The Genome-Wide Association Study Identifying TSHR and C1d as New Susceptibility Loci for Obstetric Antiphospholipid Syndrome
2Human Genetics, Graduate School of Medicine, The University of Tokyo, Japan
3Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Japan
4Center for Maternal-Fetal-Neonatal and Reproductive Medicine, National Center for Child Health and Development, Japan
Background: Antiphospholipid syndrome (APS) is the most important treatable cause of recurrent pregnancy loss (RPL). Recent genome-wide association studies (GWAS) of systemic lupus erythematosus (SLE) have shown that a number of molecules may be involved. Since APS is a lupus-related disease, genetic susceptibility has been speculated to be associated with obstetric APS. This is the first GWAS for obstetric APS focusing on RPL.
Methods: A GWAS was performed to compare 115 Japanese patients with obstetric APS, diagnosed according to criteria of the International Congress on APS, and 419 healthy individuals. A total of 600,307 SNPs were genotyped and allele or genotype frequencies were compared. Imputation analyses were also performed for the candidate regions detected by the GWAS.
Results: One SNP located on the 3’-UTR of TSHR showed a significant APS association (P=7.85E-08, OR=6.18) under a recessive model. Another SNP located around the C1D also showed a significant APS association (P=4.84E-08, OR=6.20) under an allelic model after applying the SNP imputation. In addition, analysis of HLA alleles revealed that the HLA-DQB1*05:01 allele was protective with a significant association (P=0.0037, OR=0.28).
Conclusion: Our findings demonstrate that a specific genotype of TSHR, C1D, and HLA-DQB1 genes can be a risk factor for obstetric APS.
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