Table 2

Prevalence of LDL-C-lowering variants in a population of 13,131 healthy older CHD-free individuals (ASPREE)

Gene	Variant (GRCh37)	rsID	Type	Consequence	ASPREE carriers	ASPREE MAF N=13 131	gnomAD-NFE MAF N=64 603	ASPREE blood lipid levels (mg/dL)*
								LDL-C	TC
								Non-carriers (mean n=9450)
								119.9	201.1
Rare variants (MAF <0.01)
PCSK9	NM_174936.3(PCSK9): c.709C>T (p.Arg237Trp)	rs148195424	SNV	Missense	44	0.00335	0.00093	107.3	194.5
PCSK9	NM_174936.3(PCSK9): c.1327G>A(p.Ala443Thr)	rs28362263	SNV	Missense	13	0.00099	0.00029	117.5	198.9
PCSK9	NM_174936.3(PCSK9): c.657+1G>T	rs142824171	SNV	Splice donor	7	0.00053	0.00007	116.6	202.2
PCSK9	NM_174936.3(PCSK9): c.1384T>C (p.Ser462Pro)	rs746115963	SNV	Missense	7	0.00053	0.00012	124.3	214.9
PCSK9	NM_174936.3(PCSK9): c.520C>T (p.Pro174Ser)	rs533273863	SNV	Missense	5	0.00038	0.00008	127.6	222.0
PCSK9	NM_174936.3(PCSK9): c.1863+1G>A	rs765335983	SNV	Splice donor	5	0.00038	0.00003	98.6	182.7
PCSK9	NM_174936.3(PCSK9): c.277C>T (p.Arg93Cys)	rs151193009	SNV	Missense	3	0.00023	0.00002	128.9	212.7
PCSK9	NM_174936.3(PCSK9): c.341T>C (p.Val114Ala)	rs775988212	SNV	Missense	2	0.00015	0.00003	139.2	212.7
PCSK9	NM_174936.3(PCSK9): c.471C>A (p.Asn157Lys)	rs143117125	SNV	Missense	2	0.00015	0.00005	121.8	203.1
PCSK9	NM_174936.3(PCSK9): c.1300C>T(p.Arg434Trp)	rs757143429	SNV	Missense	2	0.00015	0.00001	98.60	164.3
PCSK9	NM_174936.3(PCSK9): c.313C>T (p.Arg105Trp)	rs747072726	SNV	Missense	1	0.00008†	0.00002	116.0	247.0
PCSK9	NM_174936.3(PCSK9): c.706G>A (p.Gly236Ser)	rs149489325	SNV	Missense	1	0.00008†	0.00005	65.7	139.2
PCSK9	NM_174936.3(PCSK9): c.658-2A>C	rs371336612	SNV	Splice acceptor	1	0.00008†	–	77.3	146.9
Total 92
APOB	NM_000384.3(APOB): c.6253C>T(p.Arg2085Ter)	rs121918386	SNV	Stop gained	3	0.00023	0.00004	95.37	170.2
APOB	NM_000384.3(APOB): c.4503T>G (p.Tyr1501Ter)	rs368825685	SNV	Stop gained	1	0.00008†	0.00001	77.3	177.9
APOB	NM_000384.3(APOB): c.1315C>T (p.Arg439Ter)	rs142066904	SNV	Stop gained	1	0.00008†	0.00003	61.9	123.7
APOB	NM_000384.2(APOB): c.11153C>G (Ser3718Ter)	–	SNV	Stop gained	1	0.00008†	–	61.9	146.9
APOB	NM_000384.2(APOB): c.7300C>T (p.Gln2434Ter)	–	SNV	Stop gained	1	0.00008†	–	42.5	174
APOB	NM_000384.3(APOB): c.6538C>T (p.Gln2180Ter)	rs1041962	SNV	Stop gained	1	0.00008†	–	61.9	162.4
APOB	NM_000384.2(APOB): c.2245-2A>G	–	SNV	Splice acceptor	1	0.00008†	–	98.6	164.3
APOB	NM_000384.2(APOB) 21228615CA>C (deletion)	–	INDEL	Frameshift	1	0.00008†	–	77.3	146.9
APOB	NM_000384.2(APOB) 21 230 841G>GT (insertion)	–	INDEL	Frameshift	1	0.00008†	–	73.5	177.9
Total 11
PCSK9 R46L (MAF >0.01)
PCSK9	NM_174936.3(PCSK9): c.137G>T (p.Arg46Leu)	rs11591147	SNV	Missense
				HET	465	0.03541	0.01507	110.6	196.4
				HOMO	6	0.00046	0.0002	105.0	190.1

We sequenced n=13 131 individuals aged 70 years and older to detect cholesterol-lowering variants using two methods: (1) prediction of rare candidate loss-of-function, protein-truncating PCSK9 and APOB variants and (2) assessment of candidate variants identified in previously published functional or population studies. We also examined the effect of the common PCSK9 R46L variant with lipid-lowering effect; rs1159114725 Variants were curated following ACMG/AMP Standards26
*For variants found in more than one participant, the mean LDL-C and TC levels for all carriers of that variant are shown.
†Denotes a singleton variant detected in only one ASPREE participant/carrier (MAF=1 carrier/13 131 participants=0.0008).
ACMG/AMP, American College of Medical Genetics/Association for Molecular Pathology; ASPREE, ASPirin in Reducing Events in the Elderly; CHD, coronary heart disease; HET, heterozygote; HOMO, homozygote; INDEL, insertion/deletion; LDL-C, low-density lipoprotein cholesterol; MAF, minor allele frequency; SNV, single nucleotide variant; TC, total cholesterol.