Circulation: Cardiovascular Genetics最新文献

Background: Body height has been associated with an increased risk of venous thromboembolism (VTE), but the association can be confounded with shared familial factors (genetic/environmental). A cosibling design is useful for deeper understanding about the relationship between VTE and height.

Methods and results: From Swedish national registry databases, we used a corelative design with full siblings alongside a general Swedish population sample. A cohort of male conscripts (n=1 610 870), born in 1951 to 1992 without previous VTE, was followed from enlistment (1969-2010) until 2012. Another cohort of first-time pregnant women (n=1 093 342) from the medical birth register, without previous VTE, was followed from first pregnancy (1982-2012) until 2012. Using the Multi-Generation Register, we identified all full-sibling pairs discordant for height. This cosibling design allowed for adjustment for familial factors (genetic/environmental). Compared with the tallest women (>185 cm) and men (>190 cm), there was a graded decreased risk by lower height for both men and women. The risk was lowest in women and men with the shortest stature (<155 and <160 cm, respectively): hazard ratios=0.31 (95% confidence interval, 0.22-0.42) and 0.35 (95% confidence interval, 0.22-0.55), respectively. There was a graded association also in the cosibling design comparing siblings with varying degree of discordance for height (reference was the taller sibling): ≥10 cm difference between brothers hazard ratios=0.69 (95% confidence interval, 0.61-0.78) and sisters hazard ratios=0.65 (95% confidence interval, 0.52-0.80), respectively.

Conclusions: Height is an independent predictor of VTE. The use of sibling pairs reduces the likelihood that familial confounding explains the results. The findings are important for the understanding of the pathogenesis of VTE.

Background: Polygenic risk scores (PGS) enable rapid estimation of genome-wide susceptibility for traits, which may be useful in clinical settings, such as prediction of QT interval. In this study, we sought to validate PGS for QT interval in 2 real-world cohorts of European ancestry (EA) and African ancestry (AA).

Methods and results: Two thousand nine hundred and fifteen participants of EA and 366 of AA in the MGH CAMP study (Cardiology and Metabolic Patient) were genotyped on a genome-wide array and imputed to the 1000 Genomes reference panel. An additional 820 EA and 57 AA participants in the Partners Biobank were genotyped and used for validation. PGS were created for each individual using effect estimates from association tests with QT interval obtained from prior genome-wide association studies, with variants selected based from multiple significance thresholds in the original study. In regression models, clinical variables explained ≈9% to 10% of total variation in resting QTc in EA individuals and ≈12% to 18% in AA individuals. The PGS significantly increased variation explained at most significance thresholds (P<0.001), with a trend toward increased variation explained at more stringent P value cut points in the CAMP EA cohort (P<0.05). In AA individuals, PGS provided no improvement in variation explained at any significance threshold.

Conclusions: For individuals of European descent, PGS provided a significant increase in variation in QT interval explained compared with a model with only nongenetic factors at nearly every significance level. There was no apparent benefit gained by relaxing the significance threshold from conventional genome-wide significance (P<5×10^-8).

Background: WEMA (Whole-Exome Molecular Autopsy) and surveillance of cardiac channelopathy and cardiomyopathy genes represents the latest molecular autopsy for sudden death in the young (SDY). To date, the majority of WEMA has been performed on the SDY case only.

Methods and results: We performed whole-exome sequencing and nucleotide-level coverage analysis on 28 SDY cases (18.4±7.8 years) and their parents to determine the inheritance patterns of ultrarare, nonsynonymous variants in 99 sudden death-susceptibility genes. Nonsynonymous variants were adjudicated using the American College of Medical Genetics guidelines. Overall, 17 sudden death-susceptibility gene variants were identified in 12 of 28 (43%) SDY cases. On the basis of the American College of Medical Genetics guidelines, 6 of 28 (21%) cases had a pathogenic or likely pathogenic nonsynonymous variant with 3 (50%) being de novo. Two nonsynonymous variants would not have been elevated to likely pathogenic status without knowing their de novo status. Whole-exome sequencing reached a read depth of 10× across 90% of nucleotides within sudden death-susceptibility genes in 100% of parental exomes from fresh blood draw, compared with only 82% of autopsy-sourced SDY exomes.

Conclusions: An SDY-parent, trio-based WEMA may be an effective way of elucidating a monogenic cause of death and bringing clarity to otherwise ambiguous variants. If other studies confirm this relatively high rate of SDY cases stemming from de novo mutations, then the WEMA should become even more cost-effective given that the decedent's first-degree relatives should only need minimal cardiological evaluation. In addition, autopsy-sourced DNA demonstrated strikingly lower whole-exome sequencing coverage than DNA from fresh blood draw.