CTLA-4/CD28 gene region is associated with genetic susceptibility to coeliac disease in UK families

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...

Genomewide search and association studies in a Finnish celiac disease population: Identification of a novel locus and replication of the HLA and CTLA4 loci

“…In addition, candidate gene studies (including that of the CTLA4 exon 1 polymorphism at position þ49; þ49*A/G) have also been performed [Djilali-Saiah et al, 1998;Clot et al, 1999;Holopainen et al, 1999;Naluai et al, 2000;King et al, 2002;Popat et al, 2002b,c;Mora et al, 2003]. As for all complex traits, there are limitations in the statistical power of any single study due to limited sample sizes and to the modest genetic effect of common loci.…”

Genetic association of coeliac disease susceptibility to polymorphisms in the ICOS gene on chromosome 2q33

“…31 The association of the allele A was also detected in another Italian case-control and family study. 32 Also, families from the UK showed a significant association, not with CTLA4 but microsatellite D2S2214 33 ( Figure 1). In contrast, no evidence for this region was found in a study of Italian and Tunisian families.…”

A new locus for coeliac disease mapped to chromosome 15 in a population isolate

“…Replication studies in the Finnish population have also given some evidence for linkage to 5qter and 11q , but not to 15q26 (Susi et al 2001). Linkage to the CTLA-4/CD28 gene region has been shown in several populations in candidate gene studies (Djilali-Saiah et al 1998;Naluai et al 2000;King et al 2002) including the Finns (Holopainen et al 1999), even though this region has not been implicated in the genomewide scans.…”