Combinations of Variants Contribute to Genetic MS Risk
Genetic susceptibility to multiple sclerosis (MS) depends on an individual’s particular combination of multiple risk variants, a study reveals.
The study, “Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions,” was published in the journal BMC Medical Genomics.
The risk of developing MS is thought to be due to a combination of environmental and genetic factors. To date, more than 200 genetic risk variants, or disease-associated mutations, have been identified that potentially contribute to susceptibility to MS, either alone or in combination.
Many of the risk variants occur in genes that carry instructions for the human leukocyte antigen (HLA) — a protein complex on the surface of certain immune cells that plays a critical role in immune system activation. HLA communicates with other immune cells to identify invading infectious targets and helps distinguish between invaders and the body’s own cells.
HLA risk variants are thought to contribute to the altered immune response that targets nerve cells, the underlying cause of MS.
MS risk variants are identified as single-nucleotide polymorphisms (SNPs), which refer to single changes in the genetic code commonly found in MS. However, individual SNPs are a marker of a region in the genome and may be near or far from the actual HLA genes.
Haplotypes are a set of SNPs that tend to always occur together on the same chromosome, inherited from a single parent. One haplotype composed of 11 SNPs (a1) often occurs in the region of DNA surrounding the HLA-DRB1 gene and is associated most significantly with MS than any other SNP haplotype in the genome.
Recently, a small collection of large, stable haplotypes — known as conserved extended haplotypes (CEHs) — have been found to stretch across the genomic region that carries most of the genes for the HLA complex. Most likely, genetic susceptibility to MS depends on the nature of these CEHs rather than a specific HLA gene variant.
Furthermore, there are other haplotypes near the HLA genes identified as MS risk variants, including EOMES, related to immune T-cell growth, and ZFP36L1 and CLEC16A, both genes important for cell activation.
Researchers based at the University of California, San Francisco, now explored how different combinations of CEHs contributed to MS risk and investigated the relationship between MS-linked CEHs in the HLA region and these other risk haplotypes.
Genetic data were collected from the Wellcome Trust Case Control Consortium (WTCCC), which included 18,872 controls and 11,376 MS cases of European or European-American ancestry. Of those with MS, 72.9% were women, with an average onset age of 32.3 years, and the majority (89%) had a relapsing-remitting MS.
CEHs were classified into five haplotype groups: CEHs containing the a1 haplotype that carried two known MS-related risk variants called HLA-DRB1*15:01 and HLA-DQB1*06:02 (H plus), CEHs that contained nine other disease-associated haplotypes (extended risk, ER), and CEHs composed of eight disease-protective haplotypes (all protective, AP).
Also, a neutral group (0) made up all those CEHs that did not belong to H plus, ER, or AP, and a fifth group included patients with a CEH containing a single HLA haplotype (c1).
The team then looked at combinations of these five CEHs in MS risk. Of note, a person has two combinations of CEHs, one inherited from each parent.
On its own, the H plus haplotype contributed to disease susceptibility in an individual, although the magnitude of the effect depended on the particular H plus haplotype. In women carrying a single copy of H plus or extended risk CEHs, the MS risk was higher compared to men, whereas the risk in women and men having both of these CEHs was the same. The combination of two copies of the H plus CEH significantly increased MS disease association.
In the same way, two copies of the all protective CEHs were significantly more protective against MS than a single all protective CEH copy. The impact of these protective effects was similar to the opposing MS risks from H plus.
One copy of the extended risk CEH added to the risk of H plus, but less than a second copy of H plus. Also, the c1 CEH contributed little disease risk on its own, but added more risk in combination with any H plus haplotype.
The H plus combined with the neutral CEH (0) has a threefold higher risk compared to two neutral CEHs, whereas the double H plus combination led to a 2.1-fold higher MS risk over a combination of H plus and neutral CEHs.
“Replacing an (0)-haplotype with an [H plus]-haplotype has a significantly greater impact when the companion haplotype is an (0)-haplotype compared to when the companion is an [H plus]-haplotype,” the researchers wrote.
While the double H plus genotype was a 2.1-fold higher risk over H plus with neutral CEHs, the combination of H plus with all protective CEH carries a 3.4-fold higher MS risk than all protective CEH combined with the neutral CEH.
“The impact of replacing one haplotype with another often depends considerably (and significantly) upon the nature of the companion haplotype,” the researchers wrote. “This reflects the multiple haplotype-haplotype interactions that exist within the [HLA].”
Regarding the non-HLA haplotypes, different combinations consistently increased the MS risk when added to the H plus and neutral combined CEHs, double H plus, neutral combined with the c1 CEHs, and H plus with c1.
Conversely, when non-HLA haplotypes were added to “risk” H plus with all protective CEHs, H plus with extended risk CEHs, and “protective” CEHs combinations — such as all protective with neutral CEH as well as the all protective with c1 CEH — there was no increase in MS risk.
Finally, the different combinations of CEHs best fit an additive statistical model, reflecting that these risks based on each combination were cumulative.
“Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual’s particular combination of “risk-haplotypes” and how these [gene locations] interact,” the investigators concluded.