Individuals diagnosed with POTS by a physician were recruited during the Dysautonomia International 2019 patient conference. Orthostatic vitals, Beighton Score for generalized hypermobility (GH), medical history, and quality of life scores were obtained from participants (median age 28 years, range 13-74). Intermediate-resolution HLA typing was performed for 93 subjects using sequence specific primers (SSP-Olerup, CareDX, PA, USA) for loci A, -B, -DQA1, -DQB1, and -DRB1. Allele frequencies were compared to Caucasian Americans in the Allele Frequency Net Database (AFND, Nucleic Acids Research, 2020) to calculate odds ratios (OR) for HLA associations.

Participants were primarily female (93%), Caucasian (95%), and non-Hispanic (88%). POTS participants were more likely (OR; 95% CI) to present class I alleles B*15:01 (2.52, 1.66-3.81), B*18:01 (2.03, 1.22-3.39), and B*40:01 (2.91, 1.93-4.41). Similarly, class II alleles DQA1*02:01 (1.94, 1.32-2.86), DQB1*02:01 (2.84, 1.97-4.10), DRB1*03:01 (1.85, 1.30-2.65), and DRB1*13:01 (1.80, 1.11-2.92) were more common. 48% of cases tested positive for GH and showed associations with DQB1*02:01 (2.43, 1.41-4.23) and DRB1*15:01 (1.85, 1.07-3.20), while non-hypermobile subjects carried B*40:01 (3.59, 2.06-6.24), DRB1*04:01 (1.91, 1.05-3.46), and DRB1*13:01 (2.10, 1.09-4.05) alleles more frequently.

Class I and II HLA alleles implicated in numerous autoimmune diseases were identified as risk alleles in POTS participants, indicating potential immunogenetic predispositions. Associated alleles in US POTS subjects differed from the South Korean POTS cohort. Our data suggest that people with POTS have increased genetic risk for autoimmunity.