Table 2.

Genetic alterations in HDL metabolism-associated factors.

Gene	Annotated Mutations	Associated to CV Risk?	Affected Physiological Parameters	Ref
APOA-I	83	Yes	Mild (heterozygous) to almost complete absence (homozygous or compound heterozygous) of ApoA-I and HDL-C with a predisposition for premature CVD. (Hereditary) amyloidosis due to the accumulation of abnormal N-terminal ApoA-I fragments.	[110,111,112,113,114]
ABCA1	268	Yes	Heterozygous loss-of-function: common in people with low HDL-C presenting with a 50% reduction in cholesterol efflux and moderately reduced HDL-C. Homozygous: Tangier Disease counts 100 cases worldwide and shows drastic impairment of cholesterol efflux and hardly any plasma HDL-C and ApoA-I. ABCA1 mutations seem to be dominant: combinations with mutations that increase HDL-C levels, sustain very low HDL-C. Often accompanied by neurologic, ophthalmologic, dermatologic, hematologic, and histiocytic symptoms.	[115,116,117]
LCAT	117	Expected, but not confirmed due to low case numbers and high heterogeneity.	Mild (fish-eye disease) to severe (familial LCAT deficiency) loss of enzymatic activity resulting in a reduction of ApoA-I and HDL-C plasma levels of up to 80%.	[118,119,120]
CETP	71	Yes, but extent strongly depends on the respective mutation.	Partial to complete deficiency increases ApoA-I and HDL-C plasma levels. More frequently found in the Japanese population.	[30,121,122,123,124]
SCARB1	18	Unclear. Yes for rs4238001 and p.P376L (almost exclusive to Ashkenazi Jews).	Increased HDL-C (impaired hepatic uptake) and foam cell formation (impaired cholesterol efflux). A higher prevalence in the Icelandic population.	[105,125,126,127]
PON1	22	Unclear. Yes for Q192R and V109I (ischemic events, CAD) and suggested for L55M (AS) in diabetic patients.	Protection from oxidation diminished by impaired enzymatic activity (Q192R) or reduced concentrations (L55M).	[128,129,130,131,132,133,134]
APOM	5	Yes for T778C, T1628G, T855C, C724del.	Supposedly down-regulated ApoM expression and elevated total cholesterol levels. Almost exclusively identified in the Han Chinese population.	[135,136,137]

APOA-I: apolipoprotein A-I; HDL-C: high-density lipoprotein cholesterol; CVD: cardiovascular disease; ABCA1: ATP-binding cassette transporter A1; LCAT: lecithin–cholesterol acyltransferase; CETP: cholesteryl ester transfer protein; SCARB1: scavenger receptor class B member 1; PON1: paraoxonase 1; APOM: apolipoprotein M.