Novel rare alleles of ABCA1 are exclusively associated with extreme high-density lipoprotein-cholesterol levels among the Han Chinese.
BACKGROUND
High-density lipoprotein (HDL) is a major plasma lipoprotein directly associated with cholesterol metabolism. The ATP binding cassette transporter 1 gene (ABCA1) is one of the major genes modulating plasma levels of HDL-cholesterol (HDL-C). Rare alleles of ABCA1 associated with extreme HDL-C concentrations have not been previously investigated in the Chinese.


METHODS
Blood samples were collected from 470 subjects whose HDL-C concentrations were within the top 5% of the distribution, 335 subjects in the lowest 5%, and 220 within the range 5%-95%. First, we sequenced all exons of the ABCA1 gene from 50 subjects from the group with extremely high HDL-C, and 50 from the group with extremely low HDL-C concentrations. Next, in the remaining subjects, we genotyped the non-synonymous variants identified exclusively with either extreme group.


RESULTS
Four novel non-synonymous alleles were identified; all were rare. Alleles c.3029C>T (p.Ala1010Val) and c.5399A>G (p.Asn1800Ser) were found exclusively in the low group, c.2031C>A (p.Asp677Glu) and c.2660G>T (p.Cys887Phe) exclusively in the high group.


CONCLUSIONS
Our results show that some rare alleles of ABCA1 are associated with marked phenotypes, supporting the "rare-variant common-disease" hypothesis. Certain alleles also provide tools for identifying individuals at high risk of dyslipidaemia, allowing for early therapeutic intervention.
Hu
Suwei
S
Department of Medical Genetics, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou, PR China.
Zhong
Yanfang
Y
Hao
Yuantao
Y
Luo
Minqi
M
Zhou
Yan
Y
Guo
Hui
H
Liao
Weijiao
W
Wan
Desheng
D
Wei
Haiyun
H
Gao
Yueting
Y
Shan
Jinglan
J
Hu
Bin
B
Hultén
Maj
M
Wang
Yiming
Y
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D000818:Animals; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D002681:China / Q000208:ethnology; D008076:Cholesterol, HDL / Q000378:metabolism*; D017124:Conserved Sequence; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D051381:Rats; D013045:Species Specificity; D019914:Taq Polymerase / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D019914:Taq Polymerase