👤 James T Willerson

Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q Show less

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locus-specific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6). It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM. Show less