Common disease-common variant researchers in human genetics may get more media coverage, including the science media, but the Germ Theory people are cleaning up where it counts.

i've made this argument before, but this is a false dichotomy/distinction.

for example:

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease
...
these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

  Email | Homepage | 10.07.08 - 10:08 pm | #

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p-ter said: "this is a false dichotomy/distinction"

It is not a false dichotomy from a clinical medical perspective; because establishing a germ cause of a disease has often meant that treatment strategies can focus on (for instance) preventing exposure to the germ, enhancing immunity or killing the germ.

This has often been very successful: e.g. public health hygeine, eradication of smallpox, antibiotics and anti-virals.

A gene cause of a disease has, so far, meant that a whole different set of prevention or treatment strategies were appropriate - and so far these have been much less successful than anti-germ strategies.

So establishing a germ cause for a disease (as a necessary cause, even though not a sufficient cause) remains extremely valuable.

Bruce beat me to the punch. I'm sure there were variants underlying susceptibility to ulcers, but if you can just take antibiotics and be cured then the genetics becomes entirely academic. Ditto for STDs and safe sex, etc. Research dollars that flow into genetic studies get less long-term bang per buck than ones looking for pathogens if a disease really does have an infectious source, and if we have theoretical reasons to believe it does then rationally more money should go there.

Also pretty fresh, CMV probably causes most gliomas:

http://www.ncbi.nlm.nih.gov/pubm...pubmed/ 17951512

There's a common variant -- at about 90% in Africa (higher elsewhere) -- that underlies susceptibility to malaria, namely the non-sickle cell allele. Same for susceptibility to HIV in Africa (and outside of Europe) -- the common, ancestral variant of CCR5.

So, common variants implicated in common diseases are of the form 1) a variant whose alternative can't fix due to damage to the alternative's homozygotes, or 3) a variant that will eventually be replaced by the alternative, but where the selection pressure is very new.

This interpretation could've been made 50 years ago, so if CD-CV is supposed to be non-trivial and sexily novel, it had to have meant what everyone thought it did -- that the HapMap was going to show us that a few common variants were implicated in common, harmful diseases. But that didn't happen, so now there's this "No, we didn't really mean that" kind of track-covering.

The same is or will be true for the Thrifty Gene hypothesis, once human geneticists learn about what types of societies ever faced food-scarcity, and how that shows their hypothesis is wrong.

Chiropractors claim that most human disorders originate in the spine.

Geneticists claim that most human disorders originate in the germline.

Inside the scientific community both groups look sillier by the day.

find the infection behind cardiovascular disease, (atherosclerosis) and you're assured a nobel prize.

There's been some circumstantial evidence pointing to chlamydia in atherosclerosis, but I don't think it's panning out. Antibiotics nothing for it, and a lot of that evidence has turned out to be shakier than it looked.

http://jama.ama-assn.org/cgi/con...act/293/21/ 2641
http://www.ajhp.org/cgi/content/...stract/64/8/ 830
http://www.pubmedcentral.nih.gov...gi? artid=540187

Infection might seem like a good bet for atherosclerosis since it's linked to chronic inflammation, but I don't think it's a major contributor. Diet probably has more to do with it.

Pneumococcal Vaccine Associated With 50 Percent Lower Risk Of Heart Attacks

Dr. Mohammad Madjid from the Texas Heart Institute hypothesizes that the pneumonia vaccine protects against heart attacks because it prevents pneumonia which has been shown to trigger heart attacks. Other studies suggest that respiratory (especially influenza) and urinary tract infections are associated with heart attacks.

Hypothetically, an infectious cause of any disorder may only be the trigger. If someone cuts my arm off with an chainsaw, and a year later you investigate the wound really closely, you won't find the saw. Nor will giving me antichainsaw-otics make arm grow back.

Not finding the pututitve bug in people with heart disease may mean that it is not a stealth infection, but a delayed result of acute damage. So for say chlamydia, we'd have to find people who were never infected as a control.

I found a paper claiming that male pattern baldness and atherosclerosis could both be caused by occult fungal infection.

From the abstract

"A variety of infectious agents have been investigated as the underlying risk factor for atherogenesis, however, none have been proved to be causally linked. Also several interventions against these agents have not been proved to be of benefit in trials. The role of fungal infection, however, has not been explored in sufficient detail. Baldness particularly male pattern baldness and coronary artery disease have been linked in several epidemiological studies. There is some evidence that this type of baldness could be due to fungal infection and this link is being established even though traditionally male pattern baldness was associated with androgen effect. Seborrheic dermatitis and Pityrosporum infection have been causally linked and the benefit derived from antifungal shampoo in male pattern baldness, gives further credence to the link with fungal infection. Here it is being hypothesized that fungal infection is the underlying risk factor for both baldness and CHD. Several interventions, which have proved beneficial in CHD like statins and drug coated stents, also have anti-fungal effects, lending further credence to the present hypothesis."

http://linkinghub.elsevier.com/ r...306987704002312

At least hypothetically, a causal infection does not have to chronic. If I get arm cut off with a chainsaw, and look at the stump a year later, you won't find the saw. And giving me antichainsawotics won't do me any good. An infectious cause of heart disease may not be a chronic infection.

I found an article hypothesizing that the link between male pattern baldness and heart disease is occult fungal infection. But it's a few years old, and has never been cited. But maybe the link is predicted well by standard theories of both conditions.

http://linkinghub.elsevier.com/ r...306987704002312

I'm sorry if I posted nearly the same comment before, but I think the internets ate my first one.

At least hypothetically, a causal infection does not have to chronic. If I get arm cut off with a chainsaw, and look at the stump a year later, you won't find the saw. And giving me antichainsawotics won't do me any good. An infectious cause of heart disease may not be a chronic infection.

I found an article hypothesizing that the link between male pattern baldness and heart disease is occult fungal infection. But it's a few years old, and has never been cited. But maybe the link is predicted well by standard theories of both conditions.

http://linkinghub.elsevier.com/ r...306987704002312

I'm sorry if I posted nearly the same comment before, but I think the internets ate my first one.

Total or abdominal adiposity from the diet's excess of calories over energy expenditure though exercise (or heat production from decoupled mitochondria) is a state of immune system activation.

Inflammatory Proteins are related to total and abdominal adiposity in a healthy adolescent population: the AVENA study Warnberg Julia

Excess bodyfat may protect against some infectious diseases by producing an generalised inflammatory state

Matt McIntosh, one day I mean to look through all the antibacterials trials for heart disease, and see if anyone checked whether the detectability of C. pneumoniae in the atheromas actually declined during the therapy.

Failure of therapeutic trials certainly does give some evidence against the C pnu hypothesis, but it doesn't close the issue completely. See "Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment," PMID 11157684.

Indeed, this reflects a larger phenomenon. For almost all anibacterials, no one really grasps the complete causal chains leading to cell death, and in fact it is quite easy to render most taxa significantly refractory not only to antibacterials, but also to biocides too wantonly destructive for medical use - any severe stress can bring this about: heat shock, starvation for energy substrate or any element, pH shock, redox shock, you name it. (I'm talking immediate tolerance in the wild type, not selection of a new genotype.) Refs include PMIDs 17215163, 15807669, 17143318. Chlamydia is not the only bac that can do something similar when it is in a nonpermissive host cell type (see Barker on legionella).

The limitation is that there are relatively few human bacterioses so far involving something that looks like this. One is the rare M avium complex mycobacteriosis and other atypical and rare mycobacterioses. These are often treated for years on end with an amazing 4 to 6 different antibacterial agents, and there is rather commonly a failure to improve despite this gonzo theapy:

http://www.journalarchive.jst.go...8& startpage=670

Actually, ordinary M tubeculosis TB is (widely presumed) a little bit like this too - but different. In ordinary TB the bastards die off at almost a log a day, but then the last few (probably 1 in 10^6 or less, I think) are in a tolerant phenoptype, and it is to kill those that therapy continues for 5 months to 2 years.

And what goes on with the resistance of biofilms is probably related to all this too. Biofilms can rather commonly cause untreatable infections.

It is unclear whether HCMV plays an active role in malignant tumor progression or becomes reactivated under pathologic conditions that result in chronic inflammation or immunosuppression.

This is definitely a tough point. Tumors are chaotic, and most of them are immunosuppressive for purposes of evading immunity (altering their expression of MHC I for example). It would be interesting to see if other resident viruses are also getting antsy in these tumors - or in other tumors; I'm sure some work along these lines has been done long ago. "Unfortunately" I'm not sure that most of the resident viruses commonly penetrate the cerebrospinal thecum, so that might be a confounding factor as far as whether or not they reproduce in gliomas where CMV is partying. Ie, they cant get wild in there if they aren't in there to begin with.

"Total or abdominal adiposity from the diet's excess of calories over energy expenditure though exercise"

Am I going to have to write a post about the caloric-intake-and-exercise myth so people will stop repeating it?

Do the math: a 200 lb guy would have to walk all the way up the Sears tower to perform enough work with his muscles to burn off the calories contained in a reuben. BMR is the main driver of energy usage, not physical activity; in the long run I can burn more energy with 30 minutes of high intensity weightlifting once a week than by jogging a mile a day. Hell, several hours a day of hard *thinking* burns almost as much.

Light exercise does practically nothing, and people who work out hard typically eat more to compensate so the effect is roughly a wash in the long run. Hormones see to that. Unless you've got some sort of pathological hormonal dysregulation, diet drives adiposity. Period. Carbohydrates drive insulin drives fat accumulation, and chronic insulin signalling means trapped fat. None of this new -- it's all been known for almost half a century.

As for the association with fatness and chronic inflammation -- no shit, but you're missing a hidden variable or two. Hint: blood sugars are reducing agents -- what would we expect them to do to proteins and lipids, and how would we expect your body to deal with this?

Also, the idea that being fat makes you less likely to suffer from infections is um ... how shall I put this ... complete flapdoodle:

http://dx.doi.org/10.1016/S1473-...3099(06)70523- 0

This too is predictable if you happen to know that, for example, vitamin C competes with glucose for entry to white blood cells and lymph tissue via the same transporter, which is why diabetics also get infections more often.

I spent the summer learning every inch of this literature because men in my family have a tendency to drop dead of heart attacks before they reach retirement age. Now I have an inkling of how Greg feels all the time.

Eric,

Thanks for the chlamydia refs, I'll have a look. As for CMV, they have some trials on right now at Duke and somewhere else (I can't recall) using antivirals to treat patients who've had a glioma removed, watching how long it takes before they see regrowth again compared to untreated patients. So we'll know soon enough.

Matt MacIntosh I agree with 95% what you say but I did not mean(and I should not have implied) all infections, just TB. Inflammation is immune activation so disease in which inflamation is a factor and atopic disease will be greater in overweight people because most of the cells in a gut are immune cells. Yes ascorbate does amp up your immunity but do you really want to activate your leukocytes just for the sake of it; the devil finds work for idle hands.

Chemotherapy survival is said to be better with extra pounds too. Who says I hear you ask, well "zenpharaohs" said it and he seems to know what he is talking about. On youtube he is doing some heavy workouts (100 reps averaging over 150kg in 51 min). he also does cardio (training diary at johnstonefitness forum. He says having a gut helps with stamina too. He concentrates on trying to build muscle. I am no longer sure that trying to get lean would be a good idea for everyone.
How much energy does hard thinking burn over the 20% of energy figure usually given?
I have wondered about this.

I definitely agree that more funding and attention should be diverted to varmint hunting, but I think genetics could end up being important for the treatment of diseases discovered to be infectious.

Compared to the classical infectious diseases, "new" parasite-caused diseases might well skew towards a more indirect pathogenesis not dependent on permanent infection, or towards lesser eradicability by drugs or preventability by vaccines. (HIV and syphilis are good examples of infections which are probably not vaccine-preventable, and any chronic infection is a priori less likely to be vaccine-preventable than acute infections.)

H pylori may instantiate this - look how many antibacterials (concurrently) it takes to eradicate it. (See http://bcbsma.medscape.com/viewa...rticle/ 574479_4 for discussion.) Had it been just a little harder to treat, maybe it wouldn't be eradicable at all. Had it been significantly easier to eradicate, it would have been discovered with ease courtesy of Domagk or Waksman, before 1960.

It's certainly possible that a lot of diseases are (if infectious) rare outcomes of ultra-common, usually silent infections like EBV. Prospects for vaccines preventing EBV and HSV (or attenuating the size and effects of the infections) are unclear.

Genetics may point the way to cleaning up eg autoimmune and neoplastic states that might turn out to be infection-caused but not amenable to the classical anti-infective measures.

Matt, I may be a cardiocirculatory subprime myself. My lineage features a dominant-negative rare deleterious, a 21-bp deletion in MEF2A which I ought to get tested for. It was written up in Science.

(I don't mind being public about it since I doubt it greatly increases my expected values for health care or pension costs, though I don't know that for certain. Certainly if I croak on a hike in the woods it will be a lot cheaper than nine years of Alzheimer's.)

You might be interested in the chapter on dietary cholesterol in ISBN-13: 978-0691099996. The author is no particular authority: just a smart physics prof, if that's not redundant, from a modest university (George Mason), who enjoys evaluating heterodox ideas from scratch in a semi-popular format. He comes down as a moderate on this question, though his work is probably more valuable than his opinion.

Tod,

My comment about thinking was a little misleading. Most of what the brain burns is just for cellular upkeep, but intellectually challenging tasks are accompanied by more glucose uptake. The basal metabolic rate for brain tissue is ~10 kcal/kg/hr, which translates to about 14 kcal/hr burned by a typical 1.4 kg brain. That can jump up to about 17 kcal/hr during periods of mental effort. Someone who's about 150 lbs will burn roughly 600 kcal/hr while jogging. So in six hours of heavy thinking the brain burns about as much as the entire body does in ten minutes of jogging. Of course that's a bit of an apples to oranges comparison, but it helps get the point across.

"do you really want to activate your leukocytes just for the sake of it; the devil finds work for idle hands."

I should not have to tell you how silly this statement is.

Eric,

Yeah, I've done a fair bit of reading on cholesterol as well. My favorite theory about it, which I think would be hilarious if true, is that it's actually an anti-oxidant whose purpose is to limit damage to cell membranes, and that one purpose of the lipoprotein system is to efficiently ferry it out from the liver to peripheral tissues (LDL) and then back again to be disposed of when oxidized (HDL). This would ironically explain why statins suck so much (they have a pathetic NNT in the range of 150 on up) -- oxysterols contribute to atherosclerosis when they're not efficiently disposed of by HDL, but cutting down on LDL just means more oxidative damage to *other* things. Oops.

Cites for cholesterol as an antioxidant:

http://dx.doi.org/10.1016/0891-5...5849(95)00038- Y
http://dx.doi.org/10.1016/S0005-...2760(97)00093- 3
http://www.ncbi.nlm.nih.gov/ site...Search=10435832
http://www.neurology.org/cgi/con...ract/54/10/ 1944
http://biomed.gerontologyjournal...tract/59/3/ M293

(Keep in mind that the damage caused in stroke is mostly oxidative damage that occurs during reperfusion, not during the oxygen deprivation phase as used to be assumed.)