Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians: ethnogeographic influences in the genetics and clinical expression of myositis.
OBJECTIVE
As part of a larger, worldwide study of the ethnogeography of myositis, we evaluated the clinical, serologic, and immunogenetic features of Mestizo (Mexican and Guatemalan) and North American Caucasian patients with idiopathic inflammatory myopathy (IIM).


METHODS
Clinical manifestations, autoantibodies, HLA-DRB1 and DQA1 alleles, and immunoglobulin Gm/Km allotypes were compared between 138 Mestizos with IIM and 287 Caucasians with IIM, using the same classification criteria and standardized questionnaires.


RESULTS
IIM in Mestizo patients was characterized by a higher proportion of dermatomyositis (69% of adult Mestizos versus 35% of adult Caucasians; P < 0.001) and anti-Mi-2 autoantibodies (30% versus 7% of adults, respectively, and 32% versus 4% of children, respectively; P < 0.01). Genetic risk factors also differed in these populations. Whereas Mestizos had no HLA risk factors for IIM, HLA-DRB1*0301, the linked allele DQA1*0501, and DRB1 alleles sharing the first hypervariable region motif (9)EYSTS(13) were major risk factors in Caucasian patients with IIM. Furthermore, different HLA-DRB1 and DQA1 alleles were associated with anti-Mi-2 autoantibodies (DRB1*04 and DQA1*03 in Mestizos and DRB1*07 and DQA1*02 in Caucasians). Immunoglobulin gamma-chain allotypes Gm(1), Gm(17) (odds ratio for both 11.3, P = 0.008), and Gm(21) (odds ratio 7.3, P = 0.005) and kappa-chain allotype Km(3) (odds ratio 7.3, P = 0.005) were risk factors for IIM in Mestizos; however, no Gm or Km allotypes were risk or protective factors in Caucasians. In addition, Gm and Km phenotypes were unique risk factors (Gm 1,3,17 5,13,21 and Gm 1,17 23 21 and Km 3,3) or protective factors (Km 1,1) for the development of myositis and anti-Mi-2 autoantibodies (Gm 1,2,3,17 23 5,13,21) in adult Mestizos.


CONCLUSIONS
IIM in Mesoamerican Mestizos differs from IIM in North American Caucasians in the frequency of phenotypic features and in the immune-response genes predisposing to and protecting from myositis and anti-Mi-2 autoantibodies at 4 chromosomal loci. These and other data suggest the likelihood that the expression of IIM is modulated by different genes and environmental exposures around the world.
Center for Biologics Evaluation and Research, FDA, Bethesda, Maryland, USA. shamim@niehs.nih.gov
Ejaz A
EA
Shamim
Lisa G
LG
Rider
Janardan P
JP
Pandey
Terrance P
TP
O'Hanlon
Luis J
LJ
Jara
Eduardo A
EA
Samayoa
Ruben
R
Burgos-Vargas
Janitzia
J
Vazquez-Mellado
Jorge
J
Alcocer-Varela
Mario
M
Salazar-Paramo
Abraham Garcia
AG
Kutzbach
James D
JD
Malley
Ira N
IN
Targoff
Ignacio
I
Garcia-De la Torre
Frederick W
FW
Miller
D000328:Adult; D000483:Alleles; D003882:Dermatomyositis / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D005260:Female; D005838:Genotype; D006166:Guatemala / Q000453:epidemiology; D006683:HLA-DQ Antigens / Q000032:analysis; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens / Q000032:analysis; D059811:HLA-DRB1 Chains; D006801:Humans; D007129:Immunoglobulin Gm Allotypes / Q000032:analysis; D007133:Immunoglobulin Joining Region; D007197:Indians, Central American; D008297:Male; D008800:Mexico / Q000453:epidemiology; D009220:Myositis / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D007129:Immunoglobulin Gm Allotypes; D007133:Immunoglobulin Joining Region