Allele frequencies for candidate genes in atherosclerosis and diabetes among Trinidadian neonates.

Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations.

Polymorphisms in PNLIP, encoding pancreatic lipase, and associations with metabolic traits.

Pancreatic lipase (EC 3.1.1.3) is an exocrine secretion that hydrolyzes dietary triglycerides in the small intestine. We developed genomic amplification primers to sequence the 13 exons of PNLIP, which encodes pancreatic lipase, in order to screen for possible mutations in cell lines of four children with pancreatic lipase deficiency (OMIM 246600). We found no missense or nonsense mutations in these samples, but we found three silent single-nucleotide polymorphisms (SNPs), namely, 96A/C in exon 3, 486C/T in exon 6, and 1359C/T in exon 13. In 50 normolipidemic Caucasians, the PNLIP 96C and 486T alleles had frequencies of 0.083 and 0.150, respectively. The PNLIP 1359T allele was absent from Caucasian, Chinese, South Asian, and North American aboriginal samples, but had a frequency of 0.085 in an African sample, suggesting that it is a population-specific variant. In an association analysis of 185 African neonates, the PNLIP 1359C/T SNP genotype was significantly associated with concentrations of plasma lipoproteins. These associations were most likely due to linkage disequilibrium with another functional variant at or near PNLIP. Thus, we report three new SNPs for the PNLIP, which may serve as markers for association analyses and for pharmacogenetic studies of pancreatic lipase inhibitors.

Infection-susceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area.

The MBL gene, encoding mannose-binding lectin, determines interindividual variation in susceptibility to certain infectious agents, such as Chlamydia pneumoniae. We examined whether infection-susceptibility alleles of MBL, called "non-A alleles," would be associated with increased carotid plaque area (CPA), an intermediate phenotype of atherosclerosis. In 164 subjects, we measured CPA with 2-dimensional ultrasound. We also determined traditional atherosclerosis risk factors and genotyped all subjects for MBL codons 52, 54, and 57. We used ANOVA to determine sources of variation for CPA and tested the hypothesis that the presence of a single MBL non-A "infection-susceptibility" allele was associated with increased CPA; 45.7% of subjects had at least one non-A allele. ANOVA showed that CPA was significantly associated with MBL genotype, age, smoking, hypertension, and hyperlipidemia (P < 0.05). When MBL was used as the sole independent variable in the regression analysis, the association with CPA was even more significant (P = 0.009). Subjects with at least one MBL non-A allele had significantly higher CPA than subjects homozygous for the MBL A allele and were significantly more likely to have CPA in excess of the sample median. Thus, infection-susceptibility alleles of MBL were associated with increased CPA in this study sample; these alleles may be a determinant of interindividual differences in atherosclerosis risk.

Lipoprotein-genotype associations in Trinidadian neonates.

OBJECTIVES: We hypothesized that common variation in the angiotensinogen (AGT), beta-3-adrenergic receptor, intestinal fatty acid-binding protein, serum paraoxonase, paraoxonase-2, hepatic lipase, apolipoprotein E (APOE), and Werner helicase (WRN) genes would be associated with variation in biochemical phenotypes in a previously unstudied neonatal sample. DESIGN AND METHODS: We examined associations of both nongenetic and genetic variables with plasma lipoprotein traits in neonates from Trinidad. RESULTS: Among nongenetic variables, we found significant associations between plasma concentrations of: 1) lipoprotein(a) [Lp(a)] and both ethnicity (p = 0.037) and birth weight (p = 0.001); 2) total cholesterol and gender (p = 0.010); 3) triglyceride and birth weight (p = 0.035); and 4) apolipoprotein AI and gender (p = 0.016). Among genetic variables, we found that: 1) common variation on chromosome 1q in AGT codon 235 was significantly associated with variation in plasma apolipoproteins AI (p<0.0001) and B (p = 0.013); 2) common variation in WRN at codon 1367 was significantly associated with variation in plasma Lp(a) (p<0.0001); and 3) common variation in APOE at codons 112 and 158 was significantly associated with variation in plasma triglycerides (p = 0.013). CONCLUSIONS: The associations with AGT and WRN are novel and may have resulted either from a direct influence of the genetic variants or through linkage disequilibrium with other functional loci, such as the familial combined hyperlipidemia locus on chromosome 1q in the case of AGT. Despite the fact that there are some limitations in making determinations from cord blood, the results suggest that there may be genetic determinants of plasma lipoproteins in neonates.