Global Meta-Analysis on the Association between Behcet Syndrome and Polymorphisms from the HLA Class I (A, B, and C) and Class II (DRB1, DQB1, and DPB1) Genes

Abstract

Behcet syndrome (BS) is a multisystemic perivasculitis whose genetic susceptibility is linked to HLA region. We first meta-analysed all HLA class I and II genes involved in BS susceptibility in all ethnic groups worldwide. We identified 1141 articles and finally included 31 case-control studies after multiple rounds of selection. We analysed frequencies for 24 HLA-A alleles (3 alleles for HLA-A $\ast$ 26 at four digits), 50 HLA-B alleles (11 alleles for HLA-B $\ast$ 51 at four digits), 15 HLA-C alleles, 16 HLA-DRB1 alleles, 6 HLA-DQB1 alleles, and 15 HLA-DPB1 alleles. We meta-analysed only HLA allelic frequencies from at least three studies; therefore, we investigated 21 alleles out of 140. Going from 7.00 to 1.6 OR, we found 11 class I alleles conferring risk for BS: $\text{B}\ast 51:08$ , $\text{B}\ast 51$ , $\text{B}\ast 51:01$ , $\text{B}\ast 51:02$ , $\text{DQB}1\ast 03$ , $\text{A}\ast 26:01$ , $\text{Cw}\ast 14$ , $\text{Cw}\ast 15$ , $\text{Cw}\ast 16$ , $\text{B}\ast 15$ , and $\text{A}\ast 26$ . Overall, the studies included populations from Europe (Greece, Spain, Italy, Germany, and Ireland), Asia (Korea, China, China Han, and Thailand), Middle East (Israel, Saudi Arabia, and Iran), and Morocco (as no other North-African population was included). We collected a number of ethnical groups sufficient to conduct an ethnic-specific meta-analysis where Europeans showed 11.25 OR for B $\ast$ 51:08 and Japan 3.50 OR for $\text{A}\ast 26:01$ . A remarkable result was that the most frequent $\text{HLA}-\text{B}\ast 51$ two-digit alleles associated with BS were different among populations: $\text{HLA}-\text{B}\ast 51:08$ in Europe, $\text{HLA}-\text{B}\ast 51:01$ in Turkey, and $\text{HLA}-\text{B}\ast 51:02$ in Japan. Overall, we discussed our real-world results with other imputation studies.