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Library / health / HLA-DRB1*15:01 — multiple sclerosis risk

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HLA-DRB1*15:01 — multiple sclerosis risk

HLA-DRB1rs3135388autoimmune
Elevated

One copy of the HLA-DRB1*15:01 haplotype tag detected.

You probably carry one copy of an HLA gene version (DRB1*15:01) that raises the risk of multiple sclerosis.

One copy of HLA-DRB1*15:01 is associated with an approximately threefold increase in lifetime risk of multiple sclerosis relative to non-carriers in European-ancestry populations. The absolute lifetime risk remains low: most carriers never develop MS.

One copy of this HLA version is associated with roughly three times the average risk of multiple sclerosis in people of European ancestry. The everyday risk is still low — most carriers never develop MS — but the increase is meaningful.

5 caveats1 population3 referencesSensitive

What this means

The HLA class II region on chromosome 6 is the single strongest genetic risk locus for multiple sclerosis, and within it the DRB1*15:01 allele carries by far the largest effect. The rs3135388 T allele tags DRB1*15:01 with high accuracy in European populations. The mechanistic story is that DRB1*15:01 presents a particular set of myelin-derived peptides to T cells in a way that increases the chance of an autoimmune attack on central nervous system myelin. Risk is additive with dose: heterozygotes ~3× population risk, homozygotes ~6×. MS is a multifactorial disease — Epstein-Barr virus exposure, vitamin D status, smoking, latitude, and other genetic variants all contribute — and the absolute lifetime risk of MS even for DRB1*15:01 homozygotes remains in the low single digits. The tag SNP is less reliable outside European populations; the same allele exists but the linkage with rs3135388 is weaker.

The HLA region on chromosome 6 contains the strongest genetic risk factors for multiple sclerosis, and one particular version of one HLA gene — called DRB1*15:01 — carries the largest single effect. The DNA marker we read here is a reliable tag for that version in people of European ancestry. The biological story is that this version of the gene shows pieces of myelin (the insulation around nerve fibres) to the immune system in a way that makes an attack on the nervous system more likely. People with one copy have roughly three times the average lifetime risk of MS; people with two copies, roughly six times. The everyday risk is still small — most carriers never develop MS — but the increase is one of the cleanest signals in autoimmune genetics. Things like Epstein-Barr virus infection, vitamin D, smoking and latitude all matter alongside this gene.

Caveats

  • MS is a multifactorial disease — Epstein-Barr virus, vitamin D, smoking and latitude are all part of the story.
  • The absolute lifetime risk of MS, even for homozygous carriers in high-prevalence countries, is low.
  • rs3135388 is a tag SNP; outside European populations the linkage with DRB1*15:01 is weaker and the reading less reliable.
  • This is not a diagnosis. MS is diagnosed clinically with MRI and other criteria.
  • Disclosing HLA status can carry psychological cost. Genetic counselling is recommended before acting on the result.

Populations

  • Strongest evidence in European-ancestry populations; the tag SNP is less reliable in other ancestries

References