Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10−12 at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10−9 at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and were replicated in an independent patient collection (n=2,372; P=0.001 and 0.0001 respectively). By incorporating that disease-causing mutations in CFTR alter electrolyte and fluid flux across epithelia into an hypothesis-driven genome-wide analysis (GWAS-HD), we identified the same SLC6A14 and SLC26A9 associated SNPs, while establishing evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple constituents of the apical plasma membrane where CFTR resides (P=0.0002, testing 155 apical genes jointly and replicated, P=0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis

Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI (P = 1.99×10−5 to 1.08×10−6; Bonferroni P = 0.057 to 3.1×10−3). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2×10−4). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr−/− and Cftr−/−Msra−/− mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in CF lung disease severity. A significant association (P=3. 34 × 10-8) near EHF and APIP (chr11p13) was identified in F508del homozygotes (n=1,978). The association replicated in F508del homozygotes (P=0.006) from a separate family-based study (n=557), with P=1.49 × 10-9 for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family-based study identified a significant QTL on chromosome 20q13.2 (LOD=5.03). Our findings provide insight into the causes of variation in lung disease severity in CF and suggest new therapeutic targets for this life-limiting disorder

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Key haplotypes in <i>MSRA</i> region showing association with MI in TSS cohort.

<p><b>^a</b>Numbers in parentheses indicate physical position on chr8 in base pairs (NCBI Build 36).</p><p><b>^b</b>All observed haplotypes with frequency >1% are shown; bold indicates haplotypes noted in text.</p><p>*Protective haplotypes that reached statistical significance after Bonferroni correction for all 2,890 haplotypes tested (<i>P</i><1.73×10⁻⁵).</p>‡<p>Near significant risk haplotype containing rs614197 (italicized), the SNP that was most highly associated with MI in the initial analysis.</p

Patient characteristics.

<p><b>^a</b>Primary analysis included subjects from 133 “MI families” in which at least one sibling had MI.</p><p><b>^b</b><i>CFTR</i> mutation-specific analysis (i.e. p.Gly551Asp vs. p.Phe508del) utilized the entire TSS sample.</p

Haplotype association in <i>MSRA</i> region.

<p>In this schematic, haplotypes comprised of three consecutive SNPs are represented as dots connected by a line. Two overlapping haplotypes localized within intron 3 of <i>MSRA</i> had a statistically significant protective effect on MI (<i>P</i><1.73×10⁻⁵ after Bonferroni correction for 2,890 haplotypes tested in a 2 Mb region): rs10903323 T – rs4840475 G – rs17151637 A and rs4840475 G – rs17151637 A – rs6601427 C. A “risk” haplotype upstream of <i>MSRA</i>, rs586123 G – rs614197 G – rs2055729 C, was just below the threshold for significant association. Linkage disequilibrium patterns (pairwise r²) are displayed below the rs numbers corresponding to each SNP (physical location provided in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002580#pgen-1002580-t002" target="_blank">Table 2</a>).</p

Regional association of SNPs within a region of linkage to MI on chromosome 8p23.1.

<p>The inset plot shows the locus linked to MI on chromosome 8 identified by Blackman, et al <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002580#pgen.1002580-Blackman1" target="_blank">[12]</a>. The green shaded region under the peak extending from 17.9 cM (8.2 Mb) to 29.0 cM (17.2 Mb), where LOD score >1, indicates the region analyzed in the main plot. The map position of <i>MSRA</i> is denoted by an arrow at ∼20.2 cM. In the main plot, <i>P</i> values are plotted in log scale versus physical location in Mb. The SNP showing the strongest association with MI, rs614197, is represented by a diamond (<i>P</i> = 8.35×10⁻⁶). SNPs surrounding rs614197 are color coded to reflect their LD with this SNP (pair-wise r² using 1000 Genomes CEU, August 2009). The dashed line indicates the threshold for region-wide significance after Bonferroni correction for 2,896 SNPs (P<1.73×10⁻⁵). Genes, exon positions, and direction of transcription are denoted below plot (human genome build 18). Nine genes outside this interval were omitted for display purposes: <i>C8orf12</i>, <i>FAM167A</i>, <i>DEFB136</i>, <i>DEFB135</i>, <i>DEFB134</i>, <i>FAM66D</i>, <i>LOC392196</i>, <i>USP17L2</i>, and <i>FAM86B1</i>. The blue shaded region represents the 2 Mb encompassing rs614197 in which haplotype association was tested (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002580#pgen.1002580.s001" target="_blank">Figure S1</a>).</p

Kaplan-Meier survival curves in CF mice according to <i>Msra</i> genotype.

<p>A. CF mice homozygous for a null <i>Cftr</i> allele (<i>Cftr</i>^−/−) and wild-type for <i>Msra</i> show high mortality due to intestinal obstruction around the time of weaning (ca. 21 days; n = 30). In contrast, survival is markedly improved in <i>Cftr</i>^−/− mice lacking one (n = 33) or two <i>Msra</i> alleles (n = 46) compared to wild-type (<i>P</i> = 0.022 and <i>P</i> = 0.0001, respectively; log-rank test). B. CF mice homozygous for a missense <i>Cftr</i> allele (<i>Cftr</i>^R117H/R117H) and wild-type for <i>Msra</i> display a low rate of mortality due to intestinal obstruction around the time of weaning (n = 14). Survival is not affected in <i>Cftr</i>^R117H/R117H mice lacking one (n = 51) or two (n = 51) <i>Msra</i> alleles compared to wild-type.</p