GWAS Identifies Classical HLA Alleles Associated with Susceptibility to Infectious Diseases. C. Tian, J. Mountain, N. Eriksson, J. Tung, A. Kiefer, D. Hinds Research, 23andme, Mountain View, CA.

   The human leukocyte antigen (HLA) system is a highly polymorphic region on chromosome 6 that encodes several hundred genes critical for the immune system. HLA has long been known to play an important role in susceptibility and resistance to many infectious diseases and responsiveness to pathogens or vaccines. Many studies have shown significant associations between HLA loci and major infectious diseases, such as HIV/AIDS, hepatitis and malaria etc. However most studies have tested only candidate loci in small samples, and the associations between HLA alleles and many other infectious diseases are not well studied. We conducted genome wide association studies with over 61,000 individuals who were genotyped on the 23andMe platform and asked to report on multiple infectious diseases. We identified single nucleotide polymorphisms in the HLA region that are associated with cold scores, plantar warts, mumps, positive TB test, scarlet_fever and shingles at a genome-wide-significant level. We did not detect associations between HLA loci and bladder infection, urinary tract infection, measles, intestinal parasite, myringotomy, mononucleosis or rheumatic fever. To explore the relationship between individual HLA alleles and susceptibility to infectious diseases we used HIBAG, a statistical method combining a large database of individuals with known HLA alleles and SNP variation within the MHC region, to impute HLA alleles at key class I and class II loci over all 23andMe customers of European ancestry. We found that HLA-B*18:01 is the HLA allele most significantly (p=5.5e-07) associated, in a protective manner, with cold sores. Individuals with the HLA-DQA1*03:01 allele were less likely to have plantar warts (p=1.7e-08). HLA-A*02:05 is the HLA allele most significantly associated with mumps (p=1.6e-12). Individuals with the HLA-DRB1*01:03 allele are more susceptible to tuberculosis (p=4.5e-12). Individuals with the HLA-DQB1*03:01 allele are less likely to have scarlet_fever (p=9.0e-09). HLA-B*44:02 allele is an important factor in the resistance to shingles (p=3.4e-11). Although additional studies will be required to separate and validate the association signals in this complex region, combining accurate HLA typing with our knowledge of the function of specific HLA molecules in immune response and with GWAS can be a powerful tool for dissecting infectious disease etiology.

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