Prevalence of Variants of Lipoprotein Metabolism Genes in a Single

Prevalence of Variants of Lipoprotein Metabolism Genes in a Single Lipidology Clinic Lane B Benes, MD1, Kent Brummell, MD2, Mendel Roth, PhD3, Li Shen, PhD3 and Michael H Davidson, MD1 1Department of Medicine, Section of Cardiology, The University of Chicago, Chicago, IL, 2Department of Medicine, The University of Chicago, Chicago, IL, TAP TO RETURN 3Genben Lifesciences, San Diego, CA TO KIOSK MENU

Introduction Results

Table 1. Patient characteristics Despite rapid discovery of variants associated with abnormal lipoprotein 84 patients underwent genetic analysis. See Table 1 for patient Age 53.6 years metabolism and CAD, genetic testing is not considered routine characteristics Female sex 33.3% management for most forms of dyslipidemia or premature CAD. European descent 91.7% • Cost, uncertainty of how to use results 82 patients (97.6%) were found to have at least 1 pathogenic or Statin or red yeast rice use 62 (73.8%) • Polygenic inheritance of lipid disorders increasingly likely pathogenic variant or a variant of uncertain significance Ezetimibe use 34 (40.5%) recognized (VUS) associated with abnormal lipid metabolism or increased PCSK9 inhibitor use 18 (21.4%) We sought to determine the prevalence of pathogenic or potentially risk of CAD. See Tables 2 and 3 for genetic findings Fish oil use 23 (27.4%) pathogenic variants in a single lipid clinic Other lipid‐lowering medication use 10 (11.9%) Total cholesterol (mg/dL) 168.2 LDL‐C (mg/dL) 90.4 Tap to enlarge Tables 2 and 3 HDL‐C (mg/dL) 52.7 TG (mg/dL) 153.5 Lp(a) 9 patients above assay in nmol/L* 187.2 nmol/L Methods 40 patients above assay in mg/dL* 72.8 mg/dL LDL particle number 1186.5 Number of patients meeting more 21 (25%) Genetic testing was offered to patients with at least one of the than 1 criteria for genetic testing following: * Patients with Lp(a) levels below assay were not • Hypertriglyceridemia: pre-treatment fasting triglycerides > 150 mg/dL included in this table. • Elevated LDL-C: pre-treatment LDL-C > 190 mg/dL • Low HDL-C: HDL-C < 40 mg/dL • Elevated lipoprotein(a) (Lp(a)): Lp(a) > 50 mg/dL or > 125 nmol/L • Acute coronary syndrome or revascularization before age 40 years in men and 50 years in women Conclusions GBinsight Comprehensive Dyslipidemia Panel (GB Lifesciences, San Diego, CA) used to sequence 327 exons and selected SNPs in 129 • The vast majority of patients seeking care at a single lipid clinic have at least one variant known or suspected to be genes associated with abnormal lipoprotein metabolism or CAD • Next-generation sequencing at a read depth of 100x • The most common variants were those of LDLR, LPL, APOA5 and LPA • Pathogenicity defined according to the American College of Medical • Whether identification of the underlying genetic etiology of a lipid disorder alters management warrants further study Genetics

Acknowledgements: Karina Rodriguez, MA, Molly Horan, RN, MS and Genben Lifesciences Prevalence of Variants of Lipoprotein Metabolism Genes in a Single Lipidology Clinic

Table 2. Pathogenic/likely pathogenic variants and variants of uncertain significance in lipoprotein metabolism genes identified Number of Gene Patients Variant Molecular Consequence LIPI 1 Pathogenic/Likely pathogenic: rs11909217 Cys76Tyr LDLR 10 Pathogenic/Likely pathogenic: 1 VUS: 1 rs752596535 Cys167Ter rs774658122 Gly103Arg 1 rs121908029 Glu228Lys ABCA1 6 VUS: 2 rs758036807 Gly219del 1 rs140365800 Asp1018Gly 1 rs28942084 Pro685Leu 1 rs1375277326 Ser2127Asn 1 rs121908031 Cys681Ter 1 rs201599169 Arg666Trp 2 rs769383881 Glu113Ter 1 rs138880920 Lys776Asn 2 rs775092314 Cys677Arg 1 rs748253213 His1985Tyr 5 VUS: 1 rs756752984 Ala374Val 1 rs751234870 Phe629= (may affect splicing) LCAT 2 Pathogenic/Likely pathogenic: 1 rs72658867 and rs137853964 May affect splicing + Val827Ile 16:67977010-T-A #** Asp87Val 1 rs752846235 Val797= (Likely to affect splicing) 2 rs375877599 May affect splicing MTTP 9 VUS: rs61750974 Val168Ile APOB 1 Pathogenic/Likely pathogenic: rs150312765 Asn3580Lys # Multiple members of same family possess this variant LPL 7 Pathogenic/Likely pathogenic: **Novel variant. No dbSNP ID. Genomic coordinates are based on Reference Genome Assembly hg19 1 rs118204080 Ile252Thr Abbreviations: ABCA, ATP-binding cassette transporter; APO, apolipoprotein; GPIHBP1, 4 rs268 Asn318Ser glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1; LCAT, lecithin- 2 rs1801177 Asp36Asn cholesterol acyltransferase; LDLR, low-density lipoprotein receptor; LIPI, lipase member 1; LMF1, 2 VUS: lipase maturation factor 1; LPL, lipoprotein lipase; MTTP, microsomal triglyceride transfer protein; VUS, rs116403115 Val442Gly (May affect splicing) variant of uncertain significance APOE 5 Pathogenic/Likely pathogenic: 3 APOE4(-)-FREIBURG # Table 3. Notable genetic variants in lipoprotein metabolism genes that (rs429358/rs769452) Cys130Arg/Leu46Pro contribute to polygenic dyslipidemias identified 1 E2/E2 (rs7412 homozygous) Arg176Cys 1 rs769455 Arg163Cys Gene Number of Variant Molecular Consequence 1 VUS: Patients 19:45411975-A-G** Gln141Arg APOA5 1 rs2075291 Gly185Cys APOA5 1 VUS: 12 rs3135506 Ser19Trp rs201229911 Thr184Ser ABCA7 1 rs751899870 Thr1060_Arg1061insAspMetGluGlySerValAspThr 1 rs139214131 Arg989His GPIHBP1 1 VUS: 1 rs117187003 Val1599Met rs201685731 Gly123Glu 1 rs201932817 Asp539Glu APOA1 1 VUS: 1 rs201060968 Trp1214Ter 11:116706791-A-C** His179Gln LPA 16 rs3798220 Ile1891Met LMF1 2 VUS: 8 rs10455872 Intronic variant 1 rs35168378 Arg364Gln 1 rs41272112 Arg1421Gln 1 rs764885027 Tyr439Cys ABCA6 5 rs77542162 Cys1359Arg Abbreviations: ABCA, ATP-binding cassette transporter; APOA5, apolipoprotein A5; LPA, lipoprotein(a)