Lipoprotein Lipase Gene is Linked and Associated with Hypertension in Taiwan Young-onset Hypertension Genetic Study

Abstract

Hypertriglyceridemia has been extensively associated with hypertension. However, the mechanism behind it is poorly understood. A positive linkage signal between Lipoprotein lipase (LPL) and young-onset hypertension has been identified by us as the strongest among 18 candidate genes. Here we report our fine mapping works with seven microsatellite markers flanking LPL, sequencing results for its promoter and exons, and an extended association study with the identified single nucleotide polymorphisms(SNP). First, using data from 213 individuals in 59 nuclear families of young-onset hypertension, multipoint analysis revealed a NPL score of 3.02 for the LPL (GZ-14/GZ-15) marker in intron 6. LPL marker (p < 10(-12)) and the haplotypes containing its allele 1 (p < 0.0001) were also significantly associated with young hypertension by transmission disequilibrium test. In-depth sequencing revealed no mutation in promoter and exon regions, except two cSNP: 7754C--> A (C/A: 0.91/0.09), a silent mutation in exon 8 and S447X (C/G: 0.92/0.08), a stop codon mutation in exon 9. Other 11 cSNPs documented in NCBI GenBank are absent in our sample. Constructed from the above 2 cSNPs, haplotype AC showed a moderate TDT association with elevated triglyceride (p = 0.02) and with hypertension and elevated triglyceride combined (p = 0.06). Again, in an extended case-control study, a significant association was found between S447X and patients with persistent hypertension and elevated triglyceride (p = 0.02). We conclude that LPL variants may play a causal role in the development of hypertension in Taiwan Han Chinese. The moderate association with SNP haplotype suggests that other regulatory LPL variant may exist.

Association of lipoprotein lipase (LPL) single nucleotide polymorphisms with type 2 diabetes mellitus

“…LPL is one of the candidate genes of dyslipidemia (Hoffer et al, 1998;Julien et al, 1998;Pillarisetti and Saxena, 2003;Pruneta-Deloche et al, 2005) and hypertension (Williams et al, 1994;Yang et al, 2003b;Li et al, 2004;Chen et al, 2005) because its gene product is a major regulator of triglyceride clearance in the blood. LPL catalyzes the hydrolysis of triglycerides of circulating chylomicrons and VLDL, excesses of which are the potent causes of both disorders.…”

Candidate Genes in Hypertension

“…Mutations in locus intron 6 of LPL gene (Oka et al, 1989, Zuliani & Hobbs, 1990 lead to hypertriglyceridemia, dyslipidemia leading to various disorders as coronary artery disease, hypertension and obesity. The association betweeen hypertension and the LPL locus (8p22) was reported by several studies (Chen et al, 2005, Yang et al, 2003. Significant evidence for linkage of systolic BP, but not diastolic BP has been associated with LPL locus located on the short arm of chromosome 8 (8p22) (Du-An et al, 1992).…”

Incorporating Covariates into Multipoint Association Mapping in the Case-Parent Design

“…The estimated disease locus 19.8634 (between rs320 and rs322) with the smallest standard error (6.36 ! 10 -5 ) is located at exon 8, which is known to be associated with hypertension [26] . To further study the interactions between a SNP and the disease locus, and the SNP's relation with TG, the genotypes of rs295 at 19.860518 cM were incorporated into the parametric model.…”

“…Based on the asymptotic property, the variance estimates of ␦ ˆ can be calculated as 1 1 Var A BÂ ( ) ␦ (26) where (27) …”