Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 29,120 posts. Searching is done in the search box in upper left corner. I blog on anything to do with stroke.DO NOT DO ANYTHING SUGGESTED HERE AS I AM NOT MEDICALLY TRAINED, YOUR DOCTOR IS, LISTEN TO THEM. BUT I BET THEY DON'T KNOW HOW TO GET YOU 100% RECOVERED. I DON'T EITHER, BUT HAVE PLENTY OF QUESTIONS FOR YOUR DOCTOR TO ANSWER.
Changing stroke rehab and research worldwide now.Time is Brain!trillions and trillions of neuronsthatDIEeach day because there areNOeffective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.
What this blog is for:
My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.
Friday, April 5, 2019
Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China
Moderate
alcohol intake has been associated with reduced cardiovascular risk in
many studies, in comparison with abstinence or with heavier drinking.
Studies in east Asia can help determine whether these associations are
causal, since two common genetic variants greatly affect alcohol
drinking patterns. We used these two variants to assess the
relationships between cardiovascular risk and genotype-predicted mean
alcohol intake in men, contrasting the findings in men with those in
women (few of whom drink).
Methods
The
prospective China Kadoorie Biobank enrolled 512 715 adults between June
25, 2004, and July 15, 2008, from ten areas of China, recording alcohol
use and other characteristics. It followed them for about 10 years
(until Jan 1, 2017), monitoring cardiovascular disease (including
ischaemic stroke, intracerebral haemorrhage, and myocardial infarction)
by linkage with morbidity and mortality registries and electronic
hospital records. 161 498 participants were genotyped for two variants
that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984.
Adjusted Cox regression was used to obtain the relative risks
associating disease incidence with self-reported drinking patterns
(conventional epidemiology) or with genotype-predicted mean male alcohol
intake (genetic epidemiology—ie, Mendelian randomisation), with
stratification by study area to control for variation between areas in
disease rates and in genotype-predicted intake.
Findings
33%
(69 897/210 205) of men reported drinking alcohol in most weeks, mainly
as spirits, compared with only 2% (6245/302 510) of women. Among men,
conventional epidemiology showed that self-reported alcohol intake had
U-shaped associations with the incidence of ischaemic stroke (n=14 930),
intracerebral haemorrhage (n=3496), and acute myocardial infarction
(n=2958); men who reported drinking about 100 g of alcohol per week (one
to two drinks per day) had lower risks of all three diseases than
non-drinkers or heavier drinkers. In contrast, although
genotype-predicted mean male alcohol intake varied widely (from 4 to 256
g per week—ie, near zero to about four drinks per day), it did not have
any U-shaped associations with risk. For stroke, genotype-predicted
mean alcohol intake had a continuously positive log-linear association
with risk, which was stronger for intracerebral haemorrhage (relative
risk [RR] per 280 g per week 1·58, 95% CI 1·36–1·84, p<0·0001) than
for ischaemic stroke (1·27, 1·13–1·43, p=0·0001). For myocardial
infarction, however, genotype-predicted mean alcohol intake was not
significantly associated with risk (RR per 280 g per week 0·96, 95% CI
0·78–1·18, p=0·69). Usual alcohol intake in current drinkers and
genotype-predicted alcohol intake in all men had similarly strong
positive associations with systolic blood pressure (each p<0·0001).
Among women, few drank and the studied genotypes did not predict high
mean alcohol intake and were not positively associated with blood
pressure, stroke, or myocardial infarction.
Interpretation
Genetic
epidemiology shows that the apparently protective effects of moderate
alcohol intake against stroke are largely non-causal. Alcohol
consumption uniformly increases blood pressure and stroke risk, and
appears in this one study to have little net effect on the risk of
myocardial infarction.
Funding
Chinese
Ministry of Science and Technology, Kadoorie Charitable Foundation,
National Natural Science Foundation of China, British Heart Foundation,
Cancer Research UK, GlaxoSmithKline, Medical Research Council, and
Wellcome Trust.
in many prospective studies moderate intake (about one to two drinks
per day, or 100 g of alcohol per week) is associated with somewhat lower
incidence of stroke and myocardial infarction than no alcohol intake.
However, these apparently protective associations do not necessarily
mean that moderate alcohol intake itself is protective against either
condition. For, poor health might affect alcohol consumption (reverse
causality), and other systematic differences might exist between people
with different drinking patterns that were not fully allowed for
(residual confounding).
have shown that alcohol intake causes changes in physiological factors
such as blood pressure, HDL cholesterol, adiponectin, and fibrinogen,
but such trials cannot reliably assess realistic effects on the
incidence of stroke or myocardial infarction.
The
question of whether there are any real protective effects of moderate
alcohol intake can be investigated genetically (by Mendelian
randomisation),
particularly in populations where there are common genetic variants
that alter alcohol metabolism but, since few women drink, strongly
influence alcohol intake only in men. Alcohol is metabolised to
acetaldehyde, which can cause discomfort if too much accumulates before
it is broken down (panel, table 1), and there are genetic variants that importantly affect acetaldehyde formation and breakdown.
* ALDH2
is a tetramer of the ALDH2 gene product that requires all four parts to
be functional, so a loss-of-function variant is nearly dominant. ADH1
is a dimer that requires two functional parts from the products of any
of three similar genes, ADH1A, ADH1B, and ADH1C.
† For ALDH2 and ADH1B, each of these amino acid changes can be described as altering the “*1” into the “*2” enzyme isoform.
‡ The ADH1B-rs1229984 east Asian variant is nearly dominant, with AA and AG having similar effects on alcohol intake.
The ALDH2-rs671
variant, which is common only in east Asian populations, greatly slows
acetaldehyde breakdown, and the resulting accumulation of acetaldehyde
can cause severe discomfort that strongly reduces alcohol intake.
Studies of this variant have confirmed the trial evidence that alcohol
causally affects blood pressure and some other physiological traits.
A less important genetic variant, ADH1B-rs1229984, accelerates alcohol conversion to acetaldehyde and reduces alcohol intake.
Using
data from the nationwide China Kadoorie Biobank prospective study, we
investigated the causal relationships between alcohol and cardiovascular
disease by comparing the findings from conventional epidemiology
(classifying people by self-reported intake) and from genetic
epidemiology (using these two variants to classify people by
genotype-predicted mean alcohol intake). Since few Chinese women drink,
these genetic variants can be used to predict large absolute differences
in mean alcohol intake in men, but not in women. Hence, if alcohol
itself substantially affects the incidence of stroke or myocardial
infarction then these two genetic variants should affect disease
incidence differently in men and in women.
is a prospective cohort study of 512 715 adults recruited between June
25, 2004, and July 15, 2008, from ten diverse rural and urban areas of
China. All permanent residents (aged 35–74 years) without known major
disabilities were to be invited into the baseline survey, and 499 500
(28% of 1 801 167 invitees) participated, along with 13 215 who were
just outside the target age range. Ethics approval was obtained from
relevant local, national, and international ethics committees, and all
participants provided written informed consent.
At
baseline, participants attended survey clinics where interviewers using
laptop-based questionnaires recorded socioeconomic status, medical
history, smoking, drinking, diet, and physical activity. Measurements
included height (sitting and standing), weight, waist and hip
circumference, heart rate, and blood pressure. A non-fasting blood
sample was collected for long-term storage. Similar procedures were
followed at two separate resurveys of 4–5% of all participants
(resurveying 19 786 between May 26, 2008, and Oct 10, 2008, and 25 041
between Aug 4, 2013, and Sept 18, 2014).
Alcohol drinking patterns
Past and current alcohol drinking patterns were self-reported.
Participants were classified as current drinkers (some alcohol use in
most weeks in the past year), non-drinkers (no alcohol use in the past
year and never drank in most weeks), occasional drinkers (occasional
alcohol use in the past year but never drank in most weeks), or
ex-drinkers (none or occasional alcohol use in the past year but
previously drank in most weeks). In current drinkers, baseline alcohol
intake (from main beverage type, amount, and frequency) was
subclassified according to sex: for men, the groupings were less than
140, 140–279, 280–419, and 420 or more g per week and for women, less
than 70 and 70 or more g per week. For each of these baseline-defined
groups the usual alcohol intake was estimated from intake at the
resurveys. Further details of alcohol assessment are described in the appendix (p 4).
Follow-up for incident cardiovascular disease
Incident
cardiovascular disease and cause-specific mortality were ascertained
through ongoing linkage, via the unique national identification number,
to electronic hospital records from the nationwide health insurance
system (which has >98% coverage across the ten study areas), to
established local registries of stroke and coronary heart disease, and
to local death registries. The insurance records included information
about every hospital admission, and evidence of cardiovascular disease
was reviewed and coded according to the International Classification of
Diseases, tenth revision. The diseases analysed were ischaemic stroke,
intracerebral haemorrhage, total stroke, acute myocardial infarction,
and total coronary heart disease (first non-fatal or fatal record of
each; appendix p 4).
Genotyping and biochemistry
161 498
participants were genotyped for the two variants of interest, rs671 and
rs1229984, using custom Illumina Golden Gate or Affymetrix Axiom arrays
at BGI (Shenzhen, China). They included 151 028 randomly selected
participants (used in all genetic analyses) and an additional 10 470
participants (used only in analyses of stroke and coronary heart
disease) who had been selected because during follow-up they had had a
stroke or coronary heart disease recorded.
18 256
participants (who had been selected for nested case-control studies of
stroke and of coronary heart disease) were assayed for plasma HDL
cholesterol, LDL cholesterol, triglycerides, lipoprotein(a), C-reactive
protein, fibrinogen, and γ-glutamyl transferase at the Wolfson
Laboratory (Clinical Trial Service Unit, Oxford, UK). Of them, 98%
(17 874) were among those genotyped for the above two variants. Further
details of genotyping and biochemistry are in the appendix (p 4).
Mean alcohol intake by genotype and area
Combinations
of the genotypes for the two genetic variants of interest (rs671 and
rs1229984; each AA, AG, or GG) define nine genotypes (panel). Since alcohol use varies greatly by study area,
in each of the ten study areas mean male alcohol intake was calculated
for each of these nine genotypes (assigning occasional drinkers an
intake of 5 g per week and excluding ex-drinkers, which effectively
assigns them the mean intake in other participants in their area). The
90 combinations of genotype and area were subdivided into six categories
(1–6) according to these 90 mean values, with cutoff points of 10, 25,
50, 100, and 150 g per week (figure 1).
Classification of individual participants into the six categories was
dependent only on their genotype and study area, not on their individual
drinking patterns. Women were classified into the same six categories
of genotype and area as men, regardless of their drinking patterns, to
facilitate comparison between genotypic effects in men and in women.
Figure 1Mean
alcohol intake in men from ten study areas in China, subdivided by nine
possible genotypes of two common variants that alter alcohol metabolism
General
linear models were used to assess associations with continuous
variables (eg, systolic blood pressure), giving the adjusted mean values
in each of several exposure groups. These exposure groups were defined
either by self-reported alcohol drinking patterns or by categories of
genotype and area. Cox regression was used to assess associations with
disease rates, giving the relative risks (RRs) of disease incidence in
each exposure group, after specifying one of these as the reference
group (RR=1). The variance of the log risk in each group, including the
reference group, was calculated (from the variances and covariances of
the log RRs in all groups except the reference group) and used to obtain
group-specific 95% CIs.
Participants with a previous history of coronary heart disease, stroke,
or transient cerebral ischaemia were excluded from the analyses of
disease incidence. Analytic models and sensitivity analyses are
described in the appendix (pp 5, 6).
Conventional
epidemiological analyses related individual drinking patterns to
physiological factors, or to the RRs for disease. They were adjusted for
area, age, education, income, and smoking. To avoid the regression
dilution bias,
among current drinkers the means or log RRs were plotted against the
usual alcohol intake, along with straight lines of best fit. The slopes
of these lines were described in terms of the change in the mean, or in
the RR, per 280 g per week (ie, around four drinks per day) usual
alcohol intake. Occasionally the RR per 100 g per week was also
calculated, as described in the appendix (p 6).
Genetic
epidemiological analyses related genotype and study area (categorised
as described above) to physiological factors, or to the RRs for disease.
These analyses were stratified by area (so any differences in outcome
between the six categories of genotype and study area reflect purely
genotypic effects) and were adjusted only for age (although sensitivity
analyses also adjusted them for education, income and smoking). Means or
log RRs were plotted against the mean alcohol intake among the men in
each of the six categories. Within each study area a similar analysis
was done, and then the slope of the straight line of best fit related
outcome to exposure in that one area. To obtain a meta-analysis of these
within-area slopes (each reflecting purely genotypic effects), an
inverse-variance weighted mean of them yielded the overall slope,
stratified by area. Slopes were described in terms of the change in the
mean, or in the RR, per change of 280 g per week in genotype-predicted
mean male alcohol intake.
Genotypic
analyses in women were done not to assess the effects of alcohol in
women (since women's alcohol intake was known to be minimal), but to
determine the extent to which the genotypes studied in men had
pleiotropic effects
(ie, effects of the genotype that were not mediated by drinking
patterns). Hence, we used the same six categories of genotype and area
as in men, relating the area-adjusted genotypic effects in women to the
mean male alcohol intake in these six categories.
For
men and for women we also calculated as sensitivity analyses
(stratified by area and adjusted for age) the separate genotypic effects
of each of the two variants. SAS (version 9.3) and R (version 3.2.1)
were used for all statistical analyses.
Role of the funding source
The
funders of the study had no role in study design, data collection, data
analysis, data interpretation, or writing of the report. IYM, RGW, LL,
RP, and ZC had access to all data and had final responsibility for the
decision to submit for publication.
Results
From
the ten study areas, 512 715 participants were enrolled (226 182 urban
and 286 533 rural residents, mean age 52 years [SD 11]) and followed for
incident cardiovascular disease. By Jan 1, 2017, after around 10 years
of follow-up, 4781 (0·9%) had been lost and 44 037 (8·6%) had died. At
baseline, 33% (69 897/210 205) of the men and 2% (6245/302 510) of the
women reported drinking some alcohol in most weeks, mainly as spirits,
but there was wide variation in the prevalence of drinking across study
areas (appendix pp 11, 12).
For
161 498 of the participants two G→A single-nucleotide polymorphisms
that alter alcohol metabolism were genotyped (rs671 and rs1229984; panel).
For rs671 the overall A-allele frequency was 0·21 (range by area
0·13–0·29) and for rs1229984 it was 0·69 (0·64–0·74), with both
A-alleles tending to be more common in southern than in northern study
areas (appendix p 13). For each variant, the genotype frequencies within each area were consistent with Hardy-Weinberg equilibrium.
The
more important variant, rs671, strongly affected drinking patterns:
among men, mean alcohol intake with its AA, AG, and GG genotype was 3,
37, and 157 g per week, respectively, and the proportion of current
drinkers was 1%, 16%, and 45%. The other variant, rs1229984, had a
definite but smaller effect: among men, mean alcohol intake with its AA,
AG, and GG genotype was 98, 106, and 157 g per week, respectively, and
the proportion of current drinkers was 32%, 33%, and 43%. Among current
drinkers, each variant was associated with flushing after drinking a
small amount of alcohol, but the effect was much stronger with rs671 (appendix p 14).
Combinations
of the rs671 genotype (AA, AG, or GG) and the rs1229984 genotype define
nine possibilities for the joint rs671/rs1229984 genotype (panel).
When written in alphabetic order from AA/AA to GG/GG, within each of
the ten study areas these nine genotypes tended to involve progressively
increasing mean male alcohol intake, with larger absolute differences
between genotypes in areas where average intake was higher (figure 1).
In Sichuan (the area with the highest levels of alcohol consumption)
mean male alcohol intake ranged from 2 g per week for individuals with
the AA/AA genotype to 443 g per week for those with the GG/GG genotype,
whereas in Gansu (the area with the lowest levels of alcohol
consumption) it ranged from 1 g per week to only 29 g per week (appendix p 15).
Figure 1
shows how the 90 combinations of genotype and study area were divided
into six categories, depending on the mean male alcohol intake in each
combination. The prevalence of drinking was more than 20 times higher in
category 6 than in category 1, and mean alcohol intake was more than 50
times higher (figure 2).
Comparisons between these six categories can, as long as they are
stratified by area, be used to estimate purely genotypic effects on
disease rates and other factors. Apart from the large differences in
drinking patterns there were no large genotype-dependent differences
between these six categories in smoking or in other self-reported
baseline characteristics (appendix p 19).
Figure 2Patterns of alcohol use in six categories of genotype and study area
Subsequent
analyses compared conventional epidemiological analyses (relating
individual drinking patterns to various factors) and genetic
epidemiological analyses (which ignore individual drinking patterns, and
for all men relate differences between the six categories in mean
alcohol intake to genotype-dependent differences between them in other
factors). Among men, blood pressure and the concentrations (where
available) of HDL cholesterol and γ-glutamyl transferase were positively
associated with alcohol intake in both conventional and genetic
epidemiological analyses (all p<0·0001; figure 3). Among current drinkers, the mean alcohol intake was about 280 g per week (appendix p 12)
and systolic blood pressure increased by 4·8 mm Hg (95% CI 4·5–5·1) per
280 g per week usual alcohol intake. Similarly, systolic blood pressure
increased by 4·3 mm Hg (3·7–4·9) per 280 g per week genotype-predicted
mean alcohol intake. The increase in HDL cholesterol per 280 g per week
alcohol intake was also similar in the conventional and in the genetic
analyses. Associations with other physiological factors are shown in the
appendix (p 21).
Figure 3Associations of physiological factors with drinking patterns and with genotypic determinants of mean alcohol intake, in men
For
male stroke rates, however, conventional and genetic epidemiological
analyses yielded very different findings. In the conventional
epidemiological analyses of stroke incidence rates among men,
self-reported alcohol intake had a U-shaped association with the
incidence of ischaemic stroke, intracerebral haemorrhage, and total
stroke (figure 4).
Moderate alcohol intake (about 100 g per week) was associated with a
risk of stroke lower than that in non-drinkers or, particularly,
ex-drinkers. Among current drinkers, stroke risk increased with the
usual alcohol intake, with a smaller proportional increase for ischaemic
stroke (RR per 280 g per week 1·28, 95% CI 1·19–1·38, p<0·0001) than
for intracerebral haemorrhage (1·59, 1·37–1·85, p<0·0001; p=0·01 for
the difference between these RRs). U-shaped associations with alcohol
intake persisted in sensitivity analyses that excluded early follow-up,
ever-smokers, and people with poor self-reported health at baseline (appendix pp 23, 24).
Figure 4Associations of stroke incidence with drinking patterns and with genotypic determinants of alcohol intake, in men
In
the genetic epidemiological analyses, however, there were no U-shaped
associations with stroke risk and there was no evidence of any
protective effects of moderate alcohol intake against ischaemic stroke,
intracerebral haemorrhage, or total stroke (figure 4).
Stroke risk increased steadily across the whole range of
genotype-predicted mean male alcohol intake (4–256 g per week), again
with a smaller proportional increase for ischaemic stroke (RR per 280 g
per week 1·27, 95% CI 1·13–1·43, p=0·0001) than for intracerebral
haemorrhage (1·58, 1·36–1·84, p<0·0001; p=0·01 for the difference
between these RRs) or total stroke (1·38, 1·26–1·51). The mean intake in
all men was about 100 g per week (appendix p 12),
and the corresponding RRs per 100 g per week were 1·09 (1·04–1·14),
1·18 (1·12–1·24), and 1·12 (1·09–1·16), respectively. Adjusting for
potential confounders in sensitivity analyses did not materially change
the results (appendix p 25).
The
genotypic analyses provided no suggestion of increased stroke risk at
very low levels of alcohol intake (although in the first of the six
categories two-thirds were non-drinkers), or of any material deviation
from log-linear relationships (figure 4).
Even if, for statistical stability, the three categories with the
lowest alcohol intake (categories 1–3, mean male intake around 25 g per
week) were pooled and compared with categories 4 and 5 (mean male intake
around 100 g per week), the genotypic analyses still indicated adverse
rather than protective effects of moderate alcohol intake against
ischaemic stroke and against intracerebral haemorrhage (appendix p 26).
The corresponding genotypic findings within each separate study area
were directionally consistent with each other, and with the overall
findings (appendix p 28). For blood pressure and for stroke, the slopes of the lines in Figure 3, Figure 4
appeared to be greater for men younger than age 60 years at baseline
than for other men, but the numbers were insufficient for this
dependence on age to be reliable (appendix p 30).
For male coronary heart disease, conventional epidemiology and genetic epidemiology again yielded different findings (figure 5).
In the conventional epidemiological analyses, there were U-shaped
associations with risk. Moderate alcohol intake was associated with
rates of acute myocardial infarction and of total coronary heart disease
that were substantially lower than the rates in non-drinkers or
ex-drinkers (and this apparently protective effect of moderate versus no
alcohol intake persisted in sensitivity analyses; appendix p 32).
Among current drinkers, usual alcohol intake was weakly positively
associated with heart disease; the RR per 280 g per week was 1·15 (95%
CI 0·96–1·38, p=0·14) for acute myocardial infarction and 1·12
(1·04–1·21, p=0·003) for total coronary heart disease.
Figure 5Associations
of coronary heart disease incidence with drinking patterns and with
genotypic determinants of alcohol intake, in men
In
the genetic epidemiological analyses, however, there was no clear
evidence of any net protective effect of moderate alcohol consumption
against acute myocardial infarction or total coronary heart disease (figure 5).
Across the whole range of genotype-predicted mean male alcohol intake,
the RR per 280 g per week was 0·96 (95% CI 0·78–1·18, p=0·69) for acute
myocardial infarction and 1·05 (0·94–1·17, p=0·40) for total coronary
heart disease.
Among women, mean alcohol intake was low in all six categories of genotype and area (figure 2).
Hence, any genotypic effects of these categories that are mediated by
drinking patterns should be much smaller in women than in men, but any
other (ie, pleiotropic) genotypic effects of them should be comparable
in both sexes. To assess any pleiotropic effects on physiological
factors or disease rates, the findings in men and in women are compared (table 2),
relating the genotypic effects in both sexes to the mean alcohol intake
only in men. Among women, systolic blood pressure, HDL cholesterol,
γ-glutamyl transferase, ischaemic stroke, intracerebral haemorrhage, and
acute myocardial infarction were not adversely associated with the
genotypes that increase alcohol intake in men—indeed, blood pressure
was, if anything, slightly favourably affected. After allowance for
multiple testing, no material genotypic effects on other physiological
factors were identified in women, except for increases of a few mm per
allele in height, waist, and hip measurements (appendix p 21).
Table 2Comparison between genotypic effects in men and in women
* Six
categories of genotype and study area; mean values of physiological
factors and RRs of disease are adjusted for age and area, leaving only
genotypic differences.
† Genotypic
effect on physiological factor (slope per 280 g per week mean MALE
alcohol intake) or on disease incidence (RR per 280 g per week mean MALE
alcohol intake); since women consumed little alcohol, comparison
between these genotypic effects in men and in women can help assess
whether the genotypic effects in men are chiefly mediated by alcohol
rather than by pleiotropic pathways that influence both sexes similarly.
Sensitivity analyses considered the two genetic variants separately (appendix pp 36–40).
Among women, there were no significant associations of either variant
with stroke or heart disease. The following results involve only men,
and assess the effects of a single copy of the variant allele. For
rs671, participants with the GG genotype had substantially higher mean
alcohol intake, systolic blood pressure, HDL cholesterol, and γ-glutamyl
transferase than did those with the AG genotype, and had a definite
excess risk of stroke (GG vs AG: RR 1·19, 1·13–1·24,
p<0·0001), though not of myocardial infarction (1·02, 0·92–1·13). For
rs1229984, the effects on alcohol intake and on these three
physiological factors were only about half as great, but again there was
a definite excess risk of stroke (GG vs AG: RR 1·19, 1·11–1·27, p<0·0001), but not of myocardial infarction (1·11, 0·95–1·31).
Discussion
Our
aim is to assess causal effects of alcohol intake that should be of
general relevance in any population, not just effects of particular
genotypes in one east Asian population. Nevertheless, genotypic studies
in China can provide generally relevant evidence about causal effects of
alcohol intake. For, two genetic variants that greatly alter alcohol
metabolism are common in China, the more important of which (rs671)
reduces alcohol intake to almost zero in both sexes. In our population
men drink more than 20 times as much as women, so these two variants
have large absolute effects on alcohol intake only among men. This
permits reliable comparison of the causal effects of negligible,
moderate, and higher levels of mean male alcohol intake. In populations
of European descent, however, only the less important of these two
variants (rs1229984) is found, so genetic studies
cannot directly compare the effects of negligible and moderate alcohol intake levels.
Mainly
for cultural rather than genetic reasons, alcohol intake differed
substantially across our ten study areas. After grouping all possible
combinations of genotype and study area into six categories according to
mean male alcohol intake, there was wide variation between these six
categories in mean intake, ranging from almost no alcohol to a mean of
about 25 drinks per week among men. By contrast, mean alcohol intake was
low among women in all six categories. Hence, the findings among women
are used mainly to show that the genotypic findings among men were
mediated chiefly by alcohol rather than by any other (ie, pleiotropic)
effects of genotype. Although the category definitions were dependent on
both genotype and study area, the genetic epidemiological analyses
allowed fully for area. So, the findings from them reflect only the
effects of within-area differences in genotype.
A meta-analysis of the findings from conventional epidemiological analyses of 83 prospective studies,
mainly in populations of European descent, excluded non-drinkers and
found that, among drinkers, stroke incidence increased steadily with the
amount of alcohol consumed, whereas the incidence of myocardial
infarction was slightly higher in drinkers whose usual intake was only
35 g per week rather than 100 g per week, and was approximately constant
over the range of 100–350 g per week. Conventional epidemiological
analyses of the present study in China are consistent with this
meta-analysis,
have shown that alcohol increases blood pressure and HDL cholesterol.
The associations between alcohol and these factors were strongly
positive in our conventional epidemiological analyses among current
drinkers (which relate usual alcohol intake to outcome) and were
similarly strongly positive in our genetic epidemiological analyses
(which relate genotype-predicted mean male alcohol intake to outcome).
Both types of analysis indicated that 280 g per week of alcohol
increases systolic blood pressure by about 5 mm Hg, which (in
conventional analyses of blood pressure and risk in this population) is
associated with increases of about 15% in ischaemic heart disease and
ischaemic stroke, and of about 30% in intracerebral haemorrhage.
For
ischaemic stroke and, more strongly, for intracerebral haemorrhage, the
genetic epidemiological comparisons across our six categories show that
risk increases continuously across the whole range from negligible to
high genotype-predicted mean intake, with no excess risk in the first of
these categories (in which two-thirds of individuals do not drink at
all and most others drink only occasionally; appendix p 17).
These comparisons also show that stroke risk is about as strongly
positively related to genetically predicted mean alcohol intake as it is
with the usual alcohol intake among current drinkers. Neither of these
two findings is what would be expected under the hypothesis that, in
comparison with abstinence, moderate drinking is substantially
protective (appendix pp 41, 42).
For, the decrease across categories in the proportions exposed to the
hypothesised excess risks of abstinence would oppose the increase across
categories in the proportions exposed to the excess risks of heavier
drinking.
Taken together, these two
findings mean that the lower stroke risks in moderate drinkers than in
non-drinkers that have been suggested by conventional epidemiological
analyses of this and previous studies were not chiefly due to protective
effects of moderate drinking, and may well have reflected biases of
reverse causation or confounding.
If
(but only if) there is no material protective effect, and the causal
relationship of alcohol intake to stroke risk is approximately
log-linear rather than U-shaped, then the genetic epidemiology provides a
direct quantitative estimate of the strength of that causal
relationship. In the genetic epidemiological analyses, the excess risks
of ischaemic stroke and intracerebral haemorrhage were 27% and 58% per
280 g alcohol per week, respectively. This alcohol intake is
approximately the mean amount consumed by the one-third of all men who
were current drinkers. Hence, the genetic findings imply that, among all
men, alcohol was responsible for about 8% of ischaemic strokes and 16%
of intracerebral haemorrhages.
These excess stroke risks are about twice as great as expected just from the effects of alcohol on systolic blood pressure.
This discrepancy might be because blood pressure differences due to
these genetic factors persist throughout adult life, or because
transient effects of alcohol on blood pressure (and hence on stroke
risk) are greater at other times than at our daytime recruitment
clinics, or because of adverse effects of alcohol on factors other than
blood pressure.
For each of the two
genetic variants, the A allele was nearly dominant in its effects on
alcohol intake, physiological factors, and stroke, but although the
decreases in alcohol intake and physiological factors with one A allele
versus none were less than half as great for rs1229984 as for rs671, the
corresponding decreases in stroke appeared surprisingly similar (appendix pp 44, 45).
This apparent discrepancy may, unless it is a chance finding, be
because rs1229984 reduces alcohol exposure both through reducing alcohol
intake and, for a given intake, through accelerating alcohol clearance.
For
heart disease, the genetic epidemiological analyses are more difficult
to interpret reliably. For acute myocardial infarction, they suggest
little net effect on risk over the range from near zero to about 250 g
per week of predicted mean intake. This is what would be expected if
moderate alcohol intake is not really protective, and if (as in the
meta-analysis of previous conventional studies
)
increased intake is not really hazardous above the range of intakes
studied. The number of cases of acute myocardial infarction was,
however, limited, so some real benefit or hazard cannot be excluded.
Considering the two variants separately, our findings for rs1229984
(based on small numbers) are consistent with previous meta-analyses in
European-origin populations,
but our findings for rs671 do not support previous meta-analyses in
east Asian populations, which suggested a moderate association between
the alcohol-tolerant rs671 allele and decreased coronary heart disease
risk.
The
lack of a positive association between genotype-predicted alcohol
intake and acute myocardial infarction suggests the adverse effects of
alcohol intake on blood pressure could be offset by cardio-protective
changes in other factors. Although HDL cholesterol increased
substantially with alcohol intake, the causal relevance of different
components of HDL cholesterol to coronary heart disease risk remain
uncertain. A previous trial
of the cholesteryl ester transfer protein inhibitor anacetrapib, which
substantially increases HDL cholesterol, reported a coronary heart
disease reduction that was no greater than would be expected just from
the LDL-cholesterol-lowering effects of the drug, and in previous
analyses
of the China Kadoorie Biobank study, a loss-of-function variant of the
cholesteryl ester transfer protein that substantially increases total
HDL cholesterol had little net effect on the incidence of coronary heart
disease.
A major limitation of all
alcohol epidemiology is that exposure is uncertain. Drinking patterns
are variable, and intake may be substantially underperceived or
under-reported. If mean intake was really substantially higher than
reported, then all our conventional and genotypic dose-response
relationships are too steep, and the real relationships are
substantially shallower. Conversely, our genotypic dose-response
relationships would have been about 10% stronger if our calculations of
mean intake had included ex-drinkers, whose previous intake was unknown,
as having zero intake rather than the mean intake of other participants
(appendix p 17).
Since
participants reported drinking mainly spirits, the effects of other
drinks (eg, red wine) could not be assessed. Although many biomarkers
were measured, they might not capture some important mechanisms by which
alcohol could affect myocardial infarction risk. The two enzymes
affected by the genetic variants we studied are involved in many
biochemical pathways, so increases or decreases in their activity could
have multiple physiological effects.
In women, however, there were no material genotypic associations with
cardiovascular risk or physiological factors, with the exception of
small effects on anthropometry and, perhaps, blood pressure. Hence, the
genotypic findings in men were probably driven mainly by alcohol
exposure rather than by pleiotropic effects.
The
genetic epidemiological analyses in this large study do not support the
apparently protective effects against stroke of moderate drinking when
compared with no drinking that are suggested by conventional
epidemiological analyses. Although alcohol increases blood pressure, we
identified no clear net association with acute myocardial infarction,
but the number of cases was limited. The number of strokes, however, was
substantial, and the genetic epidemiological analyses show that alcohol
intake uniformly increases blood pressure, ischaemic stroke, and
haemorrhagic stroke.
31772-0&id=gr1.jpg){kind=link}
31772-0&id=gr2.jpg){kind=link}
31772-0&id=gr3.jpg){kind=link}
31772-0&id=gr4.jpg){kind=link}
31772-0&id=gr5.jpg){kind=link}
No comments:
Post a Comment