Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT

Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc = 1 first-degree relative with low HDLc (familial probands) and 89 where familial status of low HDLc is uncertain (unknown probands). Mutations were most frequent in LCAT (15.7%), followed by ABCA1 (9.0%) and APOA1 (4.5%), and were found in 42.7% of familial but only 14.6% of unknown probands (p=2.44 10(-5)). Interestingly, only 16 of 24 (66.7%) mutations assessed in families conferred an average HDLc 40% of familial hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). (C) 2011 Elsevier B.V. All rights reserve

Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans

The scavenger receptor class B, member 1 (SR-BI), is a key cellular receptor for high-density lipoprotein (HDL) in mice, but its relevance to human physiology has not been well established. Recently a family was reported with a mutation in the gene encoding SR-BI and high HDL cholesterol (HDL-C). Here we report two additional individuals with extremely high HDL-C (greater than the 90th percentile for age and gender) with rare mutations in the gene encoding SR-BI. These mutations segregate with high HDL-C in family members of each proband and are associated with a 37% increase in plasma HDL-C in heterozygous individuals carrying them. Both mutations occur at highly conserved positions in the large extracellular loop region of SR-BI and are predicted to impair the function of the SR-BI protein. Our findings, combined with the prior report of a single mutation in the gene encoding SR-BI, further validate that mutations in SR-BI are a rare but recurring cause of elevated HDL-C in human

Segregation of LIPG, CETP, and GALNT2 Mutations in Caucasian Families with Extremely High HDL Cholesterol

To date, few mutations are described to underlie highly-elevated HDLc levels in families. Here we sequenced the coding regions and adjacent sequence of the LIPG, CETP, and GALNT2 genes in 171 unrelated Dutch Caucasian probands with HDLc >= 90th percentile and analyzed segregation of mutations with lipid phenotypes in family members. In these probands, mutations were most frequent in LIPG (12.9%) followed by GALNT2 (2.3%) and CETP (0.6%). A total of 6 of 10 mutations in these three genes were novel (60.0%), and mutations segregated with elevated HDLc in families. Interestingly, the LIPG mutations N396S and R476W, which usually result in elevated HDLc, were unexpectedly found in 6 probands with low HDLc (i.e., <= 10th percentile). However, 5 of these probands also carried mutations in ABCA1, LCAT, or LPL. Finally, no CETP and GALNT2 mutations were found in 136 unrelated probands with low HDLc. Taken together, we show that rare coding and splicing mutations in LIPG, CETP, and GALNT2 are enriched in persons with hyperalphalipoproteinemia and segregate with elevated HDLc in families. Moreover, LIPG mutations do not overcome low HDLc in individuals with ABCA1 and possibly LCAT and LPL mutations, indicating that LIPG affects HDLc levels downstream of these protein

Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans

While genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with large effects in candidate genes contributing to extreme HDLc in humans, utilizing family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with extremely low ( = 90th percentile) HDLc. Probands were excluded if known mutations existed in the established HDLc-regulating genes ABCA1, APOA1, LCAT, cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2). We identified 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped in the proband's family. Family-based association analyses were performed for variants with sufficient power to detect significance at P <0.05 with a total of 627 family members being assessed. Mutations in the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor 3 (LILRA3), and dynein axonemal heavy chain 10 (DNAH10) segregated with elevated HDLc levels in families, while no mutations associated with low HDLc. Taken together, we have identified mutations in four novel genes that may play a role in regulating HDLc levels in human

Additional mutations in individuals with <i>LIPG</i> mutations and low HDLc.

<p>Additional mutations in individuals with <i>LIPG</i> mutations and low HDLc.</p

Representative segregation of mutations in families.

<p><b>A, B</b>) Segregation of (<b>A</b>) <i>LIPG</i> L130F-FS and (<b>B</b>) <i>GALNT2</i> D314A with elevated HDLc. For each individual, the individual ID, HDLc (in mmol/L) plus [HDLc percentile], and genotype are shown. Squares, Males; Circles, Females; Arrow, proband. Filled shape, HDLc≥90^th percentile; half-filled, HDLc between 80–89^th percentiles; empty shape, HDLc<80^th percentile. Slash = deceased. <b>C</b>) Percent of individuals in families with mutations at given HDLc percentiles or higher.</p

<i>LIPG</i>, <i>CETP</i>, and <i>GALNT2</i> mutations.

<p><i>LIPG</i>, <i>CETP</i>, and <i>GALNT2</i> mutations.</p

Demographics of unrelated probands with extreme HDLc.

a<p>, Average (SD);</p>b<p>, N (%);</p>c<p>, Average (95% confidence interval).</p

Mutations identified in probands with high or low HDLc.

<p>A) Overview of the study design. <b>B–D</b>) Predicted mutation effects on <b>B</b>) LIPG, <b>C</b>) CETP, and <b>D</b>) GALNT2 proteins. Red sequence changes are novel, blue are previously described <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037437#pone.0037437-Edmondson1" target="_blank">[17]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037437#pone.0037437-deLemos1" target="_blank">[23]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037437#pone.0037437-Holleboom1" target="_blank">[28]</a>, and black is previously described in a subset of this cohort <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037437#pone.0037437-vanderSteeg1" target="_blank">[16]</a>.</p