A PheWAS approach in studying HLA-DRB1*1501

Area of Science:

• Genetics
• Immunology
• Computational Biology

Background:

• The Human Leukocyte Antigen (HLA) complex plays a crucial role in immune responses.
• Genetic variations within the HLA-DRB1 gene are implicated in various autoimmune diseases.
• The HLA-DRB1*1501 haplotype is a known risk factor for multiple sclerosis (MS).

Purpose of the Study:

• To investigate the association of the rs3135388 genotype, which tags the HLA-DRB1*1501 haplotype, with a wide range of health phenotypes.
• To validate the utility and feasibility of the phenome-wide association study (PheWAS) approach using external data.
• To explore potential novel associations of the HLA-DRB1*1501 locus beyond known autoimmune links.

Main Methods:

• A phenome-wide association study (PheWAS) was conducted using electronic health records from 4235 individuals.
• The study analyzed the association between the rs3135388 genotype (tagging HLA-DRB1*1501) and 4841 distinct phenotypes.
• Statistical analyses were performed to identify significant genotype-phenotype associations, including those for multiple sclerosis and other conditions.

Main Results:

• The expected association between HLA-DRB1*1501 and multiple sclerosis (ICD9 340) was confirmed (P=0.023).
• The strongest association identified was between HLA-DRB1*1501 and alcohol-induced cirrhosis of the liver (ICD9 571.2, P=0.00011).
• Additional significant associations were found with erythematous conditions (ICD9 695, P=0.0054) and benign respiratory neoplasms (ICD9 212, P=0.042).

Conclusions:

• The study successfully validated the PheWAS approach as a powerful tool for genetic discovery.
• The findings reveal a significant association between the HLA-DRB1*1501 locus and alcohol-induced liver cirrhosis, suggesting a broader role beyond autoimmunity.
• This research underscores the complex genetic underpinnings of the HLA-DRB1*1501 locus and its potential involvement in diverse pathologies.