers and crew suspected to have all died in a crash at sea. It is no doubt a tragic occurrence, and one that would be heart-breaking for the families and friends of those who were on board. I can't imagine what they must be thinking and feeling right now, but I'm pretty sure a staunch belief in the need for tougher security at airports would be fairly low on their list of priorities. 

I could be wrong and jumping the gun, but I smell bullshit in the news articles claiming that the plane was perhaps the subject of a terrorism attack. It took only about 24 hours for this suggestion to pop up, all because two of the passengers were travelling with stolen passports. In fact, we now have "aviation and security experts" claiming a bomb was most likely the cause because "a catastrophic blast would be needed to take down a Boeing 777".


Call me naive, I'm pretty sure all it would take is either a drunk pilot or a flock of kamikaze pigeons or one of the several thousand bolts coming loose in the undercarriage. 


I would also think there'd be a number of different reasons why someone would be travelling overseas with a stolen passport. Blowing up a plane with lot of people on board is probably among the least likely.

Look, I try not to get wrapped up in too many conspiracy theories - I'm quite happy with the story of humans landing on the moon, and I really couldn't give a rat's arse who President Kennedy was really shot by, but it doesn't take audacious speculation to think that the invasion of Iraq and the establishment of torture camps in Cuba was based on a load of bollocks. That our Governments ended up with significantly increased powers over their citizens, who in turn ended up being metaphorically internally searched by said Governments, doesn't make me any less skeptical.


Similarly, I fail to see the logic behind spending enormous amounts of money and resources on prohibiting Mr and Mrs Average from taking nail clippers or 105ml of water on to a plane. I honestly don't even know where to start in dreaming up a way to hurt someone with nail clippers. A pen, the arms of eye-glasses, earrings, a necklace, a piece of paper, the smashed screen of your tablet - all of these things I can imagine hurting someone with. Nail clippers....no. The amount of effort it takes just to get them on to your own toe nails should be evidence enough that they are harmless.


This is the illogical world we now live in. Where the threat of some act of terrorism, no matter how unlikely, has us all handing over the contents of our lives to the zombies who are invariably employed as airport security.


I'm probably getting annoyed over nothing, but they haven't even found the plane wreckage yet and already we're being told that the Governments' efforts to protect us all are vindicated. 


Maybe there was a bomb. Maybe the two passport thieves were up to no good. Or maybe the parasitic scumbag journalists are whipping up a hysterical frenzy of nonsense. Given that the most likely location of the plane is at the bottom of the sea, I'm not sure we'll ever find out for sure. But even if there were some nasty men with evil intentions, I don't want it used as some warped justification to trample all over our basic human rights.

I don't want to hear some brain-dead idiot shouting "I'm not getting on the plane with you unless I see the video of your colon. If you don't have anything to hide, you shouldn't be complaining."

Time to think pleasant thoughts. Maybe they'll turn up on an abandoned air strip somewhere. Or at the very least, have died quickly and painlessly.


Friday, 7 March 2014

Tardis for sale

Doubles as a TV cabinet/and or transmogrifier.

I present to you a once in a lifetime opportunity to buy this fantastic portal to many dimensions. Hand crafted from teak, this solid and very attractive piece has 4 drawers, a separate shelf for your DVD player and will encase a TV of up to 20 feet in length. If you’re a bit picky and don’t want to smash your 20 foot long TV into tiny pieces, then it would probably fit an ‘un-smashed’ 32 inch flat screen without too much hassle.

Used originally by an Indonesian time lord, this magnificent box is still in great condition because, frankly, he wasn’t very good and got eaten by The Beast fairly early on in his career.

Why am I selling it? Well, while the Darleks are about as scary and dangerous as they look (i.e. not very), the Pyrovile are as mean as all buggery and they’re a tad angry with me after our last interaction. I can’t say too much but it involved a poker game, five aces and a particularly strong batch of intergalactic mushrooms.

So, how much for this magic machine? $120. See the photos for how fantastic a bargain that is. This is no chip-board box that will fall apart any time soon – it is solid wood. You could always offer less if you want to insult the memory of our fallen fellow time lord. 
welcoming you with open arms
I can assure anyone from (insert rich suburb here) that you won’t get mugged or carjacked in the slums. I’d suggest you not come after sunset though as we (the unwashed) tend to pick up the scent of money and blood better in the dark. Isolation of senses and all that.

Transmogrifier function: As if the time and dimension travel wasn’t enough, this item also provides the ability to transmogrify any object, organic or otherwise. You can go through life feeling that you have no need for a transmogrifier, but then your friend’s vegan partner turns up at your bbq with a bowl full of chickpea and soybean salad and you wonder how you’ve ever done without it. Turning something inedible into (a) alcohol so you can put up with their constant whining about eating baby animals, (b) a big plate full of sausages and bacon, or (c) anything other than pretend food, provides so much satisfaction that you may just spontaneously combust. Transmogrifying yourself into a homo erectus and turning up at church also has its thrill factor, but then I’ve been told I’m a disturbed individual more than once.

If you’ve read this far, I’ll be honest, you deserve a bonus. If you pay $120 for the Tardis, you can have the fantastic JVC CRT TV that is currently in the Tardis. It doesn’t have a remote so it doubles as an exercise machine. If you are lazy you could always get a universal remote. For those of you who don’t know what a CRT TV is – it is a box with magic pictures on it that aren’t digital – therefore you need to plug a digital box into it to make those magical pictures become less fuzzy. 

K..L…F…aha, aha aha.

Terms, conditions, disclaimer and other rubbish – If you hand over cash for this item, you take personal responsibility for all time travel ramifications. Don’t blame me if the Priestess of Pyrovile isn’t exactly thrilled to see you turn up in a box that is burned into her spiteful memory. As to the Tardis actually working, you have to understand that its operation requires an exceptional amount of ingenuity and intelligence* and that it is a used item. Similarly, if you buy a second-hand lawn mower, you can push it around your yard making “brrm brrrm” noises, but unless you get it started, chances are your grass won’t get any shorter. 
In regard to my thinly-veiled pot shot at vegans, don’t take it personally. I’m just a self-righteous lazy person and vegans are easy targets. Just like theists and Alan Jones. Being a coward, I tend to pick targets for ridicule that are least likely to grab a sharp weapon, track me down and growl “come at me, bro”. Seriously though, I actually have an enormous amount of sympathy for people who are blind to the wonders of animal flesh.

Not really. Did I mention that I’m a compulsive liar? I mean, c’mon, if Marduk didn’t want us to eat lamb and veal he’d have made them taste like tofu. Lions only eat meat and they are invariably awesome. I sometimes pretend to be a lion by letting my hair grow and hiding in the bushes, waiting for prey. The opportunity to pounce on a passing springbok is yet to present itself but I’m now on pretty good terms with the postie. Her argument that lions can wear pants and still remain camouflaged and awesome was compelling. She also said she’d keep a look out for injured or newly-born springboks for me.
   
Despite the geekiness of this ad, the last time I watched a Dr Who episode was in the early 80’s. I caught a few seconds while channel surfing about a year ago and had nightmares for a month. It seems children aren’t scared by much these days. Except, of course, human interaction. Speaking of geekiness, it is becoming abundantly clear that what constitutes TV comedy these days is pretty much anything the Americans can put together with a hand full of untalented morons and a recorded laugh-track. I’ve come to the conclusion that watching more than 30 seconds of “The Big Bang Theory” increases your risk of a condition called “irresistibleurgetostabmyeyesoutwithabrokenbottle”by about 3500%. Or maybe I’m just old and out of touch with what’s cool with the hipsters. I suspect the former.

So, there you have it - I’m an old, bitter and obnoxious person. Just buy my damn TV cabinet already.

*ingenuity and intelligence is preferable but the mind-altering substance of your choice will probably help things.


almost exactly the same

Tuesday, 4 March 2014

ApoE - a quick look under the bonnet

The purpose of posting all that I have found on Apolipoprotein E is (a) to clear my thoughts and (b) to possibly save someone (E4 club members?) some time. Searching the internet for information on ApoE can be a frustrating exercise, assuming you want something other than the standard rubbish.

Following on from my ApoE confession, today I’m going to provide a layman’s explanation of what Apolipoprotein E is, and why you might care.

In a general sense (for simpletons like me), ApoE is a protein made up of 299 amino acids and it is synthesised by (spat out of) many organs, but mainly your liver and your brain. You could think of ApoE as the captain of little shipping vessels (lipoprotein particles) that flow through your body. Here’s a pretty picture of a lipoprotein particle that may help:

As you can sort of see, lipoprotein particles carry lots important stuff like cholesterol, triglycerides (fats) and fat-soluble vitamins and they transport them to where they are required for things like cell regeneration and maintenance, hormone production and immunity function.

The lipoprotein particles that the average Joe Blow might be familiar with are Low Density Lipoproteins (LDL) and High Density Lipoproteins (HDL) - often mistaken for ‘bad and good cholesterol’, but that’s a completely different and insanely boring story. So I won't tell it.

Apart from LDL and HDL there are also IDL (intermediate) and VLDL (very low density) and chylomicrons. I won’t go much further on this, but when you are looking at ApoE it’s important to note that as you move from chylomicrons to VLDL to IDL to LDL, the size and the amount of triglycerides within is decreasing and the amount of cholesterol is increasing. 
 
source: http://eatingacademy.com/
Back to ApoE
When I referred to ApoE as the “captain of the ship”, I meant that once ApoE is synthesised by your liver or brain (mostly) and binds itself to a lipoprotein particle (preferentially depending on the type of ApoE), it will then be a determining factor in where that particle goes and what happens to it.

It does this because it acts a ligand (a connector) to the LDL and other cell receptors. The LDL receptor family is another fascinating ‘thing’ that the cells of our body use to get that important cargo from the lipoprotein particles.

The cells of our body produce the receptor, the lipoprotein particle is cruising past with an ApoE on it and lots of good stuff inside it. The ApoE binds with the receptor and the cells get what they need. 

The ApoE is perhaps the drug dealer, and the cells are desperate for a fix of what they're carrying. Or something like that. For the purposes of this amateur lipidology lesson; ‘magic happens’ and our bodies get something out of it, in part due to ApoE. 

One (indirect, you could say) function of ApoE is to clear lipoproteins from your blood plasma, and anything those particles may have been carrying at the time.If you’re like me and prefer pretty animations to complex wordy explanations, then you may enjoy this that I linked to in the first post. That animation can get stuck sometimes, and I couldn't be certain it's 100% accurate, so be patient and non-pedantic.

ApoE is polymorphic
Which in English means that there are different types, the main ones being ApoE2, E3 and E4. Humans have an ApoE profile that is a combination of two “alleles”. An E3/E3 profile is most common, but you may also be E2/E4, E2/E3, E3/E4 or E4/E4.

As you can see from the table below, the ApoE only differ at sites 112 and 158 of the (299 amino acid) protein:
E2
E3
E4
Most animals including apes
amino acid at site 112
Cysteine
Cysteine
Arginine
Arginine
amino acid at site 158
Cysteine
Arginine
Arginine
Threonine (at site 61)

Like a lot of things, it’s your parents’ fault
It seems that you get one ApoE allele from each of your parents. I’m E4/E4, so to point out the obvious, it follows that my kids have at least one E4 allele. But given that their mother has ridiculously low plasma cholesterol, I guess that they are most likely E3/E4. Possibly E2/E4, but less likely given E2’s rarity.

Fascinating or what?

So, finally getting to some sort of point
Your particular ApoE profile matters. It matters because the ApoE alleles behave differently – E4 preferentially associates with the triglyceride-rich VLDL and chylomicrons whereas E2 and E3 and tend to cling more to the cholesterol-rich LDL and HDL particles.

Why? Another boring story to do with salt bridges, N and C terminals and other such biochemistry nonsense1. What matters to me is what happens as a result of these ‘preferences’ but the geeks among you may find this interesting:
Source: reference 3
Another observation worth noting here is in regard to the ApoE alleles’ ability to bind to the LDL receptors. It sounds like E2 is pretty hopeless at it, which is thought to be why E2 people tend to have low cholesterol. 

In contrast, E3 and E4 play very well with the receptors and E4 is particularly adept at clearing VLDL and chylomicrons from your blood. 

As far as I can ascertain, the theory espoused by SPILCs seems to be that E2 = more LDL receptors = less LDL plasma cholesterol. E4 = fewer LDL receptors = more plasma LDL cholesterol2.

I’ll stop here because I want to break the topic up into digestible chunks. But before I do, I want to pre-empt the next post by saying I think the ApoE/cholesterol relationship is an interesting observation, but it doesn't really tell us much in terms of ApoE’s role in certain health conditions. 

At least not if you're under the impression that cholesterol is good for you. If, on the other hand, you believe high cholesterol is the cause of heart disease, Alzheimer's and all sorts of nasty ailments, then the ApoE relationship will be terribly convenient for you.

References
1. Nguyen et al - Molecular mechanism of apolipoprotein E binding to lipoprotein particles, 2009.
2. Schiele et al - Apolipoprotein E serum concentration and polymorphism in six
European countries: the ApoEurope Project, 2000.
3. Egert et al - ApoE genotype: from geographic distribution to function and responsiveness to dietary factors, 2012.