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1.
Cell Rep ; 43(1): 113611, 2024 01 23.
Article in English | MEDLINE | ID: mdl-38159276

ABSTRACT

Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement's genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways' genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.


Subject(s)
Genome-Wide Association Study , Mannose-Binding Lectin , Humans , Complement Activation , Complement System Proteins/metabolism , Lectins/metabolism , Haplotypes/genetics , Mannose-Binding Lectin/genetics
2.
Nat Genet ; 51(10): 1459-1474, 2019 10.
Article in English | MEDLINE | ID: mdl-31578528

ABSTRACT

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.


Subject(s)
Cardiovascular Diseases/blood , Genetic Markers , Gout/blood , Metabolic Diseases/blood , Polymorphism, Single Nucleotide , Signal Transduction , Uric Acid/blood , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Cohort Studies , Genetic Loci , Genetic Predisposition to Disease , Genome-Wide Association Study , Gout/epidemiology , Gout/genetics , Hepatocyte Nuclear Factor 1-alpha/genetics , Hepatocyte Nuclear Factor 4/genetics , Humans , Kidney/metabolism , Kidney/pathology , Liver/metabolism , Liver/pathology , Metabolic Diseases/epidemiology , Metabolic Diseases/genetics , Neoplasm Proteins/genetics , Organ Specificity
3.
Nat Commun ; 10(1): 4130, 2019 09 11.
Article in English | MEDLINE | ID: mdl-31511532

ABSTRACT

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.


Subject(s)
Albuminuria/genetics , Chromosome Mapping , Genome-Wide Association Study , Meta-Analysis as Topic , Animals , Creatinine/urine , Diabetes Mellitus/genetics , Diabetes Mellitus/urine , Drosophila melanogaster/genetics , Gene Expression Regulation , Genetic Loci , Genetic Predisposition to Disease , Humans , Phenomics , Risk Factors
4.
Nat Genet ; 51(6): 957-972, 2019 06.
Article in English | MEDLINE | ID: mdl-31152163

ABSTRACT

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Subject(s)
Genetic Association Studies/methods , Genetic Predisposition to Disease , Quantitative Trait Loci , Quantitative Trait, Heritable , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/physiopathology , Chromosome Mapping , Genome-Wide Association Study , Glomerular Filtration Rate , Humans , Inheritance Patterns , Kidney Function Tests , Phenotype , Polymorphism, Single Nucleotide , Renal Insufficiency, Chronic/urine , Uromodulin/urine , White People
5.
Article in English | MEDLINE | ID: mdl-31139362

ABSTRACT

Background: Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods: Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results: Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion: One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance.


Subject(s)
Drug Resistance, Multiple, Bacterial , Escherichia coli Infections/microbiology , Escherichia coli/drug effects , Escherichia coli/genetics , Intestines/microbiology , Adult , Anti-Bacterial Agents/pharmacology , Bacterial Typing Techniques , Electrophoresis, Gel, Pulsed-Field , Escherichia coli Infections/transmission , Feces/microbiology , Female , Genotype , Healthy Volunteers , Humans , Infant , Infant, Newborn , Male , Microbial Sensitivity Tests , Multilocus Sequence Typing , Parents , Prospective Studies , Thailand , Virulence , Virulence Factors/genetics
6.
Hum Genet ; 136(6): 743-757, 2017 06.
Article in English | MEDLINE | ID: mdl-28374192

ABSTRACT

After the success of genome-wide association studies to uncover complex trait loci, attempts to explain the remaining genetic heritability (h 2) are mainly focused on unraveling rare variant associations and gene-gene or gene-environment interactions. Little attention is paid to the possibility that h 2 estimates are inflated as a consequence of the epidemiological study design. We studied the time series of 54 biochemical traits in 4373 individuals from the Cooperative Health Research In South Tyrol (CHRIS) study, a pedigree-based study enrolling ten participants/day over several years, with close relatives preferentially invited within the same day. We observed distributional changes of measured traits over time. We hypothesized that the combination of such changes with the pedigree structure might generate a shared-environment component with consequent h 2 inflation. We performed variance components (VC) h 2 estimation for all traits after accounting for the enrollment period in a linear mixed model (two-stage approach). Accounting for the enrollment period caused a median h 2 reduction of 4%. For 9 traits, the reduction was of >20%. Results were confirmed by a Bayesian Markov chain Monte Carlo analysis with all VCs included at the same time (one-stage approach). The electrolytes were the traits most affected by the enrollment period. The h 2 inflation was independent of the h 2 magnitude, laboratory protocol changes, and length of the enrollment period. The enrollment process may induce shared-environment effects even under very stringent and standardized operating procedures, causing h 2 inflation. Including the day of participation as a random effect is a sensitive way to avoid overestimation.


Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Bayes Theorem , Humans , Italy
7.
PLoS One ; 8(4): e61720, 2013.
Article in English | MEDLINE | ID: mdl-23637892

ABSTRACT

In February 2012 Italy was hit by an exceptional cold spell with extremely low temperatures and heavy snowfall. The aim of this work is to estimate the impact of the cold spell on health in the Italian cities using data from the rapid surveillance systems. In Italy, a national mortality surveillance system has been operational since 2004 in 34 cities for the rapid monitoring of daily mortality. Data from this system were used to evaluate the impact of the February 2012 cold spell on mortality shortly after the occurrence of the event. Furthermore, a cause-specific analysis was conducted in Roma using the Regional Mortality Registry and the emergency visits (ER) surveillance system. Cold spell episodes were defined as days when mean temperatures were below the 10(th) percentile of February distribution for more than three days. To estimate the impact of the cold spell, excess mortality was calculated as the difference between observed and daily expected values. An overall 1578 (+25%) excess deaths among the 75+ age group was recorded in the 14 cities that registered a cold spell in February 2012. A statistically significant excess in mortality was observed in several cities ranging from +22% in Bologna to +58% in Torino. Cause-specific analysis conducted in Roma showed a statistically significant excess in mortality among the 75+ age group for respiratory disease (+64%), COPD (+57%), cardiovascular disease +20% ischemic heart disease (14%) and other heart disease (+33%). Similar results were observed for ER visits. Surveillance systems need to become are a key component of prevention plans as they can help improve public health response and are a valid data source to rapidly quantify the impact on health. Cold-related mortality is still an important issue and should not be underestimated by public health Authorities.


Subject(s)
Cardiovascular Diseases/mortality , Cold Temperature , Epidemiological Monitoring , Respiratory Tract Diseases/mortality , Weather , Aged , Cities , Emergency Service, Hospital/statistics & numerical data , Humans , Italy/epidemiology
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