Jonathan Cohen, Ph.D., is a human geneticist whose research strongly links genetics to metabolism. He has made fundamental contributions to our understanding of genetic regulation in humans and its connection to metabolic diseases.
In recent years Dr. Cohen has worked closely with Helen Hobbs, M.D., the director of the Center for Human Genetics. Dr. Cohen's key research findings with and without Dr. Hobbs can be summarized briefly.
- The apo(a) gene is polymorphic in sequence and sequence variations at the apo(a) locus, other than the number of kringle 4 repeats, contribute to the plasma concentration of Lp(a).
- A major fraction of the genetically determined variation in plasma HDL-cholesterol levels is conferred by allelic variation at the hepatic lipase and the apolipoprotein AI/CIII/AIV gene loci. Further studies domucment that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-cholesterol levels.
- Mutations in the phosphotyrosine binding domain protein ARH cause autosomal recessive hypercholesterolemia, a disorder caused by defective internalization of low density lipoprotein receptors in the liver. ARH functions as an adaptor protein that couples the LDL receptor to the endocytic machinery.
- Mutations in either ATP-binding cassette (ABC) G5 or ABCG8 cause sitosterolemia, an autosomal recessive disorder of sterol trafficking.
- Sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) are associated with reduced plasma levels of LDL cholesterol. These variants confer moderate lifelong reduction in the plasma level of LDL cholesterol; the also are associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
- Genome-wide association scanning identified a 58-kilobase interval on chromosome 9p21 that was consistently associated with coronary heart disease (CHD) in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD.
- Variation in the gene for PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to nonalcoholic fatty liver disease.