Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry

Abstract

Lipoprotein abnormalities, characterized by elevated levels of LDL cholesterol (LDL-C) and triglycerides (TRIG) and low levels of HDL cholesterol (HDL-C), have a central role in the development of atherosclerotic coronary heart disease (CHD). A recent meta-analysis, including 3,000 individuals with CHD-related deaths, showed that HDL-C and LDL-C are independently associated with CHD risk ( 1 ). There is also considerable evidence that high levels of TRIG are an additional, independent risk factor for CHD ( 2, 3 ), although this is still controversial ( 4 ).Individuals of African ancestry have a more favorable lipoprotein profi le than Caucasians, characterized by lower levels of TRIG and higher levels of HDL-C ( 5-8 ).The mechanisms responsible for these ethnic differences remain to be defi ned. In particular, the differences in TRIG levels are independent of the greater degree of obesity among individuals of African ancestry and several other risk factors and appear to be consistent across African populations in different environments ( 9 ), indicating a possible role of genetic factors. Although genetic factors are important in determining lipoprotein levels, little data Abstract African ancestry individuals have a more favorable lipoprotein profi le than Caucasians, although the mechanisms for these differences remain unclear. We measured fasting serum lipoproteins and genotyped 768 tagging or potentially functional single nucleotide polymorphisms (SNPs) across 33 candidate gene regions in 401 AfroCaribbeans older than 18 years belonging to 7 multi-generational pedigrees (mean family size 51, range 21-113, 3,426 relative pairs). All lipoproteins were signifi cantly heritable ( P < 0.05). Gender-specifi c analysis showed that heritability for triglycerides was much higher ( P < 0.01) in women than in men (women, 0.62 ± 0.18, P < 0.01; men, 0.13 ± 0.17, P > 0.10), but the heritability for LDL cholesterol ( LDL-C) was higher ( P < 0.05) in men than in women (men, 0.79 ± 0.21, P < 0.01; women, 0.39 ± 0.12, P < 0.01). The top 14 SNPs that passed the false discovery rate threshold in the families were then tested for replication in an independent population-based sample of 1,750 Afro-Caribbean men aged 40+ years. Our results revealed signifi cant associations for three SNPs in two genes (rs5929 and rs6511720 in LDLR and rs7517090 in PCSK9 ) and LDL-C in both the family study and in the replication study. Our fi ndings suggest that LDLR and PCSK9 variants may contribute to a variation in LDL-C among African ancestry individuals.

Genetic architecture of lipid traits changes over time and differs by race: Princeton Lipid Follow-up Study

“…LDL-C, HDL-C, and TGs all show similar results, with strong shared genetic correlations ( g ranging from 0.82 for TGs to 0.87 for HDL-C), weak and nonsignifi cant environmental correlations ( e ranging from 0.12 for HDL-C to 0.18 for TGs), and moderate phenotypic correlations ranging from 0.42 (TGs) to 0.55 (HDL-C) across time. Heritability for plasma lipids in our African American families (e.g., 0.17 for LDL-C to 0.62 for TGs and HDL-C) is also similar to the limited previous reports in African American or Caribbean populations (e.g., 0.28 in TGs to 0.55 for HDL-C) ( 6,8,44 ), none of which were recruited prior to the obesity epidemic. Some differences occur by lipid trait, for example TGs, where African American heritability was strong (0.62) in our study, but weak to moderate (0.28-0.37) and sometimes not signifi cant in others ( 6,8,44 ).…”

“…Heritability for plasma lipids in our African American families (e.g., 0.17 for LDL-C to 0.62 for TGs and HDL-C) is also similar to the limited previous reports in African American or Caribbean populations (e.g., 0.28 in TGs to 0.55 for HDL-C) ( 6,8,44 ), none of which were recruited prior to the obesity epidemic. Some differences occur by lipid trait, for example TGs, where African American heritability was strong (0.62) in our study, but weak to moderate (0.28-0.37) and sometimes not signifi cant in others ( 6,8,44 ). The current study's estimates for African American families at LRC are lower for TC (0.22) and LDL-C (0.17) than those reported in an early analysis of a subset of this same cohort (0.39 and 0.54, respectively) ( 7 ), possibly due to differences in analysis techniques.…”

A Variant in LDLR Is Associated With Abdominal Aortic Aneurysm

“…13 LDLR rs6511720 is one of the most important LDLcholesterol-associated variants in genome-wide studies of lipid traits. [25][26][27][28][29][30][31] Importantly, a relationship between AAA and LDL-cholesterol levels is not presently established. The most complete meta-analysis of the relationship was inconclusive, and individual reports are inconsistent.…”

Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study

“…Sex-specific heritabilities of lipid traits have been previously reported [23,24]. Despite considerable advances in the identification of genetic variants influencing plasma lipid levels, few studies have examined the role of sex as a potential modifier of the effects of genetic variation on lipids.…”