IL12B gene polymorphisms have sex-specific effects in relapsing-remitting multiple sclerosis

Area of Science:

• Immunogenetics
• Neuroimmunology
• Genetics of Neurological Disorders

Background:

• Interleukin-12 (IL-12)-family cytokines are implicated in the neuroinflammation and neurodegeneration characteristic of relapsing-remitting multiple sclerosis (RRMS).
• The IL12B gene encodes a subunit common to IL-12 and IL-23, both crucial in immune responses and potentially in MS pathogenesis.
• Understanding the genetic contribution of IL12B polymorphisms to RRMS susceptibility and disease course is essential for targeted therapeutic strategies.

Purpose of the Study:

• To investigate the association of two IL12B gene polymorphisms, rs17860508 and rs3212227, with RRMS.
• To determine the functional impact of these polymorphisms on serum levels of IL-12p40 and IL-23.
• To evaluate the correlation between these polymorphisms, serum cytokine levels, and the degree of disability in RRMS patients.

Main Methods:

• Genotyping of 156 Bulgarian RRMS patients and 379 controls for IL12B polymorphisms rs17860508 and rs3212227 using polymerase chain reaction (PCR).
• Quantification of serum IL-12p40 and IL-23 levels via enzyme-linked immunosorbent assay (ELISA).
• Sex-stratified association analyses to assess the impact of genotypes and haplotypes on RRMS risk, disease course, and disability.

Main Results:

• Significantly higher serum IL-12p40 and IL-23 levels were observed in RRMS patients compared to controls, with higher levels in women than men.
• The rs3212227*CC genotype and the rs17860508*2-allele/rs3212227*C-allele haplotype were associated with increased RRMS risk in men.
• In women, the rs17860508*22-genotype correlated with lower disability and reduced IL-23 levels, while the rs3212227*AA-genotype was linked to earlier disease onset.

Conclusions:

• IL12B polymorphisms rs17860508 and rs3212227 exhibit sex-specific effects on RRMS genetic predisposition and disease progression.
• The observed gender-dependent functional impact on IL-12p40-containing cytokines likely mediates these sex-specific effects.
• These findings highlight the importance of considering sex as a biological variable in the genetic and immunologic understanding of RRMS.