| 1. |
- Choquet, Helene, et al.
(författare)
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The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:13, s. 2495-2501
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Tidskriftsartikel (refereegranskat)abstract
- A recent study reported an association between the brain natriuretic peptide (BNP) promoter T-381C polymorphism (rs198389) and protection against type 2 diabetes (T2D). As replication in several studies is mandatory to confirm genetic results, we analyzed the T-381C polymorphism in seven independent case-control cohorts and in 291 T2D-enriched pedigrees totalling 39 557 subjects of European origin. A meta-analysis of the seven case-control studies (n = 39 040) showed a nominal protective effect [odds ratio (OR) = 0.86 (0.79-0.94), P = 0.0006] of the CC genotype on T2D risk, consistent with the previous study. By combining all available data (n = 49 279), we further confirmed a modest contribution of the BNP T-381C polymorphism for protection against T2D [OR = 0.86 (0.80-0.92), P = 1.4 x 10(-5)]. Potential confounders such as gender, age, obesity status or family history were tested in 4335 T2D and 4179 normoglycemic subjects and they had no influence on T2D risk. This study provides further evidence of a modest contribution of the BNP T-381C polymorphism in protection against T2D and illustrates the difficulty of unambiguously proving modest-sized associations even with large sample sizes.
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| 2. |
- Eschbach, Judith, et al.
(författare)
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PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:17, s. 3477-3484
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.
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