Smoking and reverse cholesterol transport: evidence for gene-environment interaction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66077/1/j.1399-0004.1989.tb03201.x.pd

Interpretation of Genetic Association Studies: Markers with Replicated Highly Significant Odds Ratios May Be Poor Classifiers

Recent successful discoveries of potentially causal single nucleotide polymorphisms (SNPs) for complex diseases hold great promise, and commercialization of genomics in personalized medicine has already begun. The hope is that genetic testing will benefit patients and their families, and encourage positive lifestyle changes and guide clinical decisions. However, for many complex diseases, it is arguable whether the era of genomics in personalized medicine is here yet. We focus on the clinical validity of genetic testing with an emphasis on two popular statistical methods for evaluating markers. The two methods, logistic regression and receiver operating characteristic (ROC) curve analysis, are applied to our age-related macular degeneration dataset. By using an additive model of the CFH, LOC387715, and C2 variants, the odds ratios are 2.9, 3.4, and 0.4, with p-values of 10−13, 10−13, and 10−3, respectively. The area under the ROC curve (AUC) is 0.79, but assuming prevalences of 15%, 5.5%, and 1.5% (which are realistic for age groups 80 y, 65 y, and 40 y and older, respectively), only 30%, 12%, and 3% of the group classified as high risk are cases. Additionally, we present examples for four other diseases for which strongly associated variants have been discovered. In type 2 diabetes, our classification model of 12 SNPs has an AUC of only 0.64, and two SNPs achieve an AUC of only 0.56 for prostate cancer. Nine SNPs were not sufficient to improve the discrimination power over that of nongenetic predictors for risk of cardiovascular events. Finally, in Crohn's disease, a model of five SNPs, one with a quite low odds ratio of 0.26, has an AUC of only 0.66. Our analyses and examples show that strong association, although very valuable for establishing etiological hypotheses, does not guarantee effective discrimination between cases and controls. The scientific community should be cautious to avoid overstating the value of association findings in terms of personalized medicine before their time

The frequency in Japanese of genetic variants of 22 proteins: V. Summary and comparison with data on Caucasians from the British Isles

The frequencies in Hiroshima and Nagasaki of rare variants (represented in less than 2 % of the individuals surveyed) is summarized for a series of 22 proteins (25 polypeptides). The average number of persons examined for each protein was 3312. There are three pairs of homologous proteins in the series: PGM, and PGM, CA I and CA 11, and HGB A and A,. Only for the first pair is there a significant difference between the two in the total frequency and number of different kinds of variants; it is suggested this may reflect differences in the mutation rates of the corresponding structural genes. For 23 of these polypeptides, comparable data are available for British Caucasians. The average frequency of variants for loci in common in the two series is 2.0/1000 person determinations for Japanese and 1.6/1000 for Caucasoids. At two loci (PGMl and PHI) there were significantly more variants in Japanese than in British; these two loci account for the greater average frequency of variants in Japanese. However, a conservative comparison of number of diflerent variants (electromorphs) encountered, using the 0 statistic of Ewens (1972), yields no significant difference for any of the 22 possible contrasts. The potential usefulness of data of this type in reaching conclusions regarding comparability of mutation rates in two populations is discussed. For the present, the fact that one electromorph may shelter multiple different amino acid substitutions in a protein limits the inferences to be drawn from such contrasts. It is 8 pleasure to acknowledge our indebtedness to Dr Peter Smouse and Dr Warren Ewens for statistical consultations, but responsibility for the tentative interpretations is entirely our own.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66201/1/j.1469-1809.1978.tb00913.x.pd

Influence of apolipoprotein E genotype variation on the means, variances, and correlations of plasma lipids and apolipoproteins in children

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65894/1/j.1469-1809.1999.6340311.x.pd

Characterization of a new variant of human red cell carbonic anhydrase I, CA if London (Glu-102→Lys)

A new inherited variant of red cell carbonic anhydrase I (CA I), designated CA If London, was discovered during a survey of 1615 individuals from London, England. No electrophoretic variants of the other isozyme of carbonic anhydrase CA II, were observed in the same survey. Sequence analysis of a lysine-blocked tryptic peptide believed to contain the amino acid substitution in CA If showed that the glutamyl residue at position 102 had been substituted by a lysyl residue. This substitution results in a net increase of two positive charges in the mutant enzyme. Densitometric scanning of the electrophoretically separated forms in the variant hemolysate indicates that the levels of the normal and variant enzymes are approximately equal.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44118/1/10528_2004_Article_BF00485993.pd

The relationship between ciliary neurotrophic factor (CNTF) genotype and motor unit physiology: preliminary studies

BACKGROUND: Ciliary neurotrophic factor (CNTF) is important for neuronal and muscle development, and genetic variation in the CNTF gene has been associated with muscle strength. The effect of CNTF on nerve development suggests that CNTF genotype may be associated with force production via its influence on motor unit size and firing patterns. The purpose of this study is to examine whether CNTF genotype differentially affects motor unit activation in the vastus medialis with increasing isometric force during knee extension. RESULTS: Sixty-nine healthy subjects were genotyped for the presence of the G and A (null) alleles in the CNTF gene (n = 57 G/G, 12 G/A). They were tested using a dynamometer during submaximal isometric knee extension contractions that were from 10–50% of their maximal strength. During the contractions, the vastus medialis was studied using surface and intramuscular electromyography with spiked triggered averaging to assess surface-detected motor unit potential (SMUP) area and mean firing rates (mFR) from identified motor units. CNTF genotyping was performed using standard PCR techniques from DNA obtained from leucocytes of whole blood samples. The CNTF G/A genotype was associated with smaller SMUP area motor units and lower mFR at higher force levels, and fewer but larger units at lower force levels than G/G homozygotes. The two groups used motor units with different size and activation characteristics with increasing force generation. While G/G subjects tended to utilize larger motor units with increasing force, G/A subjects showed relatively less increase in size by using relatively larger units at lower force levels. At higher force levels, G/A subjects were able to generate more force per motor unit size suggesting more efficient motor unit function with increasing muscle force. CONCLUSION: Differential motor unit responses were observed between CNTF genotypes at force levels utilized in daily activities

The frequency in Japanese of genetic variants of 22 proteins

This paper presents the results of an electrophoretic survey of approximately 4000 individuals from the cities of Hiroshima and Nagasaki, Japan, for four serum proteins: albumin, ceruloplasmin, haptoglobin and transferrin. The haptoglobin gene frequencies obtained for the HP 1 -HP 2 polymorphism are in agreement with earlier reports. Rare electrophoretic variants of albumin, ceruloplasmin and haptoglobin occur with frequencies of 2.48, 0.50 and 0.58 per 1000 determinations, respectively. The noteworthy finding of 8 distinct transferrin variants in these populations, with a combined frequency of 20.90 per 1000 determinations, is also presented. Four of these variants (D Ch1 , B 1 , B 3 and D hir2 which corresponds electrophoretically to D 4 ) have been reported in other populations in Japan, but the other five have not previously been differentiated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66399/1/j.1469-1809.1977.tb01859.x.pd

Association between common alleles of the low-density lipoprotein receptor gene region and interindividual variation in plasma lipid and apolipoprotein levels in a population-based sample from Rochester, Minnesota

This paper presents an analysis of the relationship between variation in the low-density lipoprotein receptor (LDLR) gene region and interindividual variation in plasma lipid and apolipoprotein levels in a sample representative of the adult population of Rochester, Minn. (217 females and 187 males aged 26 to 63). This relationship was analyzed by estimating the average excesses of alleles of the LDLR gene defined using RFLP markers both singly and simultaneously. We also used a cladistic approach to illustrate the consequences of incorporating evolutionary information into the analysis of genotype-phenotype relationships. Although results from both approaches supported the inference that common variation in the LDLR gene region associates with small effects on plasma lipid and apolipoprotein levels, only the cladistic approach provides direction for further work aimed at identifying the functional DNA sequence variations responsible for the observed associations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42270/1/439-99-1-108_60990108.pd