A stop-gain variant in is associated with atherogenic lipid profiles.

Huti Watson, Ryan L Minster, Daniel E Weeks, Tony R Merriman, Stephen T McGarvey, Ranjan Deka, John Tuitele, Satupa'itea Viali, Muagututi'a Sefuiva Reupena, Take Naseri, Rinki Murphy, Muhammad Qasim, Erin E Kershaw, Janak R de Zoysa, Nicola Dalbeth, Hong Cheng, Jaye Moors, Nicola L Hawley, Jerry Z Zhang, Emily M Russell, Samantha L Rosenthal, Mohanraj Krishnan, Jenna C Carlson, Lisa K Stamp

Journal: HGG advances 2023;4(1):100155

PMID: 36340932

Free Full Text on Elsevier Science View on PubMed

Abstract

Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (β = -1.60 mg/dL, = 7.63 × 10; β = 12.00 mg/dL, = 3.82 × 10). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.

Address: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.; Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.; Department of Biochemistry, University of Otago, Dunedin, New Zealand.; Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.; Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Ngāti Porou Hauora Charitable Trust, Te Puia Springs, Tairāwhiti East Coast, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.; Ministry of Health, Government of Samoa, Apia, Samoa.; Lutia i Puava ae Mapu i Fagalele, Apia, Samoa.; School of Medicine, National University of Samoa, Apia, Samoa.; Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.; Department of Public Health, Government of American Samoa, Pago Pago, American Samoa.; Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; International Health Institute, Department of Epidemiology, Brown University, Providence, RI, USA.; Department of Anthropology, Brown University, Providence, RI, USA.

DOI: 10.1016/j.xhgg.2022.100155

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MeSH Terms: Adult, Humans, Atherosclerosis, Butyrophilins, Cholesterol, HDL, Dyslipidemias, Triglycerides, Pacific Island People