Association between markers in chromosomal region 17q23 and young onset hypertension: a TDT study

Abstract

H ypertension is one of the most important risk factors for cardiovascular diseases. Despite extensive research examining the causes of blood pressure variation, a significant proportion of blood pressure variation is yet to be explained. Studies of families and twins suggest that 20-40% of blood pressure variation can be attributed to genetic factors.1 Evidence shows that the genetic contribution is even greater for young onset hypertension. 2 We feel that genetic approaches focusing on young onset hypertension will provide new insight into the pathogenesis of hypertension.In our previous report, the affected sib pairs (25 independent, affected sib pairs) method showed positive signs of linkage for markers of the atrial natriuretic peptide gene (NPPA) (D1S1612, p=0.0162), angiotensinogen gene (AGT) (D1S547, p=0.0263), lipoprotein lipase gene (LPL) (D8S1145, p=0.0284), and angiotensin converting enzyme gene (DCP1) (D17S2193, p=0.0256), 3 indicating that multiple pathogenic pathways may be involved in the aetiology of young onset hypertension. Owing to this aetiological complexity, in the current study we focus on high resolution mapping of AGT (located on 1q42-43) and DCP1 (located on 17q23), genes of the renin angiotensin system (RAS). Renin catalyses the first step of the activation pathway of angiotensinogen to angiotensin I, which is then cleaved to angiotensin II by angiotensin I converting enzyme. This cascade can lead to aldosterone release, vasoconstriction, and increased blood pressure. Although the RAS has been extensively studied, it remains unclear how and to what extent RAS gene variants contribute to the blood pressure variations in various human populations. MATERIALS AND METHODSWe have recruited 59 nuclear families (a total of 214 subjects) from a hypertension clinic at Taipei Veterans General Hospital, Taiwan. Our study group included 81 young onset hypertensive patients (59 probands and 22 affected sibs, mean age 30.4 (SD 0.95)), 39 normotensive sibs (mean age 32.2 (SD 1.6)), and 94 parents. Our previous study included 25 affected sib pairs from 18 families for affected sib pair analysis. This transmission disequilibrium test (TDT) study used information from all 59 families with probands. Therefore, the former is a subset of the latter. The protocol of this study was approved by the Human Investigation Committee of the Institute of Biomedical Sciences, Academia Sinica.Polymorphic microsatellite markers located on 1q42-43 and 17q23 were selected based on GeneMap'99 and comprehensive human genetic maps from the Marshfield Medical Research Foundation, and obtained from Multi-Colored Fluorescent Human MapPairs Markers of Research Genetics (Huntsville, AL). Nine markers on 1q42-43 were selected: D1S2805 (245.05 cM), D1S3462 (247.23 cM), D1S459 (247.23 cM), D1S1540 (252.12 cM), D1S235 (254.64 cM), D1S517 (262.96 cM), D1S1149 (262.96 cM), D1S1594 (265.49 cM), and D1S547 (267.51 cM). The six markers on 17q23 were D17S1297 (83.40 cM), D17S1295 (83.40 cM), D17S942 (85.94 cM), ATA108a05 (88.76 cM), D17...

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

“…[17]. Although our preliminary results points to four potential genes, only angiotension converting enzyme (DCP1) [18] and LPL (the present study) sustained their genetic effects in our fine mapping endeavors. We demonstrated in Taiwan Han Chinese that the LPL marker located in the intron 6 of LPL gene was positively linked with young-onset hypertension.…”

“…This finding was further supported by TDT either via single microsatellite marker or the haplotype analyses. The degree of linkage and association for LPL is much greater than that of DCP1 [18] in our young-onset hypertension study, indicating the relative importance of LPL in the development of hypertension in Taiwan Han Chinese. On the other hand, only 32% of the family demonstrated a positive linkage score for LPL marker, suggesting the existence of genetic heterogeneity of hypertension.…”

“…Here we reported the follow-up fine mapping processes, using seven microsatellite markers around or in the LPL gene, in a twostage linkage approach. We found that the degree of this linkage and association with LPL is the strongest among 18 hypertension candidate genes including angiotensin converting enzyme we previously reported elsewhere [18]. Furthermore, we sequenced the promoter and coding regions of LPL in order to find new and common SNPs (Single Nucleotide Polymorphisms) which may explain the blood pressure variaton.…”

Genome-Wide Scan for Quantitative ACE Activity in Taiwan Young-Onset Hypertension Study

“…Pan et al [41] conducted an affected-sib-pair linkage study on young-onset hypertension pedigrees revealing potential linkage between hypertension and ACE gene. Wu et al [42] continued Pan's research and carried out a transmission disequilibrium analysis with more microsatellite markers around the ACE . The results of all these studies have linked hypertension and/or blood pressure to markers flanking ACE on chromosome 17.…”