title: Association of three systemic lupus erythematosus susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin, with autoimmune manifestations in Icelandic multicase systemic lupus erythematosus families.
abstract: OBJECTIVE
  To study autoimmune diseases and autoantibodies in Icelandic multicase systemic lupus erythematosus (SLE) families and to determine the association of 3 SLE susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin (MBL), with autoimmune disease in this population.
  
  
  METHODS
  Eight SLE multicase families were studied, comprising a total of 124 family members (23 patients with SLE and 101 relatives). The diagnosis of an autoimmune disease was established and autoantibodies were measured in each family. In addition, PD-1.3A alleles were genotyped, and C4AQ0 allotypes were established by electrophoresis and haplotype analysis. Low levels of MBL were determined using enzyme-linked immunosorbent assay and variant-allele genotyping.
  
  
  RESULTS
  In the SLE multicase families there was a high frequency of other autoimmune diseases (32.2%) and a high frequency of autoantibodies (53.2%). Of all family members, 59.7% were determined to have SLE, other autoimmune diseases, antinuclear antibodies, and/or other autoantibodies. The families showed genetic heterogeneity for PD-1.3A, C4AQ0, and low MBL levels; the frequency of each factor ranged from 0% to 85%. The frequencies of PD-1.3A and C4AQ0 were significantly increased in patients with SLE, relatives with other autoimmune diseases, and non-autoimmune disease relatives compared with controls. In the 7 families whose members had low levels of MBL, this factor was significantly associated with SLE, but the frequency of low MBL was decreased in relatives with other autoimmune diseases as compared with non-autoimmune disease relatives and controls. There were indications of an additive effect, and 91% of patients with SLE, 78% of relatives with other autoimmune diseases, and 75% of non-autoimmune disease relatives carried at least 1 of the 3 factors.
  
  
  CONCLUSIONS
  These results demonstrate a high frequency of autoimmune diseases and autoantibodies in SLE multicase families. PD-1.3A and C4AQ0 are part of a predisposing genetic background. Other genetic and/or environmental factors are necessary for disease expression, demonstrated by a high frequency of PD-1.3A and C4AQ0 in non-autoimmune disease relatives. Low MBL levels may be one such contributing factor. The results of this study provide an example of epistatic genetic effects and overlapping genetics in autoimmune diseases.
authors.affiliation: Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Helga
authors.initials: H
authors.lastname: Kristjansdottir
authors.forename: Saedis
authors.initials: S
authors.lastname: Saevarsdottir
authors.forename: Gerdur
authors.initials: G
authors.lastname: Gröndal
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: Kristjan
authors.initials: K
authors.lastname: Erlendsson
authors.forename: Helgi
authors.initials: H
authors.lastname: Valdimarsson
authors.forename: Kristjan
authors.initials: K
authors.lastname: Steinsson
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics; D015934:Complement C4a / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D005192:Family Health; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology* / Q000235:genetics*; D037601:Mannose-Binding Lectin / Q000097:blood*; D061026:Programmed Cell Death 1 Receptor
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D037601:Mannose-Binding Lectin; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D015934:Complement C4a