HLA-DRB1*15:01 and multiple sclerosis: a female association?

ABSTRACT

BACKGROUND: The association between multiple sclerosis (MS) and the HLA-DRB1*1501 haplotype has been proven to be strong, but its molecular basis remains unclear. Vitamin D receptor (VDR) gene variants and sex have been proposed to modulate this association. OBJECTIVES: 1) Test the association of MS with *1501 and VDR variants; 2) check whether VDR variants and/or sex modulate the risk conferred by *1501; 3) study whether *1501, VDR variants and/or sex affect HLA II gene expression. METHODS: Peripheral blood from 364 MS patients and 513 healthy controls was obtained and DNA and total RNA were extracted from leukocytes. HLA-DRB1, DRB5 and DQA1 gene expression measurements and *1501 genotyping were performed by qPCR. VDR variants were genotyped by PCR-RFLP. RESULTS: Our data confirms that the *1501 haplotype confers a higher risk of suffering from MS (OR = 1.364; 95% CI = 1.107-1.681). No association was found between VDR variants and MS, but they were shown to moderately modulate the risk conferred by *1501. Sex confers a much stronger modulation and the *1501-MS association seems to be female specific. A higher *1501 frequency has been observed in Basques (45.1%). *1501 positive samples showed a significant overexpression of DRB1 (p < 0.001), DRB5 (p < 0.001) and DQA1 (p = 0.004) in patients. DRB1 (p = 0.004) and DRB5 (p < 0.001) were also overexpressed in *1501 controls. CONCLUSIONS: We confirm the *1501-MS association and support that it is female specific. The relevance of ethnic origin on association studies has also been highlighted. HLA-DRB1*1501 seems to be a haplotype consistently linked to high HLA II gene expression.