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PubMed2025

Genome-wide association meta-regression identifies stem cell lineage orchestration as a key driver of acne risk.

Over 85% of the population experience acne at some point in their lives, with its severity spanning a quantitative spectrum, from mild, transient outbreaks to more persistent, severe forms of the condition. Moderate to severe disease poses a substantial global burden arising from both the physical and psychological impacts of this highly visible condition. The analytical approach taken in this study aimed to address the impact of variation in the dichotomisation of acne case control status, driven by ascertainment and study design, on effect size estimates across independent genetic association studies of acne. Through a fixed intercept meta-regression framework, we combined evidence genome-wide for association with acne across studies in which case-control status had been ascertained in different settings, allowing for different severity threshold definitions. Across a combined sample of 73,997 cases and 1,103,940 controls of European, South Asian and African American ancestry we identify genetic variation at 165 genomic loci that influence acne risk. There is evidence for both shared and ancestry specific components to the genetic susceptibility to acne and for sex differences in the magnitude of effect of risk alleles at three loci. We observe that common genetic variation explains 13.4% of acne heritability on the liability scale. Consistent with the hypothesis that genetic risk primarily operates at the level of individual pilosebaceous units, a polygenic score derived from this case-control study of acne susceptibility is associated with both self-reported and clinically assessed acne severity in adolescence, further strengthening the link between genetic risk and disease severity. Prioritisation of causal genes at the identified acne risk loci, provides genetic validation of the targets of established and emerging acne therapies, including retinoid treatments. The identified acne risk loci are enriched for genes encoding downstream effectors of RXRA signalling, including SOX9 and components of the WNT and p53 pathways. Illustrating that the control of stem cell lineage plasticity and cellular fate are important mechanisms through which genetic variation influences acne susceptibility within the pilosebaceous unit.

Journal Article↗
PubMed2006

Interaction of homocysteine and conventional predisposing factors on risk of ischaemic stroke in young people: consistency in phenotype-disease analysis and genotype-disease analysis.

BACKGROUND AND OBJECTIVES: Whether the association between mild hyperhomocysteinaemia and ischaemic stroke is the consequence of a predisposing genetic background or is due to the confounding influence of established predisposing factors remains to be determined. METHODS: Plasma total homocysteine (tHcy) concentration and the distribution of the C677T genotypes of the methylenetetrahydrofolate reductase gene (MTHFR) were compared in 174 consecutive patients with stroke aged <45 years and 155 age and sex-matched controls. The effect of conventional risk factors on the relationship between phenotype-disease and genotype-disease was analysed by two-way and three-way interaction analysis and by the classification and regression trees (CART) model. RESULTS: tHcy concentrations were markedly higher in patients with ischaemic stroke (median 11.9 micromol/l, range 2.0-94.0) than in controls (median 9.8 micromol/l, range 4.7-49.6). An increased risk was also associated with the TT677 genotype (odds ratio (OR) 1.98; 95% confidence interval (CI) 1.04 to 3.78) and with the T allele (1.40; 95% 1.03 to 1.92) of the MTHFR gene. A differential effect of Hcy levels on risk of stroke was observed according to the distribution of environmental-behavioural risk factors, with a stronger influence in the subcategory of people with hypertension and smokers (OR 24.8; 95% CI 3.15 to 196). A comparable environmental-dependent TT677 MTHFR genotype-stroke association was observed in the genotype-disease analysis. CONCLUSIONS: A consistency of phenotype-disease analysis and genotype-disease analysis is indicated by analysing specific subcategories of patients, defined by the distribution of established risk factors. The assumption that the Hcy-stroke relationship is unlikely due to a reverse-causality bias is indirectly supported by our data.

Adolescent↗
PubMed2002

Modifier genes for hypertrophic cardiomyopathy.

During the past decade, more than 100 mutations in 11 causal gene coding for sarcomeric proteins, the gamma subunit of AMP-activated protein kinase and triplet-repeat syndromes and in mitochondrial DNA, have been identified in patients with hypertrophic cardiomyopathy (HCM). Genotype-phenotype correlation studies show significant variability in the phenotype expression of HCM among affected individuals with identical causal mutations. Overall, causal mutations account for a fraction of the variability of phenotypes and genetic background, referred to as the modifier genes, play a significant role. The final phenotype is the result of interactions between the causal genes, genetic background (modifier genes), and probably the environmental factors. The individual modifier genes for HCM remain largely unknown, and a large-scale genome-wide approach and candidate gene analysis are needed. Current studies are limited to simple polymorphism association studies, which explore the association of functional single nucleotide polymorphisms in genes implicated in cardiac growth with the severity of the clinical phenotypes, primarily cardiac hypertrophy. Several potential modifier genes including genes encoding the components of the renin-angiotensin-aldosterone system have emerged. The most commonly implicated is an insertion/deletion polymorphism in the angiotensin-1 converting enzyme 1 gene, which is associated with the risk of sudden cardiac death and the severity of hypertrophy. Therapeutic interventions aimed at targeting the modifier genes have shown salutary effects in animal models of HCM. It has now recognized that modifier genes affect the expression of cardiac phenotype. Identification of the modifier genes will complement the results of studies of causative genes and could enhance genetic based diagnosis, risk stratification, and implementation of preventive and therapeutic measures in patients with HCM.

Animals↗
PubMed2026

Cross-ancestry proteome-wide Mendelian randomization prioritizes 12 plasma protein candidates for breast cancer risk.

The plasma proteome provides a molecular bridge between genetic variation and disease risk, yet its contribution to breast cancer susceptibility across ancestries remains unclear. We conducted a proteome-wide Mendelian randomization (MR) study of 2,923 plasma proteins using cis-protein quantitative trait loci from 34,557 European participants in the UK Biobank Pharma Proteomics Project, integrated with genome-wide association studies of 156,901 breast cancer cases and 204,634 controls of European, East Asian, and African ancestries. Cross-ancestry meta-analysis identified 12 candidate proteins associated with breast cancer risk (P < 2.5&#xd7;10-5), including six previously reported and six newly implicated in MR studies. DNPH1 showed cross-ancestry heterogeneity, with a risk-increasing association in European populations and a nominally inverse association in East Asian populations. CASP8, RALB, and USP28 displayed subtype-differentiated associations. Orthogonal validation provided variable support: six demonstrated strong evidence of statistical colocalization; four replicated in an independent European proteomic dataset (deCODE, n = 35,559); two replicated in an independent East Asian proteomic dataset (JCTF, n = 1,384); and four were supported by polygenic-score analyses in the ancestrally diverse All of Us cohort (9,250 cases, 214,857 controls). These findings prioritize a high-confidence subset of plasma proteins, including LRRC25, PARK7, and LRRC37A2, for future mechanistic and translational investigation.

Mendelian randomization↗
PubMed1978

Structural analysis of the ADHS electromorph of Drosophila melanogaster.

Population geneticists have often determined the fitness differences that account for the dynamics of naturally occurring genetic polymorphisms. However, to understand causal aspects of evolutionary processes requires, in addition, investigation of the physiological and molecular structural differences underlying adaptively significant genetic polymorphisms. The characteristics of the alcohol dehydrogenase gene--enzyme system in Drosophila melanogaster make it well suited for this kind of study. Natural populations of this species are polymorphic for two electrophoretically detectable variants, ADHF and ADHS, of the enzyme. Structural studies reported here reveal that the two variants differ by (at least) a single amino acid replacement, threonine in ADHF for lysine in ADHS.

Alcohol Oxidoreductases↗
PubMed1989

Race differences in pubic symphyseal aging patterns in the male.

A well-documented multiracial sample of 704 male pubic bones allows for rigorous testing for racial differences in pubic symphyseal metamorphosis. The relationship between estimated age (using a modified Todd six-stage system) and age is examined as a function of race (White, Black, Mexican). One set of analyses incorporates linear regression models, while a second set does not impose such structure on the relationship. The latter analyses incorporate analysis of variance and related procedures. Significant differences in age are found across racial groups; it is seen that Blacks and Mexicans with advanced pubic symphyseal patterns tend to have lower ages than Whites. We do not address the question of causality, which may involve genetic factors and/or environmental variables such as diet, alcoholism, or drug abuse.

Adolescent↗
PubMed2001

Suppression of tumorigenicity in the human prostate cancer cell line M12 via microcell-mediated restoration of chromosome 19.

Previously we immortalized human, nontransformed prostate epithelial cells with SV40 large T-antigen (SV40TAg) and derived increasingly aggressive sublines from the immortalized line. The progression of the tumorigenic sublines to metastatic capacity was accompanied by the formation of an unbalanced translocation between chromosomes 16 and 19, resulting in loss of 19p and proximal 19q. To test whether the tumorigenic and/or metastatic phenotype was causally related to this genetic alteration, we restored a neo-tagged human chromosome 19 to M12 cells by microcell-mediated transfer and assessed their growth. In vitro, the resultant hybrids grew more slowly in monolayer culture and showed a significant reduction in anchorage-independent growth as compared to M12neo controls. In vivo, all mice (13/13) injected subcutaneously (SC) with control M12neo cells developed tumors after 9-15 days. In contrast, 9/15 mice injected SC with microcell-transferred chromosome 19 hybrid cells failed to form tumors, with 6/15 producing very small tumors after 120 days. Analysis of three of these six tumors showed consistent, new chromosomal changes. Furthermore, in one of the tumors, loss of a chromosome 19 was noted in 40% of the cells. After intraprostatic injections of the hybrid cells, only 2/7 mice developed microscopic tumors, with no metastases. These data suggest the presence of a gene or genes on chromosome 19 that function to suppress growth.

Animals↗
PubMed2006

Life-time history of suicide attempts and coronary artery disease in a community-dwelling elderly population.

BACKGROUND: Numerous studies have observed a strong relationship between coronary artery disease (CAD) and psychiatric disorder; notably depression, anxiety and panic attacks. No study has, however, explored the question of whether persons suffering from CAD might also be at high risk of suicide attempts. OBJECTIVE: The aim of the present study is to examine the relationship between CAD within a general population cohort and life-time history of psychiatric disorder and suicidal behaviour. METHOD: A representative sample of 1,843 non-institutionalized persons over 65, drawn at random from the electoral roll, was given a standardized neurological and psychiatric examination based on DSM-IV criteria. The clinical examination also included an electrocardiogram (ECG) and a questionnaire relating to life-time medical history. Cardiac events were validated by the general practitioner. RESULTS: Within this general population sample the prevalence of suicide attempts was 3.9%. A significant positive association was observed between life-time prevalence of CAD and suicide attempts (p<0.04). Suicide attempts were associated with major depression (p<0.001) co-morbid anxiety and depression (p<0.001) but not anxiety alone (p=0.16). A logistic regression analysis showed that the relationship between suicide attempts and CAD persists after adjustment for depression and anxiety. CONCLUSION: CAD is associated with suicidal behaviour independently of depression, however, longitudinal studies are required to clarify the direction of causality and to integrate genetic, biological, environmental and psychological factors into an aetiological model.

Aged↗
PubMed1994

Enzymatic amplification of synthetic oligodeoxyribonucleotides: implications for triplet repeat expansions in the human genome.

The triplet repeat sequences (CGG)n, (GCT)n, and (CAG)n, which naturally occur in the human genome, can be autonomously expanded in human DNA by an as yet unknown mechanism. These in part excessive expansions have been causally related to human genetic diseases, the fragile X (Martin-Bell) syndrome, to myotonic dystrophy (Curschmann-Steinert), to spinal and bulbar muscular atrophy (Kennedy disease), and recently to Huntington disease. A GCC trinucleotide repeat was found to be expanded and methylated in the fragile site FRAXE on the human X chromosome. These findings were associated with mental retardation (Knight et al., 1993). In spinocerebellar ataxia type 1 (SCA1), a polymorphic CAG repeat was found to be unstable and expanded in individuals with that disease (Orr et al., 1993). We have demonstrated in in vitro experiments that the synthetic oligodeoxyribonucleotides (CGG)17, (CGG)12, (GCC)17, (CG)25, (CTG)17, or (CAG)17 plus (GTC)17, in the absence of added natural DNA, can be expanded with Taq polymerase in the polymerase chain reaction (PCR). Some expansion can already be detected after 4 PCR cycles. The E. coli Klenow DNA polymerase also functions in a similar amplification and expansion reaction performed at 37 degrees C without cycling. Other oligodeoxyribonucleotides, like, (CGG)7, (CGGT)13, or (TAA)17, are devoid of this property or have very low activity. The cytidine-methylated polymers (GCC)17 or (CG)25 yield expansion products of considerably reduced chain lengths. The expansion of the polymer (CGG)17 is affected by cytidine methylation to a lesser degree. A specific sequence and/or secondary structure and high CG content appear to be requirements for this expansion reaction by a possible slippage mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed2005

Alcohol.

Alcohol consumption affects overall mortality. Light to moderate alcohol consumption reduces the risk of coronary heart disease; epidemiological, physiological and genetic data show a causal relationship. Light to moderate drinking is also associated with a reduced risk of other vascular diseases and probably of type 2 diabetes. Mortality and disease risk increase at higher levels of alcohol consumption. A substantial portion of the benefit of moderate drinking is connected with the alcohol component. However, small differences in effects of various alcoholic beverages on minor risk factors may occur. Proposed protective mechanisms include improved vascular elasticity, anti-thrombotic and anti-inflammatory processes and most importantly, the stimulation of high-density lipoprotein-mediated processes such as reverse cholesterol transport and antioxidative effects.

Alcohol Drinking↗
PubMed2001

Clues to the immunopathogenesis of multiple sclerosis by investigating untreated patients during the very early stage of disease.

Plethora of abnormalities of the immune system has been described in multiple sclerosis (MS). They include a number of myelin antigens (e.g. MBP, MOG, PLP, MAG), the presence of reactive T cells in blood and, further enriched, in the cerebrospinal fluid (CSF), large numbers of B cells in the CSF secreting antibodies of multiple but unknown specificities, an increase of mononuclear cells (MNC) expressing and secreting both pro- and anti-inflammatory cytokines, including Th1 cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-6, the Th2 related IL-4 and IL-10, and the Th3-driven TGF-beta, elevated numbers of MNC in both blood and CSF expressing a spectrum of metalloproteinases and their inhibitors, as well as many other aberrations. However, no consistent patterns have emerged that relate any, of these findings to clinical variables such as exacerbations, duration of disease, disability, or lesions in the central nervous system (CNS) detected at magnetic resonance imaging. In order to elucidate the relevance of these immunological abnormalities in the pathogenesis of MS, my colleagues and I studied patients with acute monosymptomatic optic neuritis (ON) and compared them with patients with clinically definite MS (CDMS). The patients have not been treated and have not received corticosteroids or interferon-beta. When comparing these two groups, we were unable to identify any differences in any of the variables mentioned. Thus, very early MS, as represented by ON, shows the same full-blown pattern of immunological abnormalities seen in CDMS. Furthermore, a complete epitope spread affecting MBP, MOG, PLP, MAG and other myelin components is already present in ON. Whether any of these alterations play a pathogenetic role is still unsettled.

Brain↗
PubMed1986

Constitutional interstitial deletion of 11p11 and pericentric inversion of chromosome 9 in a patient with Wiedemann-Beckwith syndrome and hepatoblastoma.

A constitutional interstitial deletion on the short arm of chromosome #11 and an inversion of the heterochromatin of chromosome #9 were detected in a 1.5-year-old boy with Wiedemann-Beckwith syndrome (WBS) and hepatoblastoma. Of 37 malignant and nine benign neoplasms reported in approximately 250 cases with complete and incomplete forms of WBS, this is the fourth patient with hepatoblastoma. To date, 28 cases of WBS have been cytogenetically investigated with banding techniques. Constitutional anomalies have been found in only nine cases: Various anomalies resulting in a common triplication of the 11p15 region in six cases, reciprocal translocations t(11;22) and t(X;1) and an inversion of chromosome #2 in the three remaining cases. Triplication 11p15 was only present in one of four cases with a tumor. The breakpoints of the unique del(11)(p11.1p11.2) present in our case are proximal to those of del(11p13-11p14) and dup(11p15) observed thus far in both the aniridia-Wilms' tumor association and in WBS. Inversion of chromosome #9--one of the heterochromatin variants associated with elevated chromosomal instability, increased congenital abnormalities, and cancer proneness--may have been causally connected with a genetic imbalance resulting in the de novo deletion of 11p11. Therefore, we suggest that in these high-risk groups, C-banding studies should be performed together with high resolution chromosome analysis in order to also reveal the incidence and significance of C-band variants in individuals with such cancer prone syndromes.

Beckwith-Wiedemann Syndrome↗
PubMed1993

Renal corticosterone 6 beta-hydroxylase in the spontaneously hypertensive rat.

Excess 6 beta-OH-corticosterone production by family 3A cytochromes P-450 may play a role in genesis of hypertension in the spontaneously hypertensive rat (SHR), by producing a renal defect in Na+ excretion. Renal cytochromes P-450 may be a causal factor in this genetic model. Since family 3A P-450 is present in rat kidney (collecting duct), the renal family 3A catalytic (6 beta-OHase) and immunoreactive activities were compared in SHR and normotensive control (Wistar-Kyoto; WKY) rats. Corticosterone 6 beta-hydroxylation is markedly higher in SHR than in WKY renal microsomal preparations. Western blot analysis with antibodies to rat and rabbit liver family 3A isoforms demonstrated related proteins. Densitometry revealed greater relative intensity of staining in SHR compared to WKY with both antibodies. Both antibodies inhibited corticosterone 6 beta-hydroxylation by SHR renal microsomes. Increased renal 6 beta-OH-corticosterone production by increased renal family 3A cytochromes P-450 may play a role in the blood pressure elevation in SHR.

Animals↗
PubMed2006

Perimenopause and depression: strength of association, causal mechanisms and treatment recommendations.

Perimenopause represents a significant transition in a woman's life. The evidence to support an association between perimenopause and depression is mixed, yet recent prospective studies have provided stronger evidence to support such an association. Interpretation of study data are complicated by methodological issues, such as a lack of standard definition for perimenopause or depression, reducing comparability. A variety of causal factors, including psychological, genetic and physiological, have been implicated in depression during perimenopause, which lends weight to a multifactorial model. Physicians should consider initiating dialogue about menopause and symptom relief at age 40 and screening perimenopausal women for depressive symptoms. Selective serotonin reuptake inhibitors are a first line of treatment for depression, but hormone therapy could be considered for women experiencing menopausal symptoms unless there are contraindications. Future research should focus on establishing temporality and studying these potential relationships among women of different ethnicities.

Depressive Disorder↗
PubMed1990

Relationship between airways responsiveness and the development of chronic obstructive pulmonary disease.

The idea that increases in airways responsiveness--either as a result of exposure to cigarette smoke and/or pre-existing increases in bronchial responsiveness, possibly genetically mediated--might be causal in the pathogenesis of the development of COPD in cigarette smokers presents an attractive hypothesis. The fact that a relatively small proportion of cigarette smokers develop COPD begs for specific susceptibilities as an explanation of selective pathogenesis. In our view, the evidence for modest increases in airways responsiveness in cigarette smokers who do not have asthma or allergies is convincing. Such increases in bronchial responsiveness are modest when compared to patients with asthma and may have a different mechanism. However, the demonstration by Verma et al that two types of patients with cigarette smoke-induced COPD, "bronchitis" patients and "emphysematous" patients, have virtually identical alterations in bronchial responsiveness, and that these alterations appear to be a function of airways caliber, has led us to believe that the changes in airways tone in patients with COPD may be reflective more of changes in airways geometry imposed by the development of disease rather than a measurement of a risk factor in the development of COPD. Of the epidemiologic studies that have emerged throughout the 1980s, problems of possible inclusion of asthmatic subjects in the study groups and of baseline airflow rates as a function of bronchial responsiveness have limited the ability of data to implicate increases in airways responsiveness as a risk factor in the development of COPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗
PubMed1998

Reproductive career after breech presentation: subsequent pregnancy rates, interpregnancy interval, and recurrence.

OBJECTIVE: To assess subsequent pregnancy rates and recurrence of breech, as well as interpregnancy interval after a breech presentation. METHODS: We conducted a national population registry-based study using data from 1967 to 1994, with maternal record linkage of sibships, comprising the first to the fourth birth of a mother. RESULTS: The subsequent pregnancy rate after a surviving breech birth was lower than after a surviving nonbreech birth. Women with two births, of which one was a perinatal loss, had a higher subsequent pregnancy rate, compared with those who had surviving infants. The subsequent pregnancy rate was lower after a cesarean delivery irrespective of presentation. The interpregnancy interval was shorter if the previous infant died, whereas presentation did not influence the interval. The adjusted odds ratio of recurrence of breech increased from 4.32 (95% confidence interval [CI] 4.08, 4.59) after one previous breech delivery to 28.1 (95% CI 12.2, 64.8) after three. CONCLUSION: Breech and cesarean delivery lowered the subsequent pregnancy rate, probably because of the women's decision not to reproduce. Thus, preconceptional counseling with information, support, and reassurance regarding future pregnancies and deliveries might reduce the discouraging effect. A high odds ratio of recurrence of breech suggests effects of recurring specific causal factors of either genetic or more permanent environmental origin.

Adult↗
PubMed2004

[Familial fronto-temporal dementia with brain stem ubiquitin-positive neuronal inclusions].

INTRODUCTION: Fronto-temporal dementias (FTD) were described a century ago on the macroscopic basis of frontal and/or temporal lobe atrophy. Progress in neuropathology, immunohistochemistry, biochemistry and genetics has since shown that they are heterogeneous entities, encompassing many different diseases with similar clinical presentations. A few, such as tauopathies due to mutations of the gene coding for tau protein (MAPtau form a well-defined group. Definition and grouping of other types of FTD is still problematic. MATERIAL AND METHOD: We studied a family where the mother and 4/8 children were affected with FTD. Clinical presentation was typical of FTD. Onset was ill-defined with early (at age 40 years or less) personality changes. The clinical course was protracted (about 30 years). For a long period, the patients were able to live in the community in spite of obvious signs such as hyperorality and loss of verbal initiative; operative orientation as to place was preserved for a long time: a mute patient was still able to drive. Signs of extrapyramidal or motoneuron involvement were not observed. RESULTS: The genetic study failed to detect any mutation in MAPtau; the lod score for flanking markers was positive but not significant. Biochemical study showed no qualitative abnormality in tau protein. Neuropathological study of one affected subject showed brain atrophy (962 g), with elective frontal lobe involvement. Cortical nerve cell loss was more marked in superficial layers and in frontal areas; glia was inconspicuous; pseudolaminar spongiosis was present in the more severely affected zones. No argentophilic "Pick bodies" were seen; ubiquitin-positive, tau-negative round inclusions were present in the cytoplasm of fascia dentata neurones. "Tangles" were mostly restricted to the entorhinal cortex, partly correlated with tau immunoreactivity, but better with ubiquitin immunoreactivity. Large, ovoid or reniform, moderately dense, spongy, granular or filamentous argentophilic cytoplasmic nerve cell inclusions were observed. They were ubiquitin-positive, but did not react with other antibodies, particularly anti-tau. They were present in swollen nerve cells in the deeper cortical layers but were most conspicuous in the brain stem: in the magnocellular reticular nuclei (e.g. nucleus centralis pontis), in the pes pontis, in the inferior olive and in motor nuclei, especially in the trigeminal motor nucleus. They were not associated with nerve cell loss, atrophy nor pycnosis. Cerebellar relay nuclei neurones were swollen, and their cytoplasm contained argentophilic filaments. CONCLUSION: In our opinion, "ubiquitinopathy" would be non-specific and "Motor Neuron Disease-Inclusion Dementia" (MNDID) would not be satisfactory as a diagnosis for the present cases of FTD. Hopefully, progress in genetics may allow a causal, and thence definitive, classification.

Adult↗
PubMed1996

Hereditary predisposition to breast cancer.

The breast cancer susceptibility gene on chromosome 17q, BRCA1, has now been isolated. Mutations in this gene have been detected in many families with a predisposition to breast cancer. Most of these mutations result in truncation and presumed inactivation of the BRCA1 protein. A large number of distinct mutations have been reported, although some families have identical mutations, probably due to a founder effect. Certain evidence suggests that mutations positioned towards the 5' end of the gene carry a higher risk of ovarian cancer than those at the 3' end. BRCA1 is infrequently somatically mutated in sporadic breast or ovarian cancer. The BRCA2 gene has been localized to chromosome 13q12-q13. BRCA2 carries a risk of breast cancer similar to that of BRCA1, but is associated with a lower risk of ovarian cancer and a higher risk of male breast cancer. Additional breast cancer susceptibility genes probably exist, but may be difficult to locate by conventional methods.

BRCA1 Protein↗