We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

/pdf/exome-wide-association-study-of-plasma-lipids-in-300-000-58e44mx6sh.pdf

Exome-wide association study of plasma lipids in > 300,000 individuals

Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.

Genetics of coronary artery disease: discovery, biology and clinical translation

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in adults over 50 years old. Genetic, epidemiological, and molecular studies are beginning to unravel the intricate mechanisms underlying this complex disease, which implicate the lipid-cholesterol pathway in the pathophysiology of disease development and progression. Many of the genetic and environmental risk factors associated with AMD are also associated with other complex degenerative diseases of advanced age, including cardiovascular disease (CVD). In this review, we present epidemiological findings associating AMD with a variety of lipid pathway genes, cardiovascular phenotypes, and relevant environmental exposures. Despite a number of studies showing significant associations between AMD and these lipid/cardiovascular factors, results have been mixed and as such the relationships among these factors and AMD remain controversial. It is imperative that researchers not only tease out the various contributions of such factors to AMD development but also the connections between AMD and CVD to develop optimal precision medical care for aging adults.

/pdf/epidemiology-of-age-related-macular-degeneration-amd-1zf1tg8oxg.pdf

Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors

Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

/pdf/new-loci-and-coding-variants-confer-risk-for-age-related-24s2coaqv5.pdf

Yi Xin Zeng

Papers

New loci and coding variants confer risk for age-related macular degeneration in East Asians