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1.  THE EPITHELIAL SODIUM CHANNEL γ-SUBUNIT GENE (SCNN1G) AND BLOOD PRESSURE: FAMILY-BASED ASSOCIATION, RENAL GENE EXPRESSION AND PHYSIOLOGICAL ANALYSES 
Hypertension  2011;58(6):1073-1078.
Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in four cohorts of 1611 white European families comprising a total of 8199 individuals, we undertook staged testing of candidate SNPs for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes as well as expression of SCNN1G in human kidneys. We found that an intronic SNP of SCNN1G (rs13331086) was significantly associated with age-, sex- and BMI-adjusted blood pressure in each of the four populations (P < 0.05). In an inverse variance-weighted meta-analysis of this SNP in all four populations each additional minor allele copy was associated with a 1 mmHg increase in systolic blood pressure and 0.52 mmHg increase in diastolic blood pressure (SE = 0.33, P = 0.002 for SBP; SE = 0.21, P = 0.011 for DBP). The same allele was also associated with higher 12-h overnight urinary potassium excretion (P = 0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a non-significant (P = 0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.
doi:10.1161/HYPERTENSIONAHA.111.176370
PMCID: PMC3220739  PMID: 22006290
blood pressure; genetics; meta-analysis; risk factors; cardiovascular diseases
2.  Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome 
Lancet  2012;379(9819):915-922.
Summary
Background
A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.
Methods
We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.
Findings
Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.
Interpretation
The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.
Funding
British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.
doi:10.1016/S0140-6736(11)61453-0
PMCID: PMC3314981  PMID: 22325189

Results 1-2 (2)