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Meta-Analysis
. 2022 Oct 12;4(1):100155.
doi: 10.1016/j.xhgg.2022.100155. eCollection 2023 Jan 12.

A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles

Jenna C Carlson  1   2 , Mohanraj Krishnan  2 , Samantha L Rosenthal  2   3 , Emily M Russell  2 , Jerry Z Zhang  1 , Nicola L Hawley  4 , Jaye Moors  5 , Hong Cheng  6 , Nicola Dalbeth  7 , Janak R de Zoysa  7 , Huti Watson  8 , Muhammad Qasim  8 , Rinki Murphy  7   9 , Take Naseri  10 , Muagututi'a Sefuiva Reupena  11 , Satupa'itea Viali  12 , Lisa K Stamp  13 , John Tuitele  14 , Erin E Kershaw  15 , Ranjan Deka  6 , Stephen T McGarvey  16   17 , Tony R Merriman  5   9 , Daniel E Weeks  1   2 , Ryan L Minster  2
Affiliations
Meta-Analysis

A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles

Jenna C Carlson et al. HGG Adv. .

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 BTNL9 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 (βHDL-C = -1.60 mg/dL, p HDL-C = 7.63 × 10-10; βTG = 12.00 mg/dL, p TG = 3.82 × 10-7). 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.

Keywords: Polynesia; cardiovascular disease risk factors; genetics of complex traits; identification of disease genes; isolated population.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Meta-analysis results of rs200884524 for high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) Effect estimates (beta) and 95% confidence intervals (CIs) for HDL-C (mg/dL) and TG (mg/dL) are given for each cohort (abbreviations: Samoan [S], American Samoan [AS], Replication [Rep], Aotearoa New Zealand [An NZ], Eastern Polynesian [EP], Western Polynesian [WP]). Meta analysis results were obtained using inverse-variance fixed-effects meta-analysis. Arrows indicate CIs that have been truncated for plotting.
Figure 2
Figure 2
Variants of interest in BTNL9 region Variant IDs, position (build hg38), reference and alternate alleles, and minor allele frequency (MAF) in the Samoan discovery cohort and in gnomAD are given for the stop-gained variant in BTNL9 identified in the Samoan discovery cohort (pink), 4 variants with lipid associations in the UK Biobank (UKB; blue), a deletion upstream of BTNL9 (orange), and a variant in high linkage disequilibrium (LD) with the deletion in UKB (purple). BTNL8, BTNL3, and BTNL9 coordinates for MANE transcripts are plotted for reference, with black bars representing exonic regions. For DEL_5_65831, hg38 coordinates were obtained using LiftOver (https://genome.ucsc.edu/cgi-bin/hgLiftOver) on the positions defined in gnomAD SV v.2.1 (hg19).
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