A putatively adaptive missense variant in ICAM1 is associated with systolic blood pressure in Andean highlanders
Authors: Yu James , Gu Wanjun , Anza-Ramirez Cecilia , Huff Chad , Bohlender Ryan , Villafuerte Francisco , Simonson Tatum 
Published: May 2023

Hypobaric hypoxia exerts a significant evolutionary pressure on highlanders who have resided at high altitude for thousands of years. This evolutionary pressure has resulted in signatures of natural selection within native highlanders’ genomes, some of which associate with adaptive physiological traits. Our recent analyses examined the overlap of a priori functional candidate genes and genes identified in the composite of multiple signals test of selection in 40 Andean genomes. We identified ICAM1, which encodes the intercellular adhesion molecule 1 protein, as one of the top 10 candidate genes of positive selection in this highland population. We utilized LDproxy and CADD score analysis to prioritize variants of functional relevance in this gene. The single-nucleotide variant (SNV) rs1799969, located in exon 4, exhibited the highest CADD score of 22.0. We genotyped rs1799969 in a larger cohort of 255 Andean highlanders and found that 68% of Andeans have at least one copy of the SNV, compared to 6% and 20% in worldwide and American populations, respectively, from the 1000 Genomes data set. Given the soluble form of ICAM1 is elevated in patients with COPD, atherosclerosis, coronary heart disease, and other cardiometabolic phenotypes, and rs1799969 is associated with less soluble ICAM1 in larger, worldwide cohorts, we tested the hypothesis that putatively adaptive copies of ICAM1 would be associated with blood pressure in the high-altitude Andean cohort. We found that more copies of the putatively adaptive haplotype containing rs1799969 is associated with lower systolic blood pressure (p-value = 0.012 for 0 vs 2 alleles, 0.028 for 0 vs 1 allele; effect size = 7.1mmHg for males, 13.5mmHg for females; NS diastolic blood pressure), whereby the effect size of the number of adaptive gene copies on systolic blood pressure is comparable to commonly prescribed medications and orders of magnitude larger than previous genetic association studies of blood pressure (~1.5mmHg for rare variants, ~0.5mmHg for common variants). Because ICAM1 is activated by hypoxia, it is plausible that rs1799969 may play a protective physiological role in the context of chronic hypoxia in Andean highlanders. Hypertension is one of the strongest modifiable risk factors for cardiometabolic disease, and this may be especially relevant in hypobaric hypoxia, where chronic activation of sympathetic activity can increase blood pressure. Additionally, elevated blood pressure is a known causative agent for diseases that are exacerbated at high altitude, such as pre-eclampsia. However, studies of hypertension in native highland populations have mixed results, often reporting conflicting associations depending on the population being studied, warranting further investigations into hypertension prevalence in various highland populations and genetic factors that may impact blood pressure. Supported by NIH 1R01HL145470 to TSS This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.