Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study.
BACKGROUND
Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from families with several members with the disease and in their first-degree relatives.


METHODS
A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case-control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (CTLA4) and protein tyrosine phosphatase (PTPN22) variants with susceptibility to multiple sclerosis.


RESULTS
46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0.009) but not in families without a history of other autoimmune disorders (p=0.90).


CONCLUSIONS
The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.
Barcellos
Lisa F
LF
School of Public Health, Division of Epidemiology, University of California, Berkeley, CA, USA.
Kamdar
Brinda B
BB
Ramsay
Patricia P
PP
DeLoa
Cari
C
Lincoln
Robin R
RR
Caillier
Stacy
S
Schmidt
Silke
S
Haines
Jonathan L
JL
Pericak-Vance
Margaret A
MA
Oksenberg
Jorge R
JR
Hauser
Stephen L
SL
D000483:Alleles; D015703:Antigens, CD / Q000235:genetics; D000943:Antigens, Differentiation / Q000235:genetics; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics*; D060908:CTLA-4 Antigen; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D012306:Risk; D012737:Sex Factors
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases