@article {7134, title = {The association of lean and fat mass with all-cause mortality in older adults: The Cardiovascular Health Study.}, journal = {Nutr Metab Cardiovasc Dis}, year = {2016}, month = {2016 Jun 28}, abstract = {

BACKGROUND AND AIMS: Understanding contributions of lean and fat tissue to cardiovascular and non-cardiovascular mortality may help clarify areas of prevention in older adults. We aimed to define distributions of lean and fat tissue in older adults and their contributions to cause-specific mortality.

METHODS AND RESULTS: A total of 1335 participants of the Cardiovascular Health Study (CHS) who underwent dual-energy x-ray absorptiometry (DEXA) scans were included. We used principal components analysis (PCA) to define two independent sources of variation in DEXA-derived body composition, corresponding to principal components composed of lean ("lean PC") and fat ("fat PC") tissue. We used Cox proportional hazards regression using these PCs to investigate the relationship between body composition with cardiovascular and non-cardiovascular mortality. Mean age was 76.2~{\textpm}~4.8 years (56\% women) with mean body mass index 27.1~{\textpm}~4.4~kg/m(2). A greater lean PC was associated with lower all-cause (HR~=~0.91, 95\% CI 0.84-0.98, P~=~0.01) and cardiovascular mortality (HR~=~0.84, 95\% CI 0.74-0.95, P~=~0.005). The lowest quartile of the fat PC (least adiposity) was associated with a greater hazard of all-cause mortality (HR~=~1.24, 95\% CI 1.04-1.48, P~=~0.02) relative to fat PCs between the 25th-75th percentile, but the highest quartile did not have a significantly greater hazard (P~=~0.70).

CONCLUSION: Greater lean tissue mass is associated with improved cardiovascular and overall mortality in the elderly. The lowest levels of fat tissue mass are linked with adverse prognosis, but the highest levels show no significant mortality protection. Prevention efforts in the elderly frail may be best targeted toward improvements in lean muscle mass.

}, issn = {1590-3729}, doi = {10.1016/j.numecd.2016.06.011}, author = {Spahillari, A and Mukamal, K J and DeFilippi, C and Kizer, J R and Gottdiener, J S and Djouss{\'e}, L and Lyles, M F and Bartz, T M and Murthy, V L and Shah, R V} } @article {6793, title = {Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 May}, pages = {601-7}, abstract = {

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerstr{\"o}m Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 {\texttimes} coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 {\texttimes} 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.105}, author = {Olfson, E and Saccone, N L and Johnson, E O and Chen, L-S and Culverhouse, R and Doheny, K and Foltz, S M and Fox, L and Gogarten, S M and Hartz, S and Hetrick, K and Laurie, C C and Marosy, B and Amin, N and Arnett, D and Barr, R G and Bartz, T M and Bertelsen, S and Borecki, I B and Brown, M R and Chasman, D I and van Duijn, C M and Feitosa, M F and Fox, E R and Franceschini, N and Franco, O H and Grove, M L and Guo, X and Hofman, A and Kardia, S L R and Morrison, A C and Musani, S K and Psaty, B M and Rao, D C and Reiner, A P and Rice, K and Ridker, P M and Rose, L M and Schick, U M and Schwander, K and Uitterlinden, A G and Vojinovic, D and Wang, J-C and Ware, E B and Wilson, G and Yao, J and Zhao, W and Breslau, N and Hatsukami, D and Stitzel, J A and Rice, J and Goate, A and Bierut, L J} } @article {8260, title = {Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.}, journal = {Pharmacogenomics J}, year = {2019}, month = {2019 Dec 06}, abstract = {

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 {\texttimes} 10) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

}, issn = {1473-1150}, doi = {10.1038/s41397-019-0132-y}, author = {de Las Fuentes, L and Sung, Y J and Sitlani, C M and Avery, C L and Bartz, T M and Keyser, C de and Evans, D S and Li, X and Musani, S K and Ruiter, R and Smith, A V and Sun, F and Trompet, S and Xu, H and Arnett, D K and Bis, J C and Broeckel, U and Busch, E L and Chen, Y-D I and Correa, A and Cummings, S R and Floyd, J S and Ford, I and Guo, X and Harris, T B and Ikram, M A and Lange, L and Launer, L J and Reiner, A P and Schwander, K and Smith, N L and Sotoodehnia, N and Stewart, J D and Stott, D J and St{\"u}rmer, T and Taylor, K D and Uitterlinden, A and Vasan, R S and Wiggins, K L and Cupples, L A and Gudnason, V and Heckbert, S R and Jukema, J W and Liu, Y and Psaty, B M and Rao, D C and Rotter, J I and Stricker, B and Wilson, J G and Whitsel, E A} }