The literature search for genes previously reported for association with HDLC was performed in PubMed using search terms such as “(meta-analysis OR associat* OR epidemiolog*) AND (polymorphism OR genetic OR mutation) AND HDL AND human” with an Entrez Date in PubMed until April 2008 (EDAT: the date the citation was added to PubMed). Results were complemented by knowledge of the lipid-experienced investigators of this study.
Eligible studies for data extraction were meta-analyses, population-based studies, studies in the general population, healthy control populations, hospital-based controls, control populations selected for not having type 2 diabetes mellitus (T2DM), and case-control studies for cardiovascular disease (CVD) or T2DM. Studies which were included in a meta-analysis were only indirectly considered by showing the results of this meta-analysis in the tables instead of each single study. We did not consider studies with special patient populations other than cardiovascular disease or T2DM (e.g. patients with chronic kidney disease).
Exclusion criteria for our search were studies in a non-English language where only the abstract was available in English and small studies with less than 500 individuals.
Studies which investigated a large number of genetic variants were only considered to provide statistically significant association, if the associations were strong enough to hold for a significance level corrected for the multiple comparisons. This was usually not sufficiently accounted for in the reported associations. Moreover, we omitted studies on polymorphisms with a too low minor allele frequency (MAF) yielding less than about 30 study participants with the minor allele considering the number of individuals investigated.
If the results of a particular polymorphism of a certain study population were considered in more than one publication, only one of these publications was referenced in our tables.
A gene was considered an HDLC candidate gene if at least two eligible studies reported a statistically significant association of genetic variation within or related to the particular gene with HDLC levels. An exception from this rule was made for LCAT for which strong functional evidence was available combined with one large and a few small association studies.
Rarely investigated genetic variations that showed a significant association with HDLC levels in at least one large study (n>1000) are listed in an additional table ().
Genetic variants in genes rarely investigated, which showed significant association with HDLC levels in at least one large study (n>1000).
- and the Supplementary Table
show the results of all eligible candidate gene association studies which were accessible in PubMed until the Entrez Date April 2008. Even though we draw our attention to the fact not to miss the most important studies, we are aware that it might not have been possible to have complete lists of all studies which deal with candidate genes for HDL cholesterol.
Genetic variants within the CETP gene coding for the cholesteryl ester transfer protein and their association with HDLC concentrations.
It should be noted that identifying the precise rs numbers of some polymorphisms was very tedious if not impossible as rs numbers were often lacking or mistakenly reported and in some of these cases we were only able to derive rs numbers by combining literature reports with databases such as HapMap or NCBI. In some cases the effect size of the investigated SNP on HDL cholesterol was only displayed in a figure and allowed only an approximate estimate of the numerical value.
For the single nucleotide polymorphisms (SNPs) of the candidate genes reported in the - we imported data from HapMap and constructed an r2-plot using HaploView 4.1 to illustrate the correlation of the SNPs reported for each gene. For APOA1, APOC3 and PON1 no r2-plot was constructed since only one or none of the tabulated SNPs was available in HapMap. Furthermore, rs2303790 of CETP and rs2066718 of ABCA1 are not displayed in the r2-plots since the MAF of these SNPs was 0.0% for the imported HapMap data.
Genetic variants within the genes GHRL, LDLR and PON1 coding for ghrelin, LDL-receptor and paraoxonase 1, respectively and their associations with HDLC concentrations.a
A further chapter reviews the evidence recently derived from genome-wide association (GWA) studies. SNPs derived from these studies are not listed in - but are provided in an extra table ().
SNPs associated with HDLC concentrations in GWA studies. For each study and each gene, the SNP with the best p value is shown.