Multiple sclerosis

Multiple sclerosis (MS) is thought to be an autoimmune disease in which a person's immune system damages the central nervous system, causing a wide variety of symptoms, including difficulties moving. It is the most common neurologic disease affecting young adults. MS is also an inflammatory disease of the brain and spinal cord that damages the in the insulating cover of nerve cells, called the myelin sheath. [PMID 24289837] Wikipedia has an excellent overview.

Symptoms of MS include:

• Vision problems, Numbness and tingling.
• Muscle spasms, stiffness, itchiness, and pain,
• Difficulty walking, dizziness and sensations of spinning
• Bladder, bowel and sexual problems,
• Cognitive and mental health problems
• Extreme tiredness and fatigue
• Headache
• Seizures
• Hearing loss
• Speech and swallowing problems

MS symptoms appear as attacks, and may disappear and return without warning. Because there is no known cure for MS, treatments are designed to mitigate the impact of these attacks and possibly prevent future attacks. Symptoms may become permanent as damage accumulates over time. [PMID 24289837]

In general the cause of MS is not known, and it is suspected to be the result of a number of contributing environmental and genetic factors. [PMID 24289836] Environmental factors include geography, smoking, infectious agents, such as human herpes viruses, and the Epstein-Barr virus [PMID 24218486] and, to a lesser extent, stress. [PMID 24104400]

MS is more common in people who live the furthest from the equator, in the north and south ends of the world. Vitamin D has been associated with multiple sclerosis since 1973, when it was first discovered that people in areas of the world with less sun are more susceptible to MS. Decreased sunlight exposure results in decreased vitamin D production. Low levels of Vitamin D are reported in individuals with multiple sclerosis, and Vitamin D therapy has been identified as a possible preventative cure for MS. [PMID 24320602]

Genetics is also a contributing factor. Multiple sclerosis more common in northern European populations and is considered 30-35% heritable. Most SNPs associated with MS are located in genes playing roles in the immune system. PMC 3105160 The majority of this heritability is accounted for in the HLA region on Chromosome 6.

The HLA (Human Leukocyte Antigen) region, a collection of genes which encodes for the regulation of and interaction of white blood cells, has been associated with MS for over 30 years. [PMID|24019748]

The main allele implicated to date is known as HLA-DRB1*1501, a Class II member of the major histocompatibility complex (MHC). An HLA-DRB1 SNP that is highly correlated with HLA-DRB1*1501, and thus multiple sclerosis, is rs3135388. Specifically, the HLA-DRB1*1501-associated allele, rs3135388(T), is associated with a 3 to 6 fold higher risk for developing multiple sclerosis. The risk per allele (or per haplotype) appears additive, meaning a (T;T) genotype has a higher risk than the (C;T) haplotype, with (C;C) having no increased risk. [PMID 24278027]

A recent hypothesis is that a possible way to reduce the frequency of rs3135388(T) carriers developing multiple sclerosis would be to ensure sufficient vitamin D production, presumably through sunlight exposure, during as yet unknown critical periods in development.10.1371/journal.pgen.1000369 Another SNP that tags the HLA-DRB1*1501 allele is rs3135391. Template:PMID 20593013

A study of ~2,300 patients has also reported that SNPs from other HLA regions, most notably rs4959039, can be shown to increase risk for multiple sclerosis regardless of HLA-DRB1*1501 status. [PMID 20593013] Sixteen additional genes have been associated with MS using genome-wide association studies (GWAS). This modern approach has been used to help identify some, but not all, of the missing heritability of MS. [PMID 24385918]

Less pronounced yet still statistically significant increased risk has been reported for the following SNPs [PMID 17660530]:

• a rare 3-variant, 2 gene haplotype (P2RX7 rs140915863:C>T [p.T205M], P2RX7 rs201921967:A>G [p.N361S], and P2RX4 rs765866317:G>A [p.G135S])[PMID 28326637]
• rs10492972, in the KIF1B gene
• rs12722489 and rs2104286, both located in intron 1 of the IL2RA gene;
• rs6897932, located in the coding region of the IL7RA gene [PMID 17660530]
• rs6498169, in the KIAA0350 gene
• rs6604026, in the RPL5 gene
• rs10984447, in the DBC1 gene
• rs12044852, in the CD58 gene
• rs7577363, in the ALK gene
• rs7536563 and rs11164838, in the FAM69A gene
• rs10975200, in the ANKRD15 gene
• rs10735781 and rs6680578, in the EVI5 gene
• rs4763655, in the KLRB1 gene
• rs12487066, in the CBLB gene
• rs1321172, in the PDE4B gene

A 2011 study in the Annals of Neurology reported that rare variants in CYP27B1 were found in 35 children with Multiple Sclerosis. CYP27B1 plays a key role Vitamin D metabolism, however, these findings were not able to be later reproduced in subsequent studies. [PMID 22190362] [PMID 23444327]

An algorithm has been developed combining 16 SNPs that appears to "modestly predict" multiple sclerosis risk. [PMID 19879194] A more recent study combining known MS SNPs concludes that prediction of MS "cannot be achieved with the currently available genetic data." [PMID 21280076]

Additional SNPs (from other studies) include:

• rs9282860, for females, in the STK11 gene
• rs870849, a SNP in the lymphocyte activation gene LAG3
• rs8702, a protective SNP in the KLC1 gene
• rs926103 and a GA repeat polymorphism forming a risk haplotype in Norwegian patients [PMID 18554728]
• rs12708716 and rs2041670, in the CLEC16A gene
• rs763361, in the CD226 gene
• rs1800693 and rs4149584, in the TNFRSF1A gene [PMID 19525953]
• rs17445836, near the IRF8 gene
• rs11117432, in the IRF8 gene [PMID 19525953]
• rs2300747, in the CD58 gene [PMID 19525953]
• rs17824933 and rs929230, in the CD6 gene
• rs3135388, mentioned above [PMID 19525953]
• rs12722561, a protective allele at the IL2RA locus [PMID 17660530]
• rs4728142, rs3807306 and a 5 bp insertion-deletion linked multiple sclerosis in three populations [PMID 18285424]

23andMe blog Variant Nearest Gene Version Odds Ratio

rs1738074	TAGAP	T	0.88
rs669607	None	C	1.15
rs1077667	TNFSF14	T	0.88
rs17066096	IL22RA2	G	1.14
rs11154801	MYB	A	1.09
rs4902647	ZFP36L1	T	0.88
rs7595037	PLEK	G	0.87
rs2248359	CYP24A1	T	0.90
rs2546890	IL12B	G	0.87
rs9282641	CD86	A	0.83

[PMID 24385918] Quantifying Missing Heritability at Known GWAS Loci.

[PMID 24289837] Decoding multiple sclerosis: an update on genomics and future directions.

[PMID 24278027] Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.

[PMID 22190362] Rare variants in the CYP27B1 gene are associated with multiple sclerosis.

[PMID 23444327] No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis.

[PMID 24019748] The genetics of multiple sclerosis: review of current and emerging candidates.

[PMID 24289836] Environmental factors in multiple sclerosis.

[PMID 24218486] Epstein-Barr virus is a necessary causative agent in the pathogenesis of multiple sclerosis: Yes.

[PMID 24104400] Stress in multiple sclerosis: review of new developments and future directions.

[PMID 24320602] Vitamin D and multiple sclerosis: where do we go from here?