Exploring the Genetic Underpinnings of MS: Heritability of Plasma Protein Levels in Sardinian Families

Multiple Sclerosis (MS) is a complex autoimmune disease affecting the central nervous system, characterized by a multifactorial etiology involving both genetic and environmental factors. Despite significant advancements in understanding the disease's pathophysiology, the genetic underpinnings of MS remain partially understood. In this context, a recent study by Nova et al. (2022) delves into the heritability of MS-related plasma protein levels in Sardinian families, shedding light on the genetic components contributing to these protein levels.

The study focuses on estimating the narrow-sense heritability (h2) of 56 plasma protein levels related to MS. The analysis was conducted on 212 individuals from 20 extended Sardinian families, comprising 69 MS cases and 143 healthy controls. By leveraging pedigree information and advanced statistical methods, the researchers aimed to quantify the genetic variance contributing to the variability in plasma protein levels.

Sample Collection and Protein Measurement: Plasma protein levels were measured using high-throughput techniques, utilizing polyclonal antibodies from the Human Protein Atlas. The study involved a detailed analysis of 56 proteins selected based on their suggested association with MS. Heritability Estimation: The researchers employed the Haseman-Elston regression method to estimate narrow-sense heritability, considering additive genetic effects and adjusting for potential shared environmental influences. pQTL Analysis: For proteins with significant heritability, a protein quantitative trait loci (pQTL) analysis was performed using Immunochip genotyping data from 155 healthy controls (both related and unrelated). This analysis aimed to identify specific single nucleotide polymorphisms (SNPs) contributing to the variability in plasma protein levels.

Key Findings
The study identified seven plasma proteins with significant heritability after multiple testing correction:

Gc (Vitamin D Binding Protein): Exhibited the highest heritability (h2 = 0.77), highlighting its crucial role in binding and transporting vitamin D metabolites, which are known to have immunomodulatory properties.

Plat (Plasminogen Activator): Showed a heritability of 0.70, emphasizing its importance in maintaining axonal integrity and clearing fibrinogen deposits, which are critical in preventing further axonal injury in MS.

Anxa1 (Annexin A1): With a heritability of 0.68, this protein plays a significant role in resolving inflammation and controlling leukocyte migration.

Sod1 (Superoxide Dismutase 1): Demonstrated a heritability of 0.58, indicating its role in mitigating oxidative stress, a key factor in neurodegenerative diseases.

Irf8 (Interferon Regulatory Factor 8): Had a heritability of 0.56, underlining its involvement in regulating genes stimulated by type I interferons, which are crucial in immune response modulation.

Ptger4 (Prostaglandin Receptor E4): Exhibited a heritability of 0.45, highlighting its role in T-cell activation and regulation of proinflammatory factors.

Fadd (Fas-Associated Death Domain Protein): Showed a heritability of 0.41, pointing to its involvement in transmitting apoptotic signals and regulating pro-inflammatory activity.

pQTL Analysis Results
The pQTL analysis identified specific SNPs associated with the heritable proteins. For instance, six SNPs explained 67% of the variability in Gc plasma levels. Similarly, the analysis for Plat, Anxa1, Sod1, Irf8, Ptger4, and Fadd revealed SNPs explaining substantial proportions of their respective plasma level variabilities. These findings suggest that a small number of genetic variants significantly influence the levels of these MS-related proteins.

Biological Implications
The study's findings have significant implications for understanding the genetic basis of MS. The high heritability of these proteins indicates a strong genetic component in their regulation. Moreover, the identified SNPs provide insights into potential genetic loci that could be targeted for further research and therapeutic interventions.

For example, the association of the rs7041 variant with Gc plasma levels aligns with previous findings linking this variant to vitamin D levels and MS risk. Similarly, the association of rs10455872 with Plat levels underscores its role in fibrinolysis and axonal integrity.

Conclusion
Nova et al.'s study represents a significant step towards understanding the genetic regulation of MS-related plasma protein levels. By highlighting the heritability of specific proteins and identifying key genetic variants, the research provides a foundation for future studies exploring the molecular mechanisms underlying MS. This knowledge could pave the way for novel diagnostic and therapeutic strategies aimed at mitigating the impact of this debilitating disease.

References
Nova, A., Baldrighi, G. N., Fazia, T., Graziano, F., Saddi, V., Piras, M., ... & Bernardinelli, L. (2022). Heritability Estimation of Multiple Sclerosis Related Plasma Protein Levels in Sardinian Families with Immunochip Genotyping Data. Life, 12(7), 1101.