Analysis of maternal-offspring HLA compatibility, parent-of-origin effects, and noninherited maternal antigen effects for HLA-DRB1 in systemic lupus erythematosus

Abstract

Objective: Genetic susceptibility to systemic lupus erythematosus (SLE) is well established, with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association. However, HLA may also influence SLE through novel biologic mechanisms in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA class II compatibility in SLE and differences in maternal versus paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen [NIMA] effects) in other autoimmune diseases have been reported. Thus, we investigated maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 in SLE.

Methods: The cohort comprised 707 SLE families and 188 independent healthy maternal-offspring pairs (total of 2,497 individuals). Family-based association tests were conducted to compare transmitted versus nontransmitted alleles (transmission disequilibrium test) and both maternally versus paternally transmitted (parent-of-origin) and nontransmitted alleles (using the chi-square test of heterogeneity). Analyses were stratified according to the sex of the offspring. Maternally affected offspring DRB1 compatibility in SLE families was compared with paternally affected offspring compatibility and with independent control maternal-offspring pairs (using Fisher's test) and was restricted to male and nulligravid female offspring with SLE.

Results: As expected, DRB1 was associated with SLE (P < 1 x 10(-4)). However, mothers of children with SLE had similar transmission and nontransmission frequencies for DRB1 alleles when compared with fathers, including those for the known SLE risk alleles HLA-DRB1*0301, *1501, and *0801. No association between maternal-offspring compatibility and SLE was observed.

Conclusion: Maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 are unlikely to play a role in SLE.

Figure 1

Maternal–offspring HLA compatibility relationships.

Figure 2

HLA–DRB1 susceptibility allele frequencies in systemic lupus erythematosus families. A, Results of tests of parent-of-origin effects (maternally versus paternally transmitted alleles). B, Results of tests of noninherited maternal antigen effects (maternally versus paternally nontransmitted alleles).