Even when a not very virulent flu virus goes around, some people still get sick, and some of those even die. Of those people who get sick or die, some are elderly and some have co-morbidities like obesity or being a smoker that contribute to their illness, says Amalio Telenti, a professor at the University of Lausanne in Switzerland. But some of those people who get sick or die from the not-very-virulent flu virus were healthy. "That's when you start thinking about genetics," Telenti says.
The classic example of the role of genetics in susceptibility to disease is changes in globin genes, which lead to disorders like sickle-cell anemia, but also give protection against infection by the malaria parasite.
Such differences in the host affect whether the pathogen can infect and spread. Genes involved in the human immune systems are highly variable and have undergone rapid evolution, leading to host heterogeneity. That, Telenti adds, leads to differences in disease susceptibility and disease progression.
Many earlier studies looking for host genes affecting infectious disease processes have relied on candidate gene approaches, which were able to identify a number of genes — like CCR5 in HIV — involved in host susceptibility to disease or in disease progression in the host. Since then, researchers have turned to genome-wide association studies to find such genes, often with mixed results. As their search for variants associated with infectious disease susceptibility and progression deepens, researchers are beginning to use whole-exome and whole-genome approaches. Findings from such studies could, in turn, inform vaccine or treatment development efforts.
However, just how much of infectious disease susceptibility and progression is due to genetics is an open question.
"We really don't have a good way of making an overall assessment of the extent to which what happens upon exposure is genetic as opposed to non-genetic," says David Goldstein from Duke University. "In a lot of ways, the easiest way to find out the extent to which the trait is genetic is to do a genetic study, to try to find the genetic influence."
The GWAS show
With the advent of genome-wide association studies, researchers have been applying them to study a number of disease states, including infectious disease susceptibility and disease progression.
In HIV, a deletion mutation in CCR5 has been known to protect people from HIV infection. To enter some immune cells, the virus must interact with both CD4 and CCR5 receptors on the cell surface, and if the CCR5 gene is mutated and the protein is not expressed, it affects HIV entry to the cell, protecting people with the mutation from infection. Researchers, though, have wondered if there is another such protective mutation as some people who are seemingly immune to HIV have normal CCR5 genes.
A recent GWAS looking at hemophiliacs who were exposed to HIV in the 1980s, some of whom never became infected with HIV, looked into just that question, Lausanne's Telenti says.
He notes that in the general US population, about 3 percent of people are homozygous for the CCR5 deletion, and that number rises in the hemophiliac cohort to between 20 percent and 50 percent.
"This study has been done for almost 400 hemophiliacs and everybody bet that it would find a new gene," Telenti says. "And nothing came up."
He adds that another bigger, but less well-designed study, also failed to find a CCR5-like gene. Both studies did find signals at CCR5, showing, Telenti says, that the approach was correct.
"There is no other CCR5-looking-like common variant. I think that is pretty clear from these studies because they are powered to detect these types of effect sizes," he says.
Researchers have also been investigating susceptibility to Mycobacterium infection. Erwin Schurr at McGill University has been looking at susceptibility to both M. leporae and M. tuberculosis infection. He notes that his team has found SNPs in HLA are associated with leprosy infection, as has a Chinese research team, though the groups noted different alleles. Meanwhile, Schurr's team has found a role for TNF-α and IFN in protection from tuberculosis infection.
Other groups, he adds, have been investigating genetic control of mycobacterial disease. "Now, in either instance the yield has been meager," he says. "In genes that have been identified, they really have been identified by candidate gene approaches."
A similar situation has arisen out of studies of HIV control — of those people who have been infected with the virus, but don't develop the disease.
The International HIV Controllers Study, with funding from the Bill and Melinda Gates Foundation, set out to determine how people control infection. From their GWAS of a multi-ethnic cohort, the group identified a large number of SNPs in the region encoding the major histocompatibility complex that are associated with disease control.
Specifically, as the group reported in Science in 2010, those SNPs clustered around class I HLA genes, particularly HLA-B, whose gene product presents viral peptides on cell surfaces. "Of all 20,000 genes in the human genome … it's one of the most polymorphic," says the Broad Institute's Paul de Bakker, who was part of the International HIV Controllers Study.
The study further uncovered that, in the HLA-B protein, three amino acid positions had stronger association with viral control than others, and those amino acid positions are found in the peptide-binding groove.
A follow-up study that came out this past summer in Human Molecular Genetics focusing on the African-American subset of the controller cohort found that those same positions were important for disease control in African Americans. "At that level of analysis, we get very similar results between Europeans and African Americans," de Bakker says. On a finer level, he adds, there is a difference in frequencies for what alleles commonly occur at those sites.
Other studies have shown involvement of HLA in HIV control. Both Goldstein and Telenti were part of a project that found that HLA-B*5701 is highly involved in HIV control, though regions in HLA-C were also implicated.
While genome-wide association studies have identified genes linked to disease control, not much of what's been uncovered is surprising. "Unfortunately, despite a great deal of work, we've actually learned very little new about the genetics of control of HIV," Duke's Goldstein says. "It had been long known from all the candidate gene work about the role of CCR5 and of the importance of HLA. And there is, in fact, nothing beyond that that has been decisively shown. In that regard, we haven't really gotten all that far."
More on the way
Even though recent work to uncover novel genes associated with infectious disease susceptibility and control has not been very fruitful, researchers are optimistic that there are new ones to be found, though they can't be certain that there are.
"It's really hard to know, but I would be astounded if there isn't more to find," Duke's Goldstein says. "There's a really simple logical train that really does make a slam-dunk case that there is more to be found."
For HIV, he says, that case goes like this: To go through its lifecycle, HIV needs to interact with host proteins, as it does with CCR5. For many genes in the human genome, there are people in the population who don't make the gene product or who make a faulty version of the gene product. Then, he says, if you put those pieces together, there must be variation in the other proteins that HIV interacts with that would interfere with the HIV lifecycle.
"It probably is just the case that those differences are relatively rare in the population, and so they didn't turn up in the genome-wide association studies," Goldstein adds.
Many researchers, then, are turning to whole-exome or whole-genome sequencing to tease out those currently unfound variants. Goldstein notes that his group is sequencing a cohort of hemophiliacs to work out why some have not been infected with HIV despite exposure.
Meanwhile, de Bakker and the International HIV Controllers Study are in the midst of analyzing whole-exome sequencing data from that cohort to find variants linked to infection control. "If we are able to find such rare variants, then that could really be insightful, especially if that involves genes that are not part of the MHC," he says.
The MHC region, he says, shows high variability between people, making it difficult to develop a generic vaccine or other treatment. "There's no doubt that certain [HLA] alleles of those genes … are more protective than others," he says. "But you are only born with two alleles of each HLA gene, and it's not trivial to just change those alleles in everybody."
If a gene were found on a different chromosome or in a different pathway, there would still be the issue of developing it as a generic treatment or vaccine, but that may be a more tractable problem, he adds. "You could always be surprised by these genetic findings and it [could] lead to new pathways that you have not even considered before," de Bakker says.
Further, better understanding of all the variation in how people are susceptible to or can control HIV would help inform vaccine and treatment efforts, Goldstein says. "I think we could learn an awful lot from knowing why some people are essentially immune or some people control the virus really well," he adds. "We haven't learned that yet."