Dysimmunity in common variable immunodeficiency is associated with alterations in oral, respiratory, and intestinal microbiota.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections. Its aetiology remains unknown, and some patients present with severe non-infectious autoimmune or inflammatory complications with elevated associated morbimortality. Recently, intestinal dysbiosis has been proposed as a driver of immune dysregulation. In this study, we assessed the oral, respiratory, and gastrointestinal microbiota of 41 CVID patients (24 with dysimmune and 17 with infection complications) and 15 healthy volunteers using 16S rRNA gene sequencing to explore associations between microbiome profiles and CVID phenotypes. Profound differences in the composition of the microbiota in saliva, sputum, and stool were detected between dysimmune CVID patients and healthy individuals. Globally, respiratory species diversity and faecal bacterial richness were lower in CVID individuals with immune complications. Although a single species could not be identified as a robust predictor of dysimmunity, a combination of around 5-7 bacterial species in each type of sample could predict this severe phenotype with an accuracy of around 90% in the study population. Our study provides new insights into these previously unexplored but highly interrelated ecological niches among themselves and with patient profiles. Our data suggest that this disease-related systemic dysbiosis could be implicated in the immune dysregulation associated with severe cases of CVID.

Association between cardiovascular risk factors and cognitive impairment in adults aged 60 years or older from Chile: a cross-sectional study.

BACKGROUND: Few studies in Latin America have examined the association between cardiovascular risk factors and cognitive impairment (CI) in a nationally representative sample. Therefore, this study aimed to estimate the prevalence of CI in a nationally representative sample of adults aged 60 years or older from Chile and to investigate the association between cardiovascular risk factors and CI. METHODS: Data from the cross-sectional 2016-2017 National Health Survey of Chile, which included 2031 adults (63.7% women) was used. Body mass index, metabolic syndrome (blood pressure, triglycerides, fasting glucose or treatment for diabetics, waist circumference, and HDL cholesterol), risk of cardiovascular disease (history and measured variables, using the Framingham risk score), tobacco use, and physical activity were measured. CI was assessed using the Mini-Mental Status Examination (MMSE). RESULTS: Overall, the prevalence of CI was 12.2% at the national level. Significant differences in CI were observed by age, education level, risk of cardiovascular disease, and smoking. High risk of cardiovascular disease was associated with higher odds of CI (OR: 2.04; 95%CI: 1.20-3.45) compared to low risk. Smoking was significantly associated with a lower likelihood of CI (OR: 0.56; 95%CI: 0.36-0.87) compared to never smoking. Body mass index, metabolic syndrome, and physical activity were not associated with CI. CONCLUSIONS: This study provided additional support for previous findings on the relationship between cognitive decline and an elevated risk of cardiovascular disease. Worse CI was associated with the group with the highest risk of cardiovascular disease, and the presence of lifestyle factors, such as obesity and physical inactivity, exacerbate this relationship, but not being a current smoker.

Relationship between sense of coherence and health-related behaviours in adolescents and young adults: a systematic review.

BACKGROUND: The sense of coherence is developed through the learning process and contributes to the positioning of individuals in the health-disease continuum, facilitating successful and adaptive personal outcomes. Health-related behaviours represent a health determinant of utmost importance for public health and the development of adolescent and youth health promotion policies, as they are related to the main risk factors and problems of morbidity and mortality in our society. Previous studies have analysed the relationship between sense of coherence and only some individual health outcomes such as oral health, the relationship of sense of coherence with smoking and alcohol consumption, concluding that salutogenic factors are related to quality of life and preventive behaviours. The aim of this systematic review was to describe the relationship of sense of coherence with different health-related behaviours investigated so far in the adolescent and youth population. METHODS: A systematic review was carried out in databases (PubMed, CINAHL, Scopus and PsycInfo) and in the bibliographies of the retrieved articles, without limitation of time or language. Associations between sense of coherence and health-related behaviours have been assessed. RESULTS: A total of 1214 investigations were reviewed and 21 of them were included in this systematic review. The relationship between sense of coherence and eight health-related behaviours were identified (alcohol use, physical activity, tobacco use, eating habits, rest periods, use of illegal substances, behaviours related to oral health and time spent in games on the computer). CONCLUSIONS: Our results increase the available evidence and support the solid relationship of the sense of coherence with health behaviours both as a protective factor against risk behaviours and for its positive association with preventive and health promoting behaviours of adolescents, young adults and university students.

Sub Maximal Ergospirometry Parameters in Untrained Non-Frail Octogenarian Subjects.

Background and Objectives: The prevalence of chronic diseases increases with age, and in octogenarian elderly, a cardiorespiratory test with gas analysis is more effective in determining the risk of mortality than applying the conventional risk factors. Materials and Methods: 25 untrained non-frail octogenarian subjects (four men) performed a submaximal test with gas analysis, which was stopped after the second ventilatory threshold (VT2) was reached. The variables analyzed were oxygen consumption at the first threshold (VO2 VT1); ventilatory class (VE/VCO2); oxygen uptake efficiency slope (OUES); cardiorespiratory optimal point (COP); oxygen pulse difference between VT2 and VT1 (diff. VO2/HR VT2-VT1). Results: the variables were classified categorically based on cut-off points present in the literature, where the variable with the highest percentage of altered cases was dif. VO2/HR VT2-VT1 at 48%; followed by VO2 VT1 at 40%, OUES at 36%, COP at 32%, and VE/VCO2 at 24%. Chi-square analysis between the measured parameters defined that normal and altered variables were related to each other, except for the variable VE/VCO2 and OUES. Conclusions: it was found that the main altered variable was the oxygen pulse and the least altered variable was VCO2/VCO2; there was only a statistically significant difference in a pair of OUES vs. VE/VCO2 variables.

[Motives and perceptions of family care for dependent elderly]. / Motivos y percepciones del cuidado familiar de mayores dependientes.

OBJECTIVE: To identify and analyze the motives that lead people to take care of a dependent relative and their perceptions of the care situation. DESIGN: Phenomenological qualitative study. LOCATION: The study was conducted in the Jaén-Norte Sanitary District, during 2013 and 2014. PARTICIPANTS: A total of 13 primary caregivers of dependent elderly relatives with a minimum experience of one year in care participated, selected by intentional sampling. METHOD: Discourse analysis of 13 in-depth interviews considering the semantic and pragmatic content and field notes. Triangulation was performed in the analysis to favor the credibility of the study. RESULTS: The motives for caring for a dependent relative are:'Familism','Material gains' and'Social pressure'. In turn, the'Familism' include 7 dimensions/motives:'Family obligation','Affection to the person taken care of','Return the received','Well-being of the person taken care of','Respect to the decision of the person taken care of','Agreement','Habit'. When the main motive to take care of is the'Family obligation', the'Material gains' or the'Social pressure' caregivers do not manifest positive perceptions for caring, and vice versa. CONCLUSION: This study has identified that'Familism','Material gains' and'Social pressure' are reasons why people care for a dependent relative in our sociocultural environment, as well as the relationship with the perception of the care situation. This will facilitate the identification of caregivers with greater predisposition to suffer negative consequences for caring and the development of interventions aimed at the prevention of such consequences.

Higher levels of self-reported sitting time is associated with higher risk of type 2 diabetes independent of physical activity in Chile.

Background: Sitting behaviours have increased markedly during the last two decades in Chile. However, their associations with health outcomes such as diabetes have not been reported. Therefore, the aim of this study was to investigate the independent association of self-reported sitting time with diabetes-related markers and diabetes prevalence in Chile. Methods: This cross-sectional study included participants (aged ≥18 years) from the Chilean National Health Survey 2009-10 (n = 4457). Fasting glucose and haemoglobin A1c (HbA1c) were measured by standardized protocols. The prevalence of type 2 diabetes (T2D) was determined using WHO criteria. Physical activity (PA) and time spent sitting were determined using the Global Physical Activity Questionnaire (GPAQ). Results: The odds ratio for T2D was 1.10 [95% CI: 1.04-1.16, P = 0.002] and 1.08 [1.02-1.14, P = 0.002] per 1 h increase in sitting time in men and women, respectively, independent of age, education, smoking, BMI and total PA. Overall, prevalence of T2D was 10.2 and 17.2% in individuals classified in the lowest and highest categories of sitting time, respectively. No significant associations were found between sitting time and glucose or HbA1c. Conclusions: Sitting time is positively associated with diabetes risk, independent of socio-demographic, obesity and PA levels, in the Chilean population.

The start of caring for an elderly dependent family member: a qualitative metasynthesis.

BACKGROUND: The family often takes care of an elderly person who suddenly becomes dependent. This greatly affects different aspects of the caregivers' lives. The aim of this study is to explore the initial experiences, during the first year of care, of persons who suddenly become caregivers for elderly dependent relatives. METHODS: A search in CINAHL, PsycINFO, WOS, Medline, and Scopus and a metasynthesis of qualitative research were conducted including 19 articles. RESULTS: Three categories were developed to explain the process of becoming a caregiver 'taking on the role' (life changes, uncertainty and confusion, and acceptance or resistance); 'beginning to realise' (new needs, impact, and appraisal); and 'implementing strategies' (seeking help and self-learning, reordering family and social relationships, solving problems, and devising strategies to decrease negative emotions and stress). CONCLUSIONS: The synthesis provides a comprehensive understanding of the experience of becoming a caregiver in order to help health-care professionals to adapt care plans to this situation.

Dinucleotide (CA)n tandem repeats on the human X-chromosome and the history of the Mediterranean populations.

BACKGROUND: Tandem repeats (STRs) are genomic markers of particular interest in forensic and population genetics. Most of the population data currently available correspond to the variation of STRs of forensic panels, which barely include dinucleotide tandem repeats. AIMS: The aim of the study is to test the usefulness of a battery of dinucleotide STRs on the X chromosome for population and forensic studies. SUBJECTS AND METHODS: A total of 672 individuals from 12 Mediterranean populations and two external references were analysed for 15 X-STR following the instructions of the commercial company and using control DNA from the CEPH centre whose sequences are published in GenBank. Genotypic results were analysed using standard population genetics methods including estimates of linkage disequilibrium, population structure and gene flow. Common forensic efficiency parameters were calculated. RESULTS: The analysed X-STRs show high values of genetic diversity, comparable to other STRs of more common use. No significant associations between markers were found. A slight population structure was detected between the two shores of the Mediterranean. The X-STRs studied here present a similar degree of variability to that of other X-STRs used in forensics. CONCLUSION: Tandem-repeated dinucleotides are a good tool for evidencing population differences here. Forensic parameters indicate that the dinucleotide X-STRs are suitable for forensic use.

UDP-glucuronosyltransferase genetic variation in North African populations: a comparison with African and European data.

BACKGROUND: Genetic variation in glucuronosyltransferases (UGT) is crucial in drug metabolism and risk of some diseases. AIM: To examine genetic variation in UGT in North African populations. SUBJECTS AND METHODS: Allele frequencies of SNPs UGT1A424Thr, UGT1A448Val, UGT2B1585Tyr, UGT2B15523Thr and UGT2B17 CNV deletion from Morocco, Algeria, Tunisia and Libya were compared to European and Sub-Saharan populations. RESULTS: North Africans are the group with the highest genetic heterogeneity given by internal differences in the occurrence of UGT2B17 deletion, UGT1A448Val and UGT1A4 haplotypes. UGT2B15 SNPs differentiate Sub-Saharans from the rest of the populations. CONCLUSION: North African populations show a high frequency of carriers of UGT2B15523Thr, a variant linked to an increased risk of prostate cancer. High Atlas Moroccans and Algerians show low frequency of UGT2B17del, a variant associated with high concentrations of testosterone and oestradiol.

[Association of physical inactivity with obesity, diabetes, hypertension and metabolic syndrome in the chilean population]. / No cumplir con las recomendaciones de actividad física se asocia a mayores niveles de obesidad, diabetes, hipertensión y síndrome metabólico en población chilena.

BACKGROUND: Physical inactivity is an important cardiovascular risk factor. AIM: To investigate the association of physical inactivity with obesity, metabolic markers, type 2 diabetes mellitus, hypertension and metabolic syndrome in Chilean adults. MATERIAL AND METHODS: Participants from the National Health Survey 2009-10 (n = 5,157) were included in this study. Body mass index, waist circumference, metabolic markers (blood glucose, glycosylated hemoglobin and lipid profile) were the outcomes. Type 2 diabetes, hypertension and metabolic syndrome were determined using international criteria. Physical activity levels were determined using the Global Physical Activity Questionnaire and physical inactivity was defined as < 600 METs/minutes/week. RESULTS: Compared to their physically active peers, inactive men and women had a higher odds ratio (OR) for obesity (OR: 1.77 [95% confidence intervals (CI): 1.29-2.42], p < 0.01 and 1.25 [95% CI: 102-1.54], p < 0.035, respectively), diabetes (OR: 2.47 [1.80-3.38], p < 0.01 and 1.72 [1.35-2.19], p = 0.002, respectively) and hypertension (OR: 1.66 [1.31-2.09], p < 0.01 and 1.83 [1.54-2.18] respectively. An association of physical inactivity with central obesity and metabolic syndrome was observed only in men (OR: 1.92 [1.42- 2.58], p < 0.01 and 1.74 [1.23-2.47], p < 0.01, respectively). CONCLUSIONS: Not meeting the physical activity recommendations is associated with obesity, diabetes, hypertension and metabolic syndrome, which are important cardiovascular risk factors.

[The first moments of the carer: The process of becoming a caregiver of a dependent elderly relative]. / Primeros momentos del cuidado: el proceso de convertirse en cuidador de un familiar mayor dependiente.

AIM: Describe the initial process through which people who imminently become caregivers of a dependent elderly relative. DESIGN: Qualitative study, for which its analysis has been directed by Grounded Theory principles. LOCATION: This study was conducted in the Health Districts of Jaén, during 2015 and 2016 at the community level. PARTICIPANTS AND/OR CONTEXTS: The recruitment was carried out by managers of the Health Centres of each Health District, who located the participants who met the inclusion criteria and invited them to participate in the study. METHOD: Eleven in-depth interviews were carried out, until saturation of information, on individuals who had been caring for an older relative with dependency for less than one year. RESULTS: Three phases have been described during this process. An initial phase of changes, in which the caregiver assumes new activities; a second phase full of emotions, in which the needs and consequences emerge in caregivers; and a third phase that emphasises acceptance as a coping strategy and uncertainty as an expectation of the future. DISCUSSION: The description of this process provides a comprehensive understanding of the experience of becoming a family caregiver, in order to help health professionals to adapt to the plans of care for this initial situation.

Determinants of depression in primary caregivers of disabled older relatives: a path analysis.

BACKGROUND: Despite the large literature analysing factors related to depression, several factors such as caregiving obligation and the interrelationships among the different variables relating to depression have been little studied. The current study aimed to analyse the effect of caregiving obligation (beliefs regarding obligation and social pressure) on depression, and the mediating effects of perceived burden on the relationship between stressors and depression, in primary caregivers of older relatives. METHODS: Cross-sectional study design. A probabilistic sample of caregivers from Spain (N = 200) was used. The data collection was conducted in 2013 through structured interviews in the caregivers' homes. The measures included sense of obligation for caregiving, perceived burden, stressors and depression. RESULTS: Depression had a direct and positive association with perceived burden, behavioural problems, and social pressure, and it was indirectly related through perceived burden to behavioural problems, independence for the activities of daily living and beliefs of obligation. CONCLUSIONS: Our results support the multidimensional concept of obligation, suggesting the existence of both an external obligation (social pressure) and an internal obligation (beliefs of obligation); (b) our findings support the hypothesis that external obligation is related to negative caregiving consequences, while internal obligation protects from these consequences; and (c) our findings support the partial mediation of stressors on depression by perceived burden. The relevance of the research to clinical practice includes the importance of understanding the perceived obligation of caregiving related to both internal and external sources of obligation.

Analysis of Genomic Regions Associated With Coronary Artery Disease Reveals Continent-Specific Single Nucleotide Polymorphisms in North African Populations.

BACKGROUND: In recent years, several genomic regions have been robustly associated with coronary artery disease (CAD) in different genome-wide association studies (GWASs) conducted mainly in people of European descent. These kinds of data are lacking in African populations, even though heart diseases are a major cause of premature death and disability. METHODS: Here, 384 single nucleotide polymorphisms (SNPs) in the top four CAD risk regions (1p13, 1q41, 9p21, and 10q11) were genotyped in 274 case-control samples from Morocco and Tunisia, with the aim of analyzing for the first time if the associations found in European populations were transferable to North Africans. RESULTS: The results indicate that, as in Europe, these four genetic regions are also important for CAD risk in North Africa. However, the individual SNPs associated with CAD in Africa are different from those identified in Europe in most cases (1p13, 1q41, and 9p21). Moreover, the seven risk variants identified in North Africans are efficient in discriminating between cases and controls in North African populations, but not in European populations. CONCLUSIONS: This study indicates a disparity in markers associated to CAD susceptibility between North Africans and Europeans that may be related to population differences in the chromosomal architecture of these risk regions.

X-Chromosome Alu Insertions in Bahía Blanca, Argentina: Assessment of Population Information from Varied Genetic Markers and Usefulness of X-Chromosome Markers to Trace Sex-Biased Parental Contributions.

Bahía Blanca is an urban city in a historically and geographically strategic location for the mixture of different populations in Argentina. In the present study, 10 Alu elements from the X chromosome are analyzed to characterize the genetic composition of the city's population, to compare it with other worldwide populations, and to explore the usefulness of X-chromosome markers for human population genetics purposes. In the Bahía Blanca sample, 7 of 10 Alu insertion frequencies are polymorphic. X-chromosome Alu results in Bahía Blanca are compared with eight different populations from Africa, Europe, and America. Genetic distance analysis indicates that the Bahía Blanca sample is closer to the European and North African samples (average distances of 0.106 and 0.113) than to the Native American (0.163) and sub-Saharan African samples (0.247). Genetic relationships shown by multidimensional scaling illustrate the intermediate position of Bahía Blanca compared with groups in other regions (European, Native American, and African). Admixture results of the Bahía Blanca sample for X-chromosome markers indicate similar proportions of Native American (0.472) and European parental contributions (0.479) and a minor sub-Saharan African contribution (0.049). These results are consistent with the past decade's genetic studies of Argentinean populations that reported higher Native American and sub-Saharan African contributions than previous data.

Population structure from NOS genes correlates with geographical differences in coronary incidence across Europe.

OBJECTIVES: The population analysis of cardiovascular risk and non-risk genetic variation can help to identify adaptive or random demographic processes that shaped coronary incidence variation across geography. MATERIAL AND METHODS: In this study, 114 single nucleotide polymorphisms and 17 tandem repeat polymorphisms from Nitric Oxide Synthases (NOS) regions were analyzed in 1686 individuals from 35 populations from Europe, North Africa, and the Middle East. NOS genes encode for key enzymes on nitric oxide availability, which is involved in several cardiovascular processes. These genetic variations were used to test for selection and to infer the population structure of NOS regions. Moreover, we tested whether the variation in the incidence of coronary events and in the levels of classical risk factors in 11 of these European populations could be explained by the population structure estimates. RESULTS: Our results supported, first, the absence of clear signs of selection for NOS genetic variants associated with cardiovascular diseases, and second, the presence of a continuous genetic pattern of variation across European and North African populations without a Mediterranean barrier for gene flow. Finally, population structure estimates from NOS regions are closely correlated with coronary event rates and classical risk parameters (explaining 39-98%) among European populations. CONCLUSION: Our results reinforce the hypothesis that genetic bases of cardiovascular diseases and associated complex phenotypes could be geographically shaped by random demographic processes.

Population variation of LIN28B in the Mediterranean: Novel markers for microgeographic discrimination.

OBJECTIVES: The aim of this study is to determine whether the LIN28B gene is differentially distributed in the Mediterranean region through the analysis of the allele distribution of three single nucleotide polymorphisms (SNPs), namely rs7759938, rs314277, and rs221639, in 24 populations. These SNPs have been recently related to the age at menarche, pubertal height growth, peripubertal body mass index, levels of prenatal testosterone exposure, and cancer survival. METHODS: A total of 1,197 DNA samples were genotyped. The allele frequencies were used to determine the relationship between populations, with data from the 1000 Genomes Project being used for external comparisons. The genotype distributions and the population structure between populations and groups of populations were determined. RESULTS: The population results indicate a significant degree of variation (FST = 0.043, P < 0.0001). Allele frequencies show significant differences among populations. A hierarchical variance analysis is consistent with a primary differentiation between populations on the North and South coasts of the Mediterranean. This difference is especially evident in the unexpected distribution of the SNP rs221639, which shows one of the highest FST (11.5%, P < 0.0001) values described in the Mediterranean region thus far. CONCLUSION: The population differentiation and the structuring of the genetic variance, in agreement with previous studies, indicate that the SNPs in question are good tools for the study of human populations, even at a microgeographic level. Am. J. Hum. Biol. 28:905-912, 2016. © 2016Wiley Periodicals, Inc.

Silencing of mammalian Sar1 isoforms reveals COPII-independent protein sorting and transport.

The Sar1 GTPase coordinates the assembly of coat protein complex-II (COPII) at specific sites of the endoplasmic reticulum (ER). COPII is required for ER-to-Golgi transport, as it provides a structural and functional framework to ship out protein cargoes produced in the ER. To investigate the requirement of COPII-mediated transport in mammalian cells, we used small interfering RNA (siRNA)-mediated depletion of Sar1A and Sar1B. We report that depletion of these two mammalian forms of Sar1 disrupts COPII assembly and the cells fail to organize transitional elements that coordinate classical ER-to-Golgi protein transfer. Under these conditions, minimal Golgi stacks are seen in proximity to juxtanuclear ER membranes that contain elements of the intermediate compartment, and from which these stacks coordinate biosynthetic transport of protein cargo, such as the vesicular stomatitis virus G protein and albumin. Here, transport of procollagen-I is inhibited. These data provide proof-of-principle for the contribution of alternative mechanisms that support biosynthetic trafficking in mammalian cells, providing evidence of a functional boundary associated with a bypass of COPII.

Inferring the genetic history of lactase persistence along the Italian peninsula from a large genomic interval surrounding the LCT gene.

OBJECTIVE: Although genetic variants related to lactase persistence in European populations were supposed to have firstly undergone positive selection in farmers from the Balkans and Central Europe, demographic and evolutionary dynamics that subsequently shaped the distribution of this adaptive trait across the continent have still to be elucidated. To deepen the knowledge about potential routes of diffusion of lactase persistence to Western Europe we investigated variation at a large genomic region surrounding the LCT gene along the Italian peninsula, a geographical area that played a key role in population movements responsible for Neolithic diffusion across Europe. METHODS: By genotyping 40 highly selected SNPs in more than 400 Italian individuals we described gradients of nucleotide and haplotype variation potentially related to lactase persistence and compared them with those observed in several European and Mediterranean human groups. RESULTS: Multiple migratory events responsible for earlier introduction of the examined alleles in Italy than in Northern European regions could be invoked. Different demic processes occurred along the western and eastern sides of the peninsula were also inferred via linkage disequilibrium and population structure analyses. CONCLUSION: The appreciable genetic continuum observed between people from Northern or Central-Western Italy and Central European populations suggested a local arrival of lactase persistence-related variants mainly via overland routes. On the contrary, diversity of Central-Eastern and Southern Italian groups entailed also gene flow from South-Eastern Mediterranean regions, in accordance to the earlier entrance of the Neolithic in Southern Italy via maritime population movements along the Mediterranean coastlines.

The Association of Satisfaction and Perceived Burden With Anxiety and Depression in Primary Caregivers of Dependent Elderly Relatives.

Some researchers have viewed caregiver burden and satisfaction as two ends of the same continuum rather than as independent aspects of the caregiving experience. We conducted a cross-sectional study of primary caregivers of dependent elderly relatives in Spain (N = 200; probabilistic sample), to determine whether satisfaction and perceived burden coexisted in caregivers, and whether these variables, considered separately and in combination, were associated with anxiety and depression, while controlling for objective aspects of care recipients' needs. Data on satisfaction with care, perceived burden, objective burden, anxiety, and depression were gathered in 2013 by interviews in caregivers' homes. Descriptive, bivariate, and multivariate analyses were performed. Of the 200 primary caregivers, 12.5% reported both high satisfaction with care and high perceived burden. Anxiety and depression levels were lower in caregivers with high satisfaction and low perceived burden than in those with low satisfaction and high burden or with high satisfaction and high burden. Our findings support the following conclusions: (1) Satisfaction may be experienced despite the presence of stressful factors; (2) the combination of high satisfaction and low burden might have protective effects on anxiety and depression in caregivers.

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.