Key result
Next-generation sequencing identified mutations in four novel genes (GCKR, RNASEL, LILRA3, and DNAH10) that segregated with elevated HDL cholesterol levels in families.
Observational (n=827)
Mutations in GCKR, RNASEL, LILRA3, and DNAH10 were identified as novel genetic variants that segregate with elevated HDL cholesterol levels in families.
Heritability estimates of 47-76% for plasma HDL cholesterol (HDLc) levels suggest that genetic variation plays a pivotal role in HDL metabolism ( 1-3 ). However, despite major advances in family-and population-based association studies ( 2, 4 ), most genetic causes of extreme HDLc levels in humans remain unknown. Cohen et al. ( 5 ) reported mutations in the established HDLc genes ABCA1 , APOA1 , and LCAT in only 12.4% of individuals with low HDLc (<5th percentile). Similarly, we reported that mutations in the known HDLc-regulating genes ABCA1 , APOA1 , and LCAT were found in 28.7% of unrelated individuals with low HDLc levels ( 10th percentile) ( 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 ( 10th percentile) or high ( 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- -D-galactosamine:polypeptide N -acetylgalactosaminyltransferase 2 ( GALNT2 ). We identifi ed 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped in the proband's family. Familybased association analyses were performed for variants with suffi cient power to detect signifi cance 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 identifi ed mutations in four novel genes that may play a role in regulating HDLc levels in humans. -Singaraja, R.
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Singaraja et al. (2014) conducted an observational in Extreme HDL cholesterol levels (n=827). Next-generation sequencing was evaluated on Segregation of novel rare mutations with extreme HDLc levels. Next-generation sequencing identified mutations in four novel genes (GCKR, RNASEL, LILRA3, and DNAH10) that segregated with elevated HDL cholesterol levels in families.
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