Risk factors for inguinal hernia repair among US adults.

PURPOSE: To investigate demographic, clinical, and behavioral risk factors for undergoing inguinal hernia repair within a large and ethnically diverse cohort. METHODS: We conducted a retrospective case-control study from 2007 to 2020 on 302,532 US individuals from a large, integrated healthcare delivery system with electronic health records, who participated in a survey of determinants of health. Participants without diagnosis or procedure record of an inguinal hernia at enrollment were included. We then assessed whether demographic (age, sex, race/ethnicity), clinical, and behavioral factors (obesity status, alcohol use, cigarette smoking and physical activity) were predictors of undergoing inguinal hernia repair using survival analyses. Risk factors showing statistical significance (P < 0.05) in the univariate models were added to a multivariate model. RESULTS: We identified 7314 patients who underwent inguinal hernia repair over the study period, with a higher incidence in men (6.31%) compared to women (0.53%). In a multivariate model, a higher incidence of inguinal hernia repair was associated with non-Hispanic white race/ethnicity, older age, male sex (aHR = 13.55 [95% confidence interval 12.70-14.50]), and more vigorous physical activity (aHR = 1.24 [0.045]), and alcohol drinker status (aHR = 1.05 [1.00-1.11]); while African-American (aHR = 0.69 [0.59-0.79]), Hispanic/Latino (aHR = 0.84 [0.75-0.91]), and Asian (aHR = 0.35 [0.31-0.39]) race/ethnicity, obesity (aHR = 0.33 [0.31-0.36]) and overweight (aHR = 0.71 [0.67-0.75]) were associated with a lower incidence. The use of cigarette was significantly associated with a higher incidence of inguinal hernia repair in women (aHR 1.23 [1.09-1.40]), but not in men (aHR 0.96 [0.91-1.02]). CONCLUSION: Inguinal hernia repair is positively associated with non-Hispanic white race/ethnicity, older age, male sex, increased physical activity, alcohol consumption and tobacco use (only in women); while negatively associated with obesity and overweight status. Findings from this large and ethnically diverse study may support future prediction tools to identify patients at high risk of this surgery.

Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study.

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects' alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10-72) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10-4) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10-20 for drinker status and beta=-0.19, P=1.91 × 10-35 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10-7 and beta=-0.21, P=2.58 × 10-6, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=-0.04, P=3.41 × 10-10 for drinks/week and OR=0.96, P=4.08 × 10-5 for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10-8 for drinks/week and OR=1.04, P=5 × 10-4 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

Prognostic factors and survival in acral lentiginous melanoma.

BACKGROUND: Acral lentiginous melanoma (ALM) is a rare melanoma subtype that disproportionately afflicts people of colour. ALMs have a worse prognosis than other melanoma subtypes; this has been attributed to aggressive biological behaviour, more advanced stage at presentation and possible disparities in access to health care. OBJECTIVES: To examine, using comprehensive patient data and long-term follow-up information in a well-characterized cohort, how patient, tumour and clinical management variables impact overall and melanoma-specific survival. METHODS: We characterized a consecutive cohort of 123 ALMs diagnosed from 1987 to 2013 and analysed predictors of overall and melanoma-specific survival for their association with survival. RESULTS: Univariate hazard ratios and 95% confidence intervals using Cox regression models showed that increased Breslow depth, presence of ulceration, receipt of radiation, chemo- and vaccine therapy were associated with worse melanoma-specific survival. Notably, nonwhite race/ethnicity was not associated with worse overall or melanoma-specific survival. Multivariate modelling adjusting for patient, tumour and management variables revealed Breslow depth > 2 mm and disease extent as significantly associated with poor melanoma-specific survival. CONCLUSIONS: Melanoma-specific mortality among patients with ALM is associated with increased tumour thickness and more advanced stage at presentation, but not with race/ethnicity. Advanced tumour features at presentation and access to care may account for less favourable survival outcomes reported among nonwhite patients.

Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.

The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping.

ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.

Genetic variation in aldosterone synthase predicts plasma glucose levels.

The mineralocorticoid hormone, aldosterone, is known to play a role in sodium homeostasis. We serendipitously found, however, highly significant association between single-nucleotide polymorphisms in the aldosterone synthase gene and plasma glucose levels in a large population of Chinese and Japanese origin. Two polymorphisms--one in the putative promoter (T-344C) and another resulting in a lysine/arginine substitution at amino acid 173, which are in complete linkage disequilibrium in this population--were associated with fasting plasma glucose levels (P = 0.000017) and those 60 (P = 0.017) and 120 (P = 0.0019) min after an oral glucose challenge. A C/T variant in intron 1, between these polymorphisms, was not associated with glucose levels. Arg-173 and -344C homozygotes were most likely to be diabetic [odds ratio 2.51; 95% confidence interval (C.I.) 1.39-3.92; P = 0.0015] and have impaired fasting glucose levels (odds ratio 3.53; 95% C.I. 2.02-5.5; P = 0.0000036). These results suggest a new role for aldosterone in glucose homeostasis.

Sib-pair analysis of the collaborative study on the genetics of alcoholism data set.

Nonparametric sib-pair analysis was performed on the Collaborative Study on the Genetics of Alcoholism data set. Concordant and discordant pair groups were examined using the ASPEX package of programs. Allele sharing and multipoint lod scores for six comparison groups were obtained. Sharing and lod score patterns were not consistent with a simple genetic interpretation.

Effectiveness of extreme discordant sib pairs to detect oligogenic disease loci.

A method for the genomic screening of quantitative traits using extreme discordant sib pairs (EDSPs) has recently been described by Risch and Zhang [1995; 1996]. For many models relevant to common, genetically complex diseases, EDSPs are the most powerful siblings for detecting linkage. Thus, if such siblings can be identified and collected, powerful studies with reasonable genotyping budgets can be conducted. Using a subset of the GAW10 data, we have simulated a genomic screen using EDSPs. From the 4,780 total families in the first 20 replicates of 239 families, there were 100, 104, 155, 107, and 180 EDSP families for Q1, Q2, Q3, Q4, and Q5, respectively. EDSP data were analyzed for each trait using a modified version of MAPMAKER/SIBS capable of handling extreme discordant sib pairs. Four regions, one for Q1, one for Q2, and two for Q4, were able to exceed a threshold for linkage corresponding to a 0.001 pointwise significance level. In three cases, maximum lod score (MLS) peaks occurred within 3.8 cM of a major gene. In the fourth case, the MLS peak occurred 28.4 cM from a major gene. Omission of parents and an alternative definition of EDSP were also investigated.

Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy (LGMD) is a diagnostic classification encompassing a broad group of proximal myopathies. A gene for the dominant form of LGMD (LGMD1A) has recently been localized to a 7-cM region of chromosome 5q between D5S178 and IL9. We studied three additional dominant LGMD families for linkage to these two markers and excluded all from localization to this region, providing evidence for locus heterogeneity within the dominant form of LGMD. Although patterns of muscle weakness were similar in all families studied, the majority of affected family members in the chromosome 5-linked pedigree have a dysarthric speech pattern, which is not present in any of the five unlinked families. The demonstration of heterogeneity within autosomal dominant LGMD is the first step in attempting to subclassify these families with similar clinical phenotypes on a molecular level.

Nematicides and nonconventional soil amendments in the management of root-knot nematode on cotton.

Granular and liquid commercial humates, with micronutrients, and a microbial fermentation product were compared in several combinations with nematicides for their effects on cotton lint yield and root-knot nematode suppression. Fumigant nematicides effectively reduced cotton root galling caused by root-knot nematodes, and cotton lint yields increased. Organophosphates and carbamates were not effective. Occasionally, cotton lint yields were increased or maintained with combination treatments o f humates, micronutrients, and a microbial fermentation product, but galling o f cotton roots by root-knot nematodes was usually not reduced by these treatments.

Interaction of Population Levels of Fusarium oxysporum f. sp. vasinfectum and Meloidogyne incognita on Cotton.

In autoclaved greenhouse soil without Fusarium oxysporum f. sp. vasinfectum, Meloidogyne incognita did not cause leaf or vascular discoloration of 59-day-old cotton plants. Plants had root galls with as few as 50 Meloidogyne larvae per plant. Root galling was directly proportional to the initial nematode population level. Fusarium wilt symptoms occurred without nematodes with 77,000 fungus propagules or more per gram of soil. As few as 50 Meloidogyne larvae accompanying 650 fungus propagules caused Fusarium wilt. With few exceptions, leaf symptoms appeared sooner as numbers of either or both organisms increased. In soils infested with both organisms, the extent of fungal invasion and colonization was well correlated with the extent of nematode galling and other indications of the Fusarium wilt syndrome.

Granular Nematicides as Adjuncts to Fumigants for Control of Cotton Root-knot Nematodes.

Growth and yield of cotton were best with combinations of fumigants and organophosphate and carbamate nematicides. Organophosphates or carbamates used alone did not give season-long control of root-knot nematodes. Long-term control was poor because the temporary sublethal effects of these materials diminished soon enough lhat the nematodes could reproduce. The nematodes survived the treatments and a year of nonhost culture, and damaged a susceptible host crop 2 years after treatment. No such damage occurred in plots treated with fumigant, fumigant plus organophosphate, or fumigant plus carbamate. Treatment of seed and treatment of cotton, either in furrow at planting or sidedressing at midseason, with organophosphate and carbamate nematicides resulted in little or no yield increase, because nematode control was only minimal and temporary; or in a yield decrease, because the toxicity of the materials was manifested when nematode populations were low.

Influence of Soil Fumigation on the Fusarium-Root-knot Nematode Disease Complex of Cotton in California.

For control of the root-knot nematode, Meloidogyne incognita, and the pathogenic wilt fungus, Fusarium oxysporum, on cotton, soil fumigants were applied in the field at conventional and higher rates. Conventional rates suppressed Fusarium wilt but higher rates gave quicker early growth, better stands, less stand loss over the season, a lower percentage of plants infected with wilt, fewer plants with vascular discoloration, and fewer nematodes. The best treatment about doubled the yields of untreated controls in one experiment and quadrupled them in another.

Antagonistic Interaction of Heterodera schachtii Schmidt and Fusarium oxysporum (Woll.) on Sugarbeets.

In a field experiment, nematicides controlled the disease of sugarbeets caused by Heterodera schachtii and Fusarium oxysporum. Biocides that were both fungicidal and nematicidal also controlled the disease, but sugar yields were no higher than those obtained with the plain nematicides. In greenhouse experiments, the interaction between H. schachtii and F. oxysporam was disadvantageous to the nematode. Damage to sugarbeets was less when the fungus and the nematode were present than when only the nematode was present. The fungus inhibited nematode invasion and development in sugarbeet seedlings, thereby decreasing the number of nematodes that matured about 3-fold.