Excess of Rare Variants in Non–Genome-Wide Association Study Candidate Genes in Patients With Hypertriglyceridemia Academic Article uri icon

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abstract

  • BACKGROUND: Rare variant accumulation studies can implicate genes in disease susceptibility when a significant burden is observed in patients versus control subjects. Such analyses might be particularly useful for candidate genes that are selected based on experiments other than genome-wide association studies (GWAS). We sought to determine whether rare variants in non-GWAS candidate genes identified from mouse models and human mendelian syndromes of hypertriglyceridemia (HTG) accumulate in patients with polygenic adult-onset HTG. METHODS AND RESULTS: We resequenced protein coding regions of 3 genes with established roles (APOC2, GPIHBP1, LMF1) and 2 genes recently implicated (CREB3L3 and ZHX3) in TG metabolism. We identified 41 distinct heterozygous rare variants, including 29 singleton variants, in the combined sample; in total, we observed 47 rare variants in 413 HTG patients versus 16 in 324 control subjects (odds ratio=2.3; P=0.0050). Post hoc assessment of genetic burden in individual genes using 3 different tests suggested that the genetic burden was most prominent in the established genes LMF1 and APOC2, and also in the recently identified CREB3L3 gene. CONCLUSIONS: These extensive resequencing studies show a significant accumulation of rare genetic variants in non-GWAS candidate genes among patients with polygenic HTG, and indicate the importance of testing specific hypotheses in large-scale resequencing studies.

authors

  • Johansen, Christopher T
  • Wang, Jian
  • McIntyre, Adam D
  • Martins, Rebecca A
  • Ban, Matthew R
  • Lanktree, Matthew B
  • Huff, Murray W
  • Péterfy, Miklós
  • Mehrabian, Margarete
  • Lusis, Aldons J
  • Kathiresan, Sekar
  • Anand, Sonia
  • Yusuf, Salim
  • Lee, Ann-Hwee
  • Glimcher, Laurie H
  • Cao, Henian
  • Hegele, Robert A

publication date

  • February 2012

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