| 1. |
- Sarwar, Nadeem, et al.
(author)
-
Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
- 2012
-
In: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
-
Journal article (peer-reviewed)abstract
- Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
|
|
| 2. |
- Jiao, Xiang, et al.
(author)
-
PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
- 2017
-
In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
-
Journal article (peer-reviewed)abstract
- Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
|
|
| 3. |
- Adamovic, T, et al.
(author)
-
The p.G146A and p.P125P polymorphisms in the steroidogenic factor-1 (SF-1) gene do not affect the risk for hypospadias in Caucasians
- 2012
-
In: Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation. - : S. Karger AG. - 1661-5433. ; 6:6, s. 292-297
-
Journal article (peer-reviewed)abstract
- Hypospadias is a frequent congenital malformation in boys and is characterized by incomplete fusion of the urethral folds. The steroidogenic factor-1 <i>(SF-1, NR5A1)</i> gene plays a key role in hypothalamic-pituitary-steroidogenic organ development, and has previously been reported to be mutated in individuals with 46,XY disorder of sex development. Here, we investigated the role of <i>SF-1</i> in hypospadias, a milder form of 46,XY disorder of sex development. We performed direct sequencing analysis of the <i>SF-1</i> gene in 2 male Caucasian twins exhibiting very severe hypospadias, and in 95 Caucasian boys with mild and severe hypospadias. We further extended the analysis by investigating 332 mild and severe hypospadias cases and 422 male controls using TaqMan assays. Our sequencing revealed a novel heterozygous p.R313H (c.938G>A) missense mutation in each twin, and no mutations in the 95 Caucasian cases. Instead, a missense p.G146A (c.437G>C), and a silent known p.P125P (c.375C>T) polymorphism, respectively, was found in several of the latter cases. Further investigation of the 2 polymorphisms in the larger material of cases and controls showed no significant genotypic or allelic association. In conclusion, the <i>SF-1</i> gene may not play a significant role in the development of hypospadias in Caucasians.
|
|
| 4. |
|
|
| 5. |
- Omrani, MD, et al.
(author)
-
17-β-hydroxysteroid dehydrogenase type 3 deficiency in three adult Iranian siblings
- 2011
-
In: Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation. - : S. Karger AG. - 1661-5433. ; 5:6, s. 273-276
-
Journal article (peer-reviewed)abstract
- 17-β-hydroxysteroid dehydrogenase type 3 (17-β-HSD 3) deficiency is an autosomal recessive form of 46,XY disorder of sex development (DSD). To date, a total of 27 <i>HSD17B3</i> gene mutations have been described in 46,XY patients exhibiting different phenotypes at birth and virilization at puberty, sometimes in association with gynecomastia. Herein, we investigate the 46,XY DSD in an Iranian family consisting of 7 siblings, 3 of which are affected and virilized at puberty. We clinically characterized these patients andperformed direct DNA sequencing of the steroid 5-α-reductase type 2<i> (SRD5A2)</i> and the <i>HSD17B3</i> gene, respectively. We identified a homozygous mutation in the <i>HSD17B3 </i>gene (R80W; c.238C>G) in all affected siblings. No mutation was detected in the <i>SRD5A2 </i>gene. The detected mutation in the <i>HSD17B3 </i>gene was previously described in a newborn child, who died from other congenital malformations, and in a 12-year-old girl. Hence, our report adds novel value to the phenotype classification of 17-β-HSD 3 deficiency.
|
|
