Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex-and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value &lt;5 x 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 x 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.</p

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Octochaetus kenleei Blakemore, sp. nov.

Octochaetus kenleei Blakemore sp. nov. Material examined. Museum of New Zealand Te Papa Tongarewa W.002910 (Holotype). From the tussock grassland of “Happy Valley” (Upper Waimangaroa Valley, Buller Region, West Coast, New Zealand). Collected by S. Boyer, 2010. Mature, complete, fixed in ethanol 98 % and placed in propylene glycol. Etymology. In patronymic tribute to the foremost earthworm eco-taxonomist of New Zealand, Dr Kenneth Earnest Lee (1927–2007). External characters. Body circular but posterior slightly square. Pigment lacking and generally fair. Length 220 mm with 270 segments. Prostomium prolobous. Setae lumbricine, 8 per segment, evenly spaced. Clitellum not well marked, perhaps in some or all of 14–20. Dorsal pores from 14 / 15, small. Nephropores not clear, some possibly in c and d lines or rather irregular. Spermathecal pores segmental, lateral to b lines on 8 and 9 on small mounds. Female pores just anterior to setae a on 14. Prostatic pores at b on 17 and 19. Male pores within concave seminal grooves lateral to b. Genital markings as small lens-shaped hollows paired in 8 / 9 and 9 / 10 near b lines and in 15 / 16 in a lines with a unilateral marking in 18 / 19 lhs; area bb in 19 / 20–22 / 23 tumid. Genital and penial setae not found. Internal morphology. Pharyngeal mass anterior to 4 / 5. Septa 8 / 9–10 / 11 with some thickening. Gizzards muscular in 5 and 6. Dorsal blood vessel appears single on gizzards but is doubled from 7 posteriorly. Heart paired in 10–13. Nephridia meroic as a few (ca. 4 per side) small tufted clusters in each segment. Spermathecae in 8 and 9 saccular each with small discrete and interlocular diverticula (inseminated) ringing exit. Testes free, posterio-ventrally in 10 and 11. Seminal vesicles large finely racemose anterio-dorsally in 11 and 12. Ovaries composed of several strings of largish eggs in 13; ovisacs absent. Prostates tubular in 17 and 19 exiting through narrow ducts. Vasa deferentia exits in 18. Oesophagus dilated as annular calciferous gland in 17 with several internal lamellae but not especially vascularized. Intestinal origin in 20 (valval in 19). Typhlosole large inverted T-shape developing from 21. Gut contains colloidal soil with a few quartz grits and woody fragments. Ecology. Specimen was found under 10 to 20 cm of soil. Large size, pale colouration and gut contents suggest subsoil geophagy. This species is likely to be endogeic. Remarks. The current species is compared to Octochaetus thomasi Beddard, 1892, widespread in the Canterbury Plains, that is the only other congener known to have gizzards in 5–6. As with all other members, it has spermathecal pores in 7 / 8 / 9 and on this character alone the current species is differentiated. Neodrilus campestris (Hutton, 1877) from Dunedin has segmental spermathecal pores (on 8) but differs, not least, by qualifying for inclusion in Acanthodrilidae due to its holoic nephridia.Published as part of Boyer, Stephane, Blakemore, Robert J. & Wratten, Steve D., 2011, An integrative taxonomic approach to the identification of three new New Zealand endemic earthworm species (Acanthodrilidae, Octochaetidae: Oligochaeta), pp. 21-32 in Zootaxa 2994 on page 27, DOI: 10.5281/zenodo.20517

Deinodrilus gorgon Blakemore, sp. nov.

Deinodrilus gorgon Blakemore sp. nov. Material examined. Museum of New Zealand Te Papa Tongarewa W.002909 (Holotype). From the tussock grassland of “Happy Valley” (Upper Waimangaroa Valley, Buller Region, West Coast, New Zealand). Collected by S. Boyer, 2010. Mature, posterior amputee, fixed in ethanol 98 % and placed in propylene glycol. Etymology. Noun alluding to Greek mythical monsters with sharp fangs, staring eyes and, similar perhaps to the ring of diverticula on each spermatheca – a belt of serpents. External characters. Body circular in anterior. Pigment dark, especially dorsum with paler setal auriolae; clitellum and male field white. Length 55 + mm with 73 + segments (amputee). Prostomium tanylobous. Setae perichaetine, 12 per segment, evenly spaced. Clitellum pale, tumid ½ 13–16. Dorsal pores from 10 / 11. Nephropores not found. Spermathecal pores in b lines in 7 / 8 and 8 / 9, small but gaping. Female pores anterio-ventral to a setae on 14 in common field. Prostatic pores at b on 17 and 19. Male pores within concave seminal grooves lateral to b. Genital markings as large eye-shaped papillae paired on 10; with smaller markings on 13 rhs, 16 rhs and two additional pairs on 18 as figured. Genital and penial setae not found. Internal morphology. Pharyngeal mass anterior to 4 / 5. Septa 8 / 9–10 / 11 with some thickening. Gizzard muscular in 6 (weak septum 6 / 7 can be carefully teased off to base). Dorsal blood vessel doubled. Heart paired in 10– 13. Nephridia meroic; equatorial forests especially obvious around clitellar segments. Spermathecae in 8 and 9 each with a thin duct to multiple, finger-like diverticula, five per spermatheca (inseminated) surrounding duct from where it thickens before reaching yellowish, knob-like ampulla. Testes free, posterio-ventrally in 10 and 11. Seminal vesicles small saccular in 9 (vestigial?) and larger racemose anterio-dorsally in 11 and 12. Ovaries fan-shaped in 13 with several strings of largish eggs; ovisacs vestigial in 14. Prostates compacted tubular in 17 and 19 exiting through muscular ducts. Vasa deferentia seen to exit unceremoniously in 18. Oesophagus dilated in 15–17 but lacking internal lamellae and thus not construed as calciferous glands. Intestinal origin in 18. Typhlosole thin, lamellar becoming deeper from 19. Gut contains colloidal soil and organic matter. Ecology. Specimen was found under 10 to 20 cm of soil. Dark colouration suggests at least partial surface exposure on topsoil, gut content suggests topsoil geophagy. This species is likely to be anecic. Remarks. Of the eight currently known Deinodrilus species, only two have tanylobous prostomia: D. gracilis Ude, 1905 from Stephen Island and D. parvus Lee, 1959 from Mangamuku Range. Both also have 5 or 6 spermathecal diverticula however, D. gracilis has copulatory setae, oesophageal glands and intestine from 19; while D. parvus has a saddle-shaped clitellum in 12–16, and all its reproductive pores are in a or ab. Further, their gizzards are in 6–7 and 5, respectively, rather than single in 6 as in the current species. D. montanus Lee, 1959 from Rimutaka Range is similar to D. parvus and differs for similar reasons. The current species appears unique in the distribution of its eye-like genital markings that are especially noticeable on segment 10.Published as part of Boyer, Stephane, Blakemore, Robert J. & Wratten, Steve D., 2011, An integrative taxonomic approach to the identification of three new New Zealand endemic earthworm species (Acanthodrilidae, Octochaetidae: Oligochaeta), pp. 21-32 in Zootaxa 2994 on page 24, DOI: 10.5281/zenodo.20517

Maoridrilus felix Blakemore, sp. nov.

Maoridrilus felix Blakemore sp. nov. Material examined. Museum of New Zealand Te Papa Tongarewa W.002908 (Holotype). From the tussock grassland of ‘Happy Valley’ (Upper Waimangaroa Valley, Buller Region, West Coast, New Zealand). Collected by S. Boyer, 2010. Mature, complete, fixed in ethanol 98 % and placed in propylene glycol. Etymology. Adjectival Latin for “Happy”, after the location name. External characters. Body circular in anterior, squaring off in mid-body and dorsally canaliculate in the posterior 50 or so segments. Pigment dark, especially dorsum chocolate brown with darker mid-dorsal stripe. Length 170 mm with 199 segments. Prostomium tanylobous. Setae lumbricine. Clitellum faintly marked 15-19,½ 20. Dorsal pores wanting. Nephropores, after the first few segments, alternate regularly between c and b lines with anterior segmental distributions: 3–7 c, 8 c or b, 9–10 c, 11 b, 12 c, 13 b, etc. Spermathecal pores in mid-ab lines in 7 / 8 and 8 / 9. Female pores faint, just anterior to b setae on 14. Prostatic pores approximately in a lines on 17 and 19 with protuberant penial setae. Male pores not located within concave seminal grooves, although likely central between retained ab setae. Genital markings absent, but setae ab on 16 with slight pale tumescence as on 20 lhs. Genital setae absent; penial setae longish, curving with spoon-shaped tips [one of their functions, if not primary function, is to scrape out or disrupt any prior semen from spermathecal diverticula that often correspond in depth to the setal length (see Blakemore 2000)]. Internal morphology. Pharyngeal mass anterior to 4 / 5. Septa mostly thin and translucent. Proventriculus wide and S-shaped in 5. Gizzard muscular in 6. Dorsal blood vessel single thoughout. Heart paired in 10–13. Nephridia holoic with long, sausage-shaped vesicles. Spermathecae in 8 and 9 each with a multiloculate diverticulum (inseminated) transcending anterior septum. Testes free, posterio-ventrally in 10 and 11. Seminal vesicles saccular, anterio-dorsally in 11 and 12. Ovaries compact sheets in 13 with large oviducts; ovisacs not found. Prostates tubular in 17 and 19 exiting through muscular ducts with ectal penial setal sheathes and tendons. Vasa deferentia seen to 18. Oesophagus dilated in 11–15 with blood vessels attaching dorsally but not saccular and not construed as calciferous glands. Intestinal origin in 18. Typhlosole not detected to about 26. Gut contains colloidal organic matter. Ecology: Lack of dorsal pores is more usually associated with a semi-aquatic habitat. Unidentified nematodes were found near the prostates (cf. Yeates et al., 1985). Specimen was found under 10 to 20 cm of soil. Dark colouration on the dorsum suggests at least partial surface exposure on topsoil, gut content suggests topsoil geophagy. This species is likely to be anecic. Remarks. Quintessentially Maoridrilus due to its alternating nephridiopores, this species appears unique in its lack of dorsal pores (although more information is needed on several other congeners), gizzard in 6, lack of oesophageal glands, and genital marking absence. Multiloculate spermathecae appear characteristic of the genus and in the current species their form is almost identical to Maoridrilus thomsoni Benham, 1919: fig. 4 from D’Urville Island in Cook Strait. Lee (1959) held this species, along with similar M. intermedius Michaelsen, 1923 and M. mauiensis Benham, 1904, as incertae sedis because original descriptions were inadequate. Permanence of the name M. felix depends on redescription of M. thomsoni, however, the manifestly larger penial setae and lack of oesophageal glands in 14–16 seem to separate the current species. Maoridrilus nelsoni Lee, 1959 differs in its prostatic pores in b lines, and its prominent tuberculae pubertatis ventrally on segments 10 and 16. Maoridrilus uliginosus (Hutton, 1877) differs, not least, in its paired dorsal blood vessel.Published as part of Boyer, Stephane, Blakemore, Robert J. & Wratten, Steve D., 2011, An integrative taxonomic approach to the identification of three new New Zealand endemic earthworm species (Acanthodrilidae, Octochaetidae: Oligochaeta), pp. 21-32 in Zootaxa 2994 on page 23, DOI: 10.5281/zenodo.20517

Signature Gene Expression Profiles Discriminate between Isoniazid-, Thiolactomycin-, and Triclosan-Treated Mycobacterium tuberculosis

Genomic technologies have the potential to greatly increase the efficiency of the drug development process. As part of our tuberculosis drug discovery program, we used DNA microarray technology to profile drug-induced effects in Mycobacterium tuberculosis. Expression profiles of M. tuberculosis treated with compounds that inhibit key metabolic pathways are required as references for the assessment of novel antimycobacterial agents. We have studied the response of M. tuberculosis to treatment with the mycolic acid biosynthesis inhibitors isoniazid, thiolactomycin, and triclosan. Thiolactomycin targets the β-ketoacyl-acyl carrier protein (ACP) synthases KasA and KasB, while triclosan inhibits the enoyl-ACP reductase InhA. However, controversy surrounds the precise mode of action of isoniazid, with both InhA and KasA having been proposed as the primary target. We have shown that although the global response profiles of isoniazid and thiolactomycin are more closely related to each other than to that of triclosan, there are differences that distinguish the mode of action of these two drugs. In addition, we have identified two groups of genes, possibly forming efflux and detoxification systems, through which M. tuberculosis may limit the effects of triclosan. We have developed a mathematical model, based on the expression of 21 genes, which is able to perfectly discriminate between isoniazid-, thiolactomycin-, or triclosan-treated M. tuberculosis. This model is likely to prove invaluable as a tool to improve the efficiency of our drug development programs by providing a means to rapidly confirm the mode of action of thiolactomycin analogues or novel InhA inhibitors as well as helping to translate enzyme activity into whole-cell activity

Soil gas diffusivity controls N₂O and N₂ emissions and their ratio

Knowledge of soil biological and physical interactions with respect to N₂O and N₂ fluxes is essential to ensure that agricultural land management is environmentally and economically sustainable. This study determined how varying soil relative gas diffusivity (Dp/Do) affected cumulative N₂O and N₂ fluxes under simulated ruminant urinary-N deposition. Using repacked soil cores, the effects of varying soil bulk density (rb; from 1.1 to 1.5 Mg m−3) and soil matric potential (y; −10 to −0.2 kPa) on Dp/Do were examined in a Templeton silt loam soil (Udic Haplustept) following the application of simulated ruminant urine (700 kg N ha−1). Fluxes of N₂O and N₂, soil inorganic N, pH, and dissolved organic C (DOC) dynamics were monitored over 35 d. Soil Dp/Do declined as soil bulk density and soil moisture increased. Soil N₂O emissions increased exponentially as Dp/Do decreased until Dp/Do equaled 0.005, where upon N₂O fluxes decreased rapidly due to complete denitrification, such that N₂ fluxes reached a maximum of 60% of N applied at a Dp/Do of <0.005. Regression analysis showed that Dp/Do was better able to explain the variation in N₂O and N₂ fluxes than water-filled pore space (WFPS) because it accounted for the interaction of soil rb and y. This study demonstrates that soil Dp/Do can explain cumulative N₂O and N₂ emissions from agricultural soils. Under grazed pasture systems, potential exists to reduce the emissions of the greenhouse gas N₂O and significant economic losses of N as N₂ if soil management and irrigation can be maintained to maximize Dp/Do