M. De Andrade

A Major Lung Cancer Susceptibility Locus Maps to Chromosome 6q23–25

Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

Familial segregation of venous thromboembolism

Background: Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. Objective: To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. Patients and methods: In a family‐based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering age‐specific, non‐gender‐ and gender‐specific liability classes under Mendelian and non‐Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) non‐Mendelian. Results: Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first‐degree relatives. The sporadic model was rejected in both non‐gender‐ and gender‐specific liability class analyses. Among the remaining gender‐specific models, the unrestricted (non‐Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. Conclusion: A multifactorial non‐Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.

A genome‐wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q

Summary.  Objectives:  To identify venous thromboembolism (VTE) disease‐susceptibility genes.

A genetic association study of 5-HTT LPR and GNβ3 C825T polymorphisms with irritable bowel syndrome

Abstract  A pharmacogenetic study suggests the 5‐HTT LPR polymorphism predicts response to alosetron, and another study describes a possible association of the GNβ3 C825T polymorphism with IBS in patients with dyspepsia. We performed a case–control association study to determine whether these polymorphisms are associated with irritable bowel syndrome (IBS). The study aim was to compare allele and genotype frequencies between cases and controls for the 5‐HTT LPR and the GNβ3 C825T polymorphism. Cases were 50 GI outpatients; controls were 53 General Medicine outpatients matched to cases for age, gender and race at a major medical centre. Participants completed a questionnaire and donated blood. DNA was genotyped using polymerase chain reaction based assays. Eighty‐two per cent of cases met Rome II criteria for IBS: 12% constipation‐, 46% diarrhoea‐, and 42% mixed‐IBS. Genotype and allele frequencies for both polymorphisms did not differ between cases and controls. However, the allele frequency of the short (S) allele of the 5‐HTT LPR polymorphism was greater in those with mixed‐IBS compared with controls (68%vs 45%, P < 0.05). This study suggests that the 5‐HTT LPR polymorphism may be associated with mixed‐IBS, but not IBS overall. No association was observed for the GNβ3 C825T polymorphism with IBS overall or subtypes.

Irritable bowel syndrome aggregates strongly in families: a family-based case–control study

Abstract  Irritable bowel syndrome (IBS) runs in families. Prior family studies surveyed patients inquiring about family history without surveying family members. The stigma associated with IBS may lead relatives to not share information with others, resulting in underestimates of familial aggregation of IBS. The aim of the study was to evaluate the accuracy of patient‐report of family history of IBS in cases and controls, and to estimate familial aggregation of IBS using both a case–control and a family‐study design. Fifty cases and 53 controls completed symptom questionnaires and provided contact information for first‐degree relatives. Questionnaires were mailed to relatives. Relatives were considered to have IBS if they met Rome criteria and did not have an alternate GI diagnosis. Cases and controls identified 573 relatives in their families. A total of 202 (51%) of 396 living relatives participated. The kappa statistics between proband‐ and relative‐reported IBS for case‐ and control‐relatives were 0.27 and 0.04. Cases reported 21% of relatives had IBS; relative‐reports showed 37% (P = 0.003). Controls reported 4% of relatives had IBS; relative‐reports showed 16% (P = 0.013). Regardless of whether the proband or the relative themselves were the information source, case‐relatives were threefold as likely to have IBS than control‐relatives (P < 0.05). However, overall rates were higher when data collected from relatives were used. Regardless of approach, strong familial aggregation of IBS was observed. Cases and controls underestimated the frequency of IBS in their relatives and agreement between proband‐ and relative‐report of IBS status was extremely poor, thus emphasizing the need for direct data collection from relatives in IBS family studies.

IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis

Interferon-gamma (IFNγ) treatment is deleterious in multiple sclerosis (MS). MS occurs twice as frequently in women as in men. IFNγ expression varies by gender. We studied a population-based sample of US MS patients and ethnicity-matched controls and independent Northern Irish and Belgian hospital-based patients and controls for association with MS, stratified by gender, of an intron 1 microsatellite [I1(761)*CAn], a single nucleotide polymorphism 3′ of IFNG [3′(325)*G → A] and three flanking microsatellite markers spanning a 118 kb region around IFNG. Men carriers of the 3′(325)*A allele have increased susceptibility to MS compared to noncarriers in the USA (P=0.044; OR: 2.58, 95% CI: 0.97–8.08) and Northern Ireland (P=0.019; OR: 2.37, 95% CI: 1.10–5.13). There is a nonsignificant trend in the same direction in Belgian men (P=0.299; OR: 1.50, 95% CI: 0.71–3.26). Men carriers of I1(761)*CA13, which is in strong linkage disequilibrium with the 3′(325)*A, have increased susceptibility (P=0.050; OR: 2.22, 95% CI: 0.98–5.40), while men carriers of I1(761)*CA12 have decreased susceptibility (P=0.022; OR: 0.46, 95% CI: 0.23–0.90) to MS in the USA. Similar associations were reported in Sardinia between the I1(761)*CA12 allele and reduced risk of MS in men. Flanking markers were not associated with MS susceptibility. Polymorphisms of IFNG may contribute to differences in susceptibility to MS between men and women.

Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

Summary.  Background: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h2] = 0.62) and likely to be a result of multigenic action. Objective: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE. Methods: Non‐Hispanic adults of European ancestry with objectively‐diagnosed VTE, and age‐ and sex‐ matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n = 12 296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke. Results: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non‐O blood type, and a novel association with ABO rs2519093 (OR = 1.68, P‐value = 8.08 × 10−16) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non‐carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non‐O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non‐carriers. The ABO rs2519093 population‐attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non‐O and ABO rs2519093 was 0.40. Conclusions: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non‐Hispanic adults of European ancestry.

Comparison of model-free linkage mapping strategies for the study of a complex trait.

We compared several strategies for identifying and estimating effects from a genetic locus in the etiology of a complex trait. For our analyses we used data from simulated trait 1 and chromosome 5. Results from analysis of the first 20 replicates showed that a components of variance test provided considerably better power for identifying linkage than tests that consider pair differences. We also compared the power from constructing tests with a single marker, an approximate method using five markers jointly, or a multipoint analysis using all 25 markers on chromosome 5 jointly. Results from this analysis showed substantially better power when all markers were jointly used in the analysis. Results from considering all replicates showed that all methods of estimation provided maximal test statistics at the correct marker position, but the components of variance procedure provided more power to detect the correct position than other methods.

Cystic fibrosis transmembrane regulator gene carrier status is a risk factor for young onset pancreatic adenocarcinoma

Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the USA. Although predominantly a cancer of the elderly, approximately 20% of patients are diagnosed under the age of 60 years. Younger patients are likely the best candidates for early surgical intervention, and patients at risk for young onset cancer comprise a logical focus for screening or prevention. Carriers of mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator ( CFTR ) are associated with chronic idiopathic pancreatitis.1 Chronic pancreatitis, in turn, increases the risk for pancreatic cancer by 26-fold.2 Therefore, we hypothesised that mutations in CFTR may confer a higher risk of pancreatic cancer. From October 2000 to April 2004, pancreatic cancer patients seen at the Mayo Clinic were ultra rapidly recruited to our study, with more than 75% of all such patients seen at the Mayo …

Assessing linkage on chromosome 5 using components of variance approach: Univariate versus multivariate

We report results when one disease related quantitative trait (Q1) is analyzed versus multiple related quantitative traits using a components of variance approach [Amos, 1994; de Andrade and Amos, 1996]. In both cases, we used age, sex and environmental factor (EF) as covariates. Analysis with ascertainment correction of samples selected through probands with extremely high trait values was also performed and is presented. Testing procedures to detect linkage using the components of variance approach are discussed. The univariate and multivariate analyses showed effects of locus 15 on chromosome 5 only for Q1. This result was confirmed when using ascertainment correction.