Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome

Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 (sd 2·1), AfAm 9·8 (sd 1·9) % of total fatty acids; P < 2·29 × 10??) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 (sd 2·2), AfAm 6·9 (sd 2·2); P = 1·44 × 10??). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 (sd 1·0); GG 8·5 (sd 2·1); P = 3·0 × 10??) and AA:DGLA ratios (TT 3·4 (sd 0·8), GG 6·5 (sd 2·3); P = 2·2 × 10??) but higher DGLA levels (TT 1·9 (sd 0·4), GG 1·4 (sd 0·4); P = 3·3 × 10??) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.     

Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation

The enzymes encoded by fatty acid desaturase (FADS) 1 and FADS2 are rate-limiting enzymes in the desaturation of linoleic acid [LA; 18:2(n-6)] to arachidonic acid [ARA; 20:4(n-6)], and alpha-linolenic acid [ALA; 18:3(n-3)] to eicosapentaenoic acid [EPA; 20:5(n-3)] and docosahexaenoic acid [DHA; 22:6(n-3)]. ARA, EPA, and DHA play central roles in infant growth, neural development, and immune function. The maternal ARA, EPA, and DHA status in gestation influences maternal-to-infant transfer and breast milk provides fatty acids for infants after birth. We determined if single nucleotide polymorphisms in FADS1 and FADS2 influence plasma phospholipid and erythrocyte ethanolamine phosphoglyceride (EPG) (n-6) and (n-3) fatty acids of women in pregnancy or their breast milk during lactation. We genotyped rs174553, rs99780, rs174575, and rs174583 in the FADS1 FADS2 gene cluster and analyzed plasma and erythrocyte fatty acids and dietary intake for 69 pregnant women and breast milk for a subset of 54 women exclusively breast-feeding at 1 mo postpartum. Minor allele homozygotes of rs174553(GG), rs99780(TT), and rs174583(TT) had lower ARA but higher LA in plasma phospholipids and erythrocyte EPG and decreased (n-6) and (n-3) fatty acid product:precursor ratios at 16 and 36 wk of gestation. Breast milk fatty acids were influenced by genotype, with significantly lower 14:0, ARA, and EPA but higher 20:2(n-6) in the minor allele homozygotes of rs174553(GG), rs99780(TT), and rs174583(TT) and lower ARA, EPA, 22:5(n-3), and DHA in the minor allele homozygotes G/G of rs174575. We showed that genetic variants of FADS1 and FADS2 influence blood lipid and breast milk essential fatty acids in pregnancy and lactation.     

Genetic variants in desaturase gene,erythrocyte fatty acids,and risk for type 2 diabetes in Chinese Hans

ObjectiveThe aim of this study was to examine the association of the genetic variants in the fatty acid desaturase (FADS) gene cluster with erythrocyte phospholipid fatty acids (PLFA), and their relation to risk for type 2 diabetes mellitus (T2DM) in Han Chinese.MethodsSeven hundred and fifty-eight patients with T2DM and 400 healthy individuals were recruited. The erythrocyte PLFA and single-nucleotide polymorphism were determined by standard method.ResultsMinor allele homozygotes and heterozygotes of rs174575 and rs174537 had lower PL 20:4 ω-6 levels in healthy individuals. Minor allele homozygotes and heterozygotes of rs174455 in FADS3 gene had lower levels of 22:5 ω-3, 20:4 ω-6, and Δ5desaturase activity in patients with T2DM. Erythrocyte membrane PL 18:3 ω-3 (P for trend = 0.002), 22:5 ω-3 (P for trend < 0.001), ω-3 polyunsaturated fatty acid (P for trend < 0.001), and ω-3:ω-6 (P for trend < 0.001) were significantly inversely associated with risk for T2DM.ConclusionGenetic variants in the FADS gene cluster are associated with altered erythrocyte PLFAs. High levels of PL 18:3 ω-3, 22:5 ω-3, and total ω-3 polyunsaturated fatty acid were associated with low risk for T2DM.     

Lack of association between genetic variants in the mannose-binding lectin 2 (MBL2) gene and HPV infection

Genetic variants in the immunomodulatory gene mannose-binding lectin 2 (MBL2), were associated with risk, severity, and frequency of viral infections. In a case-control setting, we investigated the association of MBL2 functional polymorphisms with Human Papillomas Virus (HPV) infection. No differences between cases (HPV⁺) and controls (HPV^–) were found in the distribution of each single genotypes or allele. Haplotype analysis did not show any difference between HPV+ and HPV^– groups. Paola Parrella and Davide Seripa contribute equally to this work.     

Genetic variants of the FADS gene cluster are associated with erythrocyte membrane LC PUFA levels in patients with mild cognitive impairment

Background

Long-chain (> 20 C-atoms) polyunsaturated fatty acids (LC PUFAs) of both the omega-6 (n-6) and omega-3 (n-3) series are important for the functional integrity of brain and thereby cognition, memory and mood. Clinical studies observed associations between altered LC PUFA levels and neurodegenerative diseases such as Alzheimer´s disease and its prodromal stage, mild cognitive impairment (MCI).

Methods

The present study examined the LC PUFA status of MCI patients with specific view on the relative LC n-3 PUFA levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocyte membranes (omega-3 index). 12 single nucleotide polymorphisms (SNPs) of the FADS1, FADS2, and FADS3 gene clusters were genotyped in 111 MCI patients and evaluated associations with PUFA levels in erythrocyte membranes (primary outcome). In addition, the associations between FADS SNPs and LC PUFA levels with serum lipid levels as well as depressive symptoms were examined (secondary outcomes).

Results

Minor allele carrier of rs174546, rs174548 (FADS1), rs3834458, rs1535, rs174574, rs174575, rs174576, and rs174578 (FADS2) showed significant higher n-6 and n-3 precursor PUFA levels (linoleic acid, and alpha-linolenic acid, respectively) and lower arachidonic acid (AA) levels in erythrocyte membranes compared to the major allele carriers. Differences in EPA and DHA levels were not significant. Minor allele carriers of rs174574, rs174576 and rs174578 (FADS2) and rs174455 (FADS3) exhibited significant higher triglyceride levels, whereas minor allele carriers for rs174449 and rs174455 (FADS3) exhibited significant higher total- and LDL-cholesterol levels compared to the more common variant. The mean omega-3 index of the study cohort was 6.19 ± 1.55 %. In more than 85 % of the patients, the omega-3 index was below 8 % and in 23 % below 5 %. Moreover, it was shown that a low DHA status and omega-3 index was associated with depressive symptoms (Beck’s depression-inventory).

Discussion and conclusion

These findings indicate an association between several FADS genotypes for higher n-6 and n-3 precursor PUFA and lower AA levels in erythrocyte membranes in minor compared to major allele carriers. To what extent FADS genotypes and a lower conversion of LA and ALA to biologically important LC PUFAs such as AA, EPA and DHA contributes to cognitive decline should be investigated in further trials. Nevertheless, the omega-3 index in this cohort of MCI patients can be classified as insufficient.

     

Diet (n-3) polyunsaturated fatty acid content and parity affect liver and erythrocyte phospholipid fatty acid composition in female rats

The fatty acid composition of membrane phospholipids affects the physicochemical properties of the membrane and thus influences cell function. In this study, the effects of 1-4 sequential pregnancies on the phospholipid fatty acid compositions of the maternal liver and erythrocytes were determined in female rats fed diets containing alpha-linolenic acid (ALA), ALA and preformed docosahexaenoic acid (DHA; ALA+DHA), or minimal ALA (low ALA). Virgin females, fed the diets for commensurate durations, served as a control for reproduction. Liver and erythrocyte total phospholipid compositions were determined at weaning by TLC/GC. In both tissues, significant main effects of diet and reproductive status were detected for many fatty acids, but a significant interaction of diet, reproductive status, and duration of treatment (no. of reproductive cycles or equivalent time period for virgins) was detected only for DHA, 22:6(n-3). Primiparous dams fed the ALA and low ALA diet had decreased liver DHA content of 31% and 74%, respectively, compared with virgin females fed the ALA diet. Liver DHA did not decrease further after additional reproductive cycles. Liver DHA content was unchanged in parous dams fed the ALA+DHA diet, but virgin females fed this diet exhibited a 50% increase in liver DHA after 13 wk of treatment. Changes in erythrocyte DHA were of similar magnitude and time course to those observed in liver, suggesting that this tissue may serve as a marker for liver DHA status.     

Cognitive decline and fatty acid composition of erythrocyte membranes--The EVA Study

BACKGROUND: Dietary factors might modify cognitive decline that results from aging. Fatty acids, which are limiting factors in brain development, are prime candidates. OBJECTIVE: We studied the relation between erythrocyte membrane fatty acid composition and cognitive decline in free-living volunteers. DESIGN: In 1995, erythrocyte membrane fatty acid composition was measured in 246 men and women (aged 63-74 y) from the Etude du Vieillissement Artériel (EVA) cohort. During a 4-y follow-up, cognitive abilities were assessed longitudinally with the Mini-Mental State Examination. Moderate cognitive decline was defined as a > or = 2-point decrease over the 4 y. The predictive value of fatty acid proportions on cognitive decline was assessed with a multivariate logistic model that included age, sex, education level, and initial Mini-Mental State Examination score as covariates. RESULTS: Higher proportions of both stearic acid (saturated, 18:0) and total n-6 polyunsaturated fatty acids were associated with greater risk of cognitive decline; the odds ratios were 1.91 (95% CI: 1.16, 3.15) and 1.59 (95% CI: 1.04, 2.44), respectively, for 1-SD differences in fatty acid proportions. Conversely, a higher proportion of total n-3 fatty acids was associated with a lower risk of cognitive decline; the odds ratio was 0.59 (95% CI: 0.38, 0.93). CONCLUSIONS: The inverse association between cognitive decline and the ratio of n-3 to n-6 fatty acids in erythrocyte membranes agrees with results obtained in some studies that assessed fatty acid intake by using dietary questionnaires. These results require confirmation but provide new rationale for studying how these modifiable risk factors might be implicated in the cognitive aging process.     

A meta-analysis of the association of N-acetyltransferase 2 gene (NAT2) variants with breast cancer

The N-acetyltransferase 2 gene (NAT2) product is an enzyme important in carcinogen metabolism via activation and detoxification pathways. Therefore, NAT2 variants may represent underlying susceptibility to breast cancer. Because a number of studies of the association of NAT2 with breast cancer have been published, the authors performed a meta-analysis. They extracted all relevant data to examine evidence for a main effect (i.e., the effect in a model that does not include any interactions) of NAT2 phenotype and genotype on breast cancer risk. They summarized the evidence for modification by smoking and meat intake, sources of exposure to aromatic and heterocyclic amines, respectively, which are metabolized by NAT2. The authors identified seven studies that measured NAT2 phenotype and 20 studies that deduced phenotype via genotyping. They found no evidence for heterogeneity (Cochran's Q statistic p=0.74) and no statistically significant increased risk from NAT2 acetylation (slow/rapid) for breast cancer (summary odds ratio=1.02, 95% confidence interval: 0.95, 1.08). These results suggest that there is no overall association between the NAT2 slow- or rapid-acetylation phenotype and breast cancer risk. However, some evidence suggests that smoking may modify this association.     

Persistent changes in the fatty acid composition of erythrocyte membranes after moderate intake of n-3 polyunsaturated fatty acids: study design implications.

To examine the incorporation of n-3 polyunsaturated fatty acids (PUFAs) into erythrocyte membranes during and after moderate n-3 PUFA intake, 12 healthy men were fed three diets for 6-wk periods in a 3 x 3 crossover design, supplying different amounts of eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3): a control diet, a fish diet (0.15 g EPA/d, 0.41 g DHA/d), and a fish + oil diet (5 g fish oil/d; 0.99 g EPA/d and 0.99 g DHA/d). A 6-wk washout period was allowed between diets. Between 6 and 12 wk after the fish + oil diet, erythrocyte EPA and DHA were still declining and it was only after 18 wk that erythrocyte EPA had returned to baseline whereas DHA had not. Investigators examining variables that are influenced by altered membrane fatty acid composition should be aware of these prolonged effects when designing studies. Protracted washout periods (greater than 18 wk) make the classic crossover design prohibitive and a parallel design becomes essential.     

Effects of n-3 polyunsaturated fatty acid supplementation in pregnancy on maternal and fetal erythrocyte fatty acid composition

OBJECTIVE: The aim of this study was to assess the effects of fish oil supplementation in pregnancy on maternal erythrocyte fatty acid composition at different stages of pregnancy and in the post-partum period, and on neonatal erythrocyte fatty acid composition. DESIGN: A double-blind, randomised, placebo-controlled study. SETTING:: Subiaco, Western Australia. SUBJECTS: In all, 98 women booked for delivery at St John of God Hospital, Subiaco, were recruited from private rooms of obstetricians. In total, 83 women and their healthy full-term babies completed the study. INTERVENTION: Women received either 4 g of fish oil (n=52) (56% docosahexaenoic acid (DHA) and 28% eicosapentaenoic acid (EPA) or placebo (olive oil) (n=46) per day from 20 weeks gestation until delivery. MAIN OUTCOME MEASURES: Erythrocyte phospholipid fatty acids were measured in maternal peripheral blood at 20, 30 and 37 weeks of pregnancy and at 6 weeks post partum, and from cord blood collected at birth. RESULTS: Compared to the control group, maternal EPA and DHA were significantly higher in the fish oil group at 30 and 37 weeks gestation, and remained elevated at 6 weeks post partum (P<0.001). The proportions of n-6 polyunsaturated (arachidonic acid, 22:3n-6 and 22:4n-6) were significantly lower in the fish oil supplemented group at the same time periods (P<0.001). Similarly, the proportions of EPA and DHA were significantly higher (P<0.001), and those of n-6 polyunsaturated fatty acids arachidonic acid, 20:3n-6, 22:3n-6 and 22:4n-6 were significantly lower (P<0.001), in erythrocytes from neonates in the fish oil group, compared to those in the control group. CONCLUSION: Fish oil supplementation from 20 weeks of pregnancy until birth is an effective means of enhancing n-3 fatty acid status of both mothers and neonates. Furthermore, the changes in maternal erythrocyte fatty acid composition are retained until at least 6 weeks post partum. It is essential to assess the effects of concomitant decreases in arachidonic acid status before any dietary recommendations can be made. SPONSORSHIP: The study was supported by grants from the NH & MRC and Raine Medical Research Foundation, Australia.     

The influence of diet and diabetes on stearoyl Conenzyme A desaturase (EC 1.14.99.5) activity and fatty acid composition in rat tissues.

1. Rats were given low-fat diets for 3 d in which the carbohydrate source was starch. The livers of animals given the fructose or sucrose had increased hepatic activities of the fatty acid synthetase and stearoyl CoA desaturase (EC 1.14.99.5) enzyme complexes: in those given fructose there was a lower activity of the enzymes in adipose tissue. 2. Similar results were obtained in rats given fructose diets for 30 d, but in animals which had previously been made diabetic with streptozotocin, the activities were lower. The dietary treatment made little difference to the fatty acid profiles of the tissue lipids. The diabetic condition on the other hand produced considerable changes in fatty acid profile. 3. With diets containing approximately 200 g fat/kg in the form of butter or of polyunsaturated margarine, the tissue lipids from rats given sucrose had less linoleic acid than those from rats given starch. In addition, there was the expected difference between the rats given butter or margarine. The results are discussed in relation to the current literature.     

Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women

BACKGROUND: Erythrocyte fatty acids may be superior to plasma fatty acids for reflecting long-term fatty acid intake because of less sensitivity to recent intake and a slower turnover rate. OBJECTIVE: The objective was to compare the fatty acid content of erythrocytes with that of plasma with respect to their abilities to reflect usual fatty acid intake. DESIGN: Fatty acids in plasma and erythrocytes were measured by capillary gas-liquid chromatography in 306 US women aged 43-69 y. Fatty acid intake was assessed with a food-frequency questionnaire, which was validated for measuring intakes of various fatty acids. RESULTS: Docosahexaenoic acid (DHA, 22:6n-3) in erythrocytes and plasma provided the strongest correlations with its intake, but erythrocyte DHA concentrations [Spearman's partial correlation coefficient (r(s))=0.56] were better than plasma DHA concentrations (r(s)=0.48) as a biomarker. Total trans fatty acids (r(s)=0.43) and total 18:1 trans isomers (r(s)=0.42) in erythrocytes were also more strongly correlated with intake than were those in plasma (r(s)=0.30 and r(s)=0.29, respectively). Moderate correlations were observed for linoleic acid (18:2n-6; erythrocytes, r(s)=0.24; plasma, r(s)=0.25), alpha-linolenic acid (18:3n-3; erythrocytes, r(s)=0.18; plasma, r(s)=0.23), and eicosapentaenoic acid (20:5 n-3; erythrocytes, r(s)=0.38; plasma, r(s)=0.21). For polyunsaturated and trans fatty acids, correlations between intakes and biomarkers improved moderately when average intakes over previous years were used. CONCLUSION: Erythrocyte n-3 fatty acids of marine origin and trans fatty acid content are suitable biomarkers for long-term intake.     

PLA2G4C基因多态性与精神分裂症的遗传相关性

目的探讨中国北方汉族人群PLA2G4C基因多态性与精神分裂症的遗传相关性.方法采用聚合酶链反应（PCR）和限制性内切酶片段长度多态性（RFLP）方法,在240个精神分裂症患者核心家系中检测PLA2G4C基因上的6个单核苷酸多态性（SNPs）,对结果进行单倍型相对风险（HRR）分析和传递不平衡分析（TDT）.结果在所检测的6个SNPs中,只有rs1366432和rs1549637位点在北方汉族人群中具有高度的多态性.rs1366432和rs1549637位点在精神分裂症病例组和对照组中基因型分布均符合Hardy-Weinberg平衡.HRR和TDT分析表明,rs1549637位点与精神分裂症关联具有显著性（X^2=5.364,P＜0.05;X^2=5.633,P＜0.05）,而rs1366432位点与精神分裂症不存在遗传相关性（X^2=0.027,P＞0.05;X^2=0.007,P＞0.05）.结论PLA2G4C基因可能是精神分裂症的易感基因.     

Fatty acid composition and fatty acid elongase and stearoyl-CoA desaturase activities in tissues of steers fed high oleate sunflower seed.

The effects of a high oleate sunflower seed diet on tissue composition and on fatty acid elongation and desaturation enzyme activities were investigated. Three Simmental calves were fed a standard corn-based diet (2.6% fat); three others were fed the corn-based diet containing 20% high oleate sunflower seed (10.4% fat). Blood samples and perianal adipose tissue samples were obtained at 7, 90 and 180 d on trial. Samples of liver, longissimus dorsi muscle and intestinal mucosa were obtained at the termination of the experiment (195 d on trial). Plasma oleate was higher (P < 0.05) in the cattle fed the sunflower seed, and oleate, myristate (P < 0.05) and stearate (P < 0.06) were elevated in perianal adipose tissue in response to the greater lipid content of the dietary sunflower seed. Dietary sunflower seed decreased the concentration of stearate (P < 0.05) in liver. The high oleate diet significantly (P < 0.05) increased the activity of stearoyl-CoA desaturase activity in muscle, and numerical increases in desaturase activity were observed in liver, adipose and small intestine samples. Elongase activity was unaffected by diet. Because stearate is the primary fatty acid available for absorption in ruminants, elevated oleate in plasma and depressed stearate in liver of cattle fed sunflower seed may have reflected an adaptive response of stearoyl-CoA desaturase in their tissues.     

Comparison between omega-3 and omega-6 polyunsaturated fatty acid intakes as assessed by a food frequency questionnaire and erythrocyte membrane fatty acid composition in young children

OBJECTIVE: We conducted a dietary validation study in youth aged 1-11 years by comparing dietary intake of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) as assessed by a parent-completed semiquantitative food frequency questionnaire (FFQ) over time to erythrocyte membrane composition of the same fatty acids. DESIGN: The study population included youth aged 1-11 years who were participants in the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal study in Denver, Colorado that is following a cohort of youth at risk for developing type I diabetes. Four hundred and four children who had erythrocyte membrane fatty acid data matched to an FFQ corresponding to the same time frame for a total of 917 visits (matches) were included. PUFA intake was expressed both as g/day (adjusted for total energy) and as percent of total fat intake. We used mixed models to test the association and calculate the correlation between the erythrocyte membrane estimates and PUFA intake using all records of data for each youth. RESULTS: Intakes of total omega-3 fatty acids (beta=0.52, P<0.0001, rho=0.23) and marine PUFAs (beta=1.62, P<0.0001, rho=0.42), as a percent of total fat in the diet, were associated with percent of omega-3 and marine PUFAs in the erythrocyte membrane. Intakes of omega-6 PUFAs (beta=0.04, P=0.418, rho=0.05) and arachidonic acid (beta=0.31, P=0.774, rho=0.01) were not associated. CONCLUSIONS: In these young children, an FFQ using parental report provided estimates of average long-term intakes of marine PUFAs that correlated well with their erythrocyte cell membrane fatty acid status.     

Dietary fatty acid intake and concentrations in serum and erythrocyte membranes of students with allergic disease

PURPOSE: An attempt was made to utilize accumulated scientific evidence for nutritional guidance concerning dietary fatty acids (FAs) for students with allergic diseases METHODS: A questionnaire survey on dietary fatty acid intake was conducted with 128 women students aged 19-20. In addition to hematological and physical examinations, fatty acid analyses were performed with serum and erythrocyte membrane samples using gas chromatography. Based on the answers to questions about allergic diseases, the subjects were divided into three groups (59 healthy students, 45 with previous experience of allergies, and 24 with allergies). We then investigated the influences of dietary fatty acids and other nutritional components on fatty acid compositions of serum and erythrocyte membranes, and statistically analyzed the results by comparing the three groups. RESULTS: 1) Dietary n-3 (g) intake by all students was lower than the tentative dietary goal in the Dietary Reference Intakes. However, there were no effects of allergic diseases on physical measurements and blood test data. Dietary n-3 (g) was negatively correlated with erythrocyte membrane n-3 (%), and dietary n-3 (%) was positively correlated with the number of acidophils (%). In addition, a positive correlation was found between serum n-3 (%) and dietary S (Saturated fatty acid) (%). 2) For the allergic group, the ratio of erythrocyte membrane M (Monounsaturated fatty asid) (%) to dietary M (%) was high. For the allergic predisposition group (allergic subjects and subjects with past history of allergic disease), a negative correlation was found between erythrocyte membrane M (%) and dietary S (%). CONCLUSION: Dietary n-3 (g) was insufficient in all subjects enrolled in this study, but erythrocyte membrane n-3 (Y%) decreased with increase of dietary n-3 (g). There was a tendency for acidophil number (%) to increase with the dietary n-3 (%). Therefore, it was suggested that if nutritional guidance is to made with attention to increasing dietary S (%), it should be stressed that serum n-3 (%) might become elevated and erythrocyte membrane M (%) depressed, especially in those with a predisposition to allergies.