.' 6
"
RESEARCH LETTERS
SHT, promoter polymorphism in
anorexia nervosa
Sandro Sorbi, Benedetta Nacmias, Andrea Tedde, Valdo RicCa,
Barbara Meuani, Carlo Maria RoteNa
A study' has shown an association between a polymorphism
(-1438GIA) in the promoter region of the 5-HT, gene and
anorexia nervosa. T w o independent groups failed to
replicate these data.'.'We studied chis polymorphism in N o
clinkal subrypcs of anorexia nervosa and in controls. We
analysed the segregation of this polymorphism in 77 female
patients with anorexia nervosa, according to DSM-W
criteria (43 restricting-type, body-mass index
14.9
[SD2.61 kg/m:', and 34 purging type, BMI 16.0 [le91 kglm',
15-34 yeam (mean age 24.58 [5.75] years). All patients or
their parents e:ave their informed written consent. We also
studied 107 ncmnal female age-matched controls (age 15-36
years, mean age 25.33 15.571 years), obtained from rhe D N A
bank of the CfiR (National Research Council, Rorence,
Ira!y). All cortuols were carefully assessed to exclude any
neurological or psychiatric disorders. DNA &om affected
and non-affected individuals was extracted from nansformed
lymphoblasts or peripheral blood samples with the phenolchloroform procedure. Amplification from 200 ng of
genomic DNA was done with a Thermal Cycler 9600
(Perkin Elmer). The - 1438G/A polymorphism was analysed
as previously 1described.lThe frequencies of 1438G/A alleles
were escimart:d by gene coundng. Statistical analysis was
done with the x* test.
The table shows the distribution of - 1438GIA alleles and
genotypes in the different groups. T h e distribution of
-1438G/A genotypes in all groups followed HardyWeinberg equilibrium. A significant difference in the
distribution of - 1 4 3 8 N A genotype was observed in
anorexia patients compared with the control group
(p<O~OOOl).' n e restricting type showed a high f?equency of
rhe -1438AIA genocype (41.86% in anorexic patients us
9.34% in co~ntrols; p<O~oOOl). Patients with the purging
type had a gznotype distribution similar to rht control group
(- 1438NA :L4#7%US 9.34%; p>O*l).
Our data lndependendy confirm and extend previous
results,' suggesting a role of the 5-HT, gene in anorexia.
Two other groups have reported negative results. However,
one study' had no controls and did not report the 1438NA
genotype in anorexia nervosa. Indeed, the - 1 4 3 8 N A
genorype is similar in all series of anorexia patients (0.3,'
0.25,' and 0*29), but Campbell's study showed a very high
frequency in the control group (0.2) compared wich the
othsr series (0-12' and 0.9 in our study). This difference in
controls may explain the dxerence in results. Our results
also suggest thar restricting and purging types of anorexia
nemosa have a different involvement of the 5-KT, gene
promoter polymorphism. This finding may lead to a better
understanding of the cwo types of this severe psychiatric
disease and suggests a different implication of the
serotonergic system in rhe pathogenesis and possibly in
a e a m e n t of anorexia nervosa.
[sm
-
ounp(m
M k -*r
-1430&/A
-14380/0 - 1 4 W
- 23-1438A/A
---(29.87%). 41 (53.24%) 13(1646%)
0435
-1438G
Amreiia nelyosa
(~77)
Anocexia restnciing
tyw ( n 4 3 )
AMfeKla purglni
type (n=%)
Controls (n=lO7)
0665'
18 (41,86%)' 21 (48.83%) 4 (9.30%) 0662'
5 (10.70%)
0.337
9 (26.47%) 0 4 1
0-558
56 (52.33%) 4 1 (38.31%) 0,355
0 644
20(%8?%)
L e k of association between 5-m, gene promoter polymorphism
mnd surcepribiliry KO anorexia nervosa. Lancet 1998; 351: 499.
Department of NeumlOg!cal and Psychletrlc Sclenw¶,Unlventty of
Florence, 60134 Florence, Italy (S Sarbi); Cas? dl Cum Vllla de) Plnl,
florence, Itaty: and Oepartment of Pathophyslolog, Unlvrrslty of
Rorence
5HT, promoter polymorphism
-1438G/A, anorexia nervosa, and
obsessivecompulsive disorder
MayAnne Enoch, Walter H Kaye, Atessandro Rotondo,
Benjamin D Greenberg, Dennis 1 Murphy, David Goldman
Hypothalamic serotonin (5-HT) dysfbnction has been
implicated in eacing disorders and obsessive-compulsi?e
disorder (OCD). Anorexia nervosa and OCD are heritable
and often comocbid disorden" that share several personality
traits, including h a m avoidance, perfectionism, and
obsessionaliry.' In this study we replicate M association of a
5-HTZ1-receptor promoter polymorphism, - 1438G/A, with
anorexia nervosa.' In addidon, we show that the assodation
elnends to OCD but not to bulimia nemosa, a disorder in
which the obsessive and perfection-seeking personaliry
fearures seen in anomia nervosa are less manifest.
We genotyped three independent sets of unrelated white
people for the -1438G/A 5-HT, polymorphism. One set was
from the USA, with 68 anorexics, 22 bulimics, and 69 normal
volunteers free of psychopathology; one set was from Italy,
with 20 anorexics and 37 bulimics; and another set was h m
the USA, with 62 padenrs with OCD and 144 normal controls
free of OCD but nor excluded for other psychopathology. AI1
p d c i p a n t s gave informed consenr under human-research
protocols approved by review boards at the relevant
insdrutions. AU were diagnosed with the suucturcd clinical
interview for DSM-III-R criteria. We followed previously
published methods' for genoryping.
As shown in the table, h e -1438A 5-HT, allele was more
common in US anorexics (0.51) than in controls (0.36,
~'=12*35, p<O.OOS). The genotype frequencies were also
different (x2=7-42, p<O-025). However, in U S bulimia
padents the 5-HT, -1438A allele frequency did not m e r
h m controls and was lower (0.34) than in patients with
anorexia (0.51, x'=16-71, p<0*005). T h i s finding was
replicated in an independent dataset of Italian eacing-disorder
padenrs. Here &e -1438 allele kequency in bulimics was 0.38
compared with 0.65 in anorexics (x2=1253, p<0.005) and
- 1438G/A genotypes and allele frequencies
knd@*mr
6uWPfwJerm
IfA
G/G
?/G
- 7 -
i
USA
Anorexia
MI
17 (0.25) 35 (0.61)
Bulimia
22
l(005) 1340.59)
6 ( 0 W a(0.55)
20
37
9 (0.45)
16 (0.24)
8(0361
25(0.36)
Controls69.- - - - -
w
Anorexia
Bulimia
- -6 USA
OCO
62
CONrOlS 144
All gmrype
10 (9.34%)
'D&W1.
Dlstdbutlonl of
Li T,Mupits D,Brown N, Trcasurc J.
1 Collier DA, Amnr MJ,
Associadon beween the 5-KT, gene promorer polymorphism and
anorcrdn oewosa. Lancet 1997; 350: 412.
2 K i ~ e A,
y Zieglcr A, Nothen MA,Remschmidt W, Hebebrand J.
S-HT, receptor gene polymoqhism, anorexic ncrvosa, and obniry.
L a n u t 1997; 350: 1324-22.
3 Campbell DA, Sundanmurthy D, Markham AF, Pien LF.
8 (040)
(0.16) 16 (0.43)
17 10.27) 28 (0.45)
25 (0.17) 69 (0,481
69 (0.51) 67 (049)
15(0*34) 29 ( O W
W(O.36) 88(0,64)
3 (0.15) 26 (0.651 14 (0.35)
15 (0.41) 28 (0.38) 46 (0.621
---
17 (0.27)
50 (0.35)
62 (0.50) 62 (0.501
119 (0.41) 169 (0.59)
bcguencies WNI in Harby-Weinbergequilibrium
Genotype and allele fmquencler of -1438Q/A M T , promoter
polymorphlrm In OCD and two populetlonr ol sstfn~dlrorder
patlenb
1785
genotype frequencies also differed (x2=6.784, pc0.05).
Finally, there was an increase in the frequency of the -438A
allele in patients with OCD (0.50) compared with controls
(0.41, x2=3,88, p<0.05), although genotype kequencies did
not differ.
These results suggest that &e S-HT, -1438G/A promoter
polymorphism, or a variant with which it is closely linked, may
contribute to a behavioural trait, for example perfectionism or
obsessionality, common to both a n o r e ~ anervosa and OCD
but uncommon in bulimia. The exact function of the 5-m,
receptor is unknown but it is thought to contribute to caring
behaviours and anxiety. These traits are associated with
anorexia nervosa and OCD.' 5-HT, is a Gprotein-coupled
receptor and controls signal transduction by activating
phospholipase C. It is not known whether the -1438G/A
alleles are functionally different. However, a functional
promoter variant might differentially alter transcription,
thereby affecdng receptor number. Our results suggest that
differences in 5-HT, function should correlate with
-1438G/A genotype and that these differences may be
detectable at either the level of 5-HT, binding or the
downstream effects of 5-W- activation.
I
Kaye W, Weluin ITE,Hsu LKG, Bulk C,McConaha C,
Sobkiewia T. Padenu with anorclja nervosa have evaluated scores on
h e Yale-Brown Obsessive-Compulsive Scale. / m y E a Dtjord 1992;12:
57-62.
Pigon TA,Alrcmur M, Rubenstein CS, era]. Symprornr of eating
disordcn in patienu with ob~ssivesornpulrivedisorder. Am 3
Rychimy 1991;148: 1552-57.
3 JawTr, Vaccarino FJ.Eadng disorder and obsessivc-compdsivc
2
disorder: neurochemical and phenomenological commonalides.
JnyChiaw NNIVI~'
1996; ZI(1): 36-41.
4 Collier DA,Amnz MJ, Li T,Mupita D, Brown N. h s o c i a w n bewccn
I-HT, gene promoter polymorphism and anoreda newosa. L n u r
1997;350: 412.
Laboratory of Heurofenetlcs, Natltlonal lwtttute on Alcohol Abwe and
hlcohollsrn, NaUonal lnstltute, of HeaM, Bethesdr, MD 208924ii0,
USA (M-A Enoch); M l n g Dlsoorben UnR. Western Rychlddc lnstltute
and Cllnlc, Unfvenfty of Pittsburgh Medlcal Cm!er, Ptttsburgh, PA, USA:
D e p a m n t 04 PIychlatry, UnkersRy of Plsa, P l a , ltatarr;and labomtoy a(
Cllnleal Sclence, Natlonal Instttute of Mental Health, Natlonal Instltuto
of Hestth, Eaumb
Follow-up of ventricular
preexcitation in Japanese
schoolchiIdren
Souichi Sano, Sadayoshi Komori, Takazoh Amano,
Kohji Tamura
We invesagated changes in ventricular pre-excitation during
growth with routine school medical examinations. AI1
schoolchildren in Yamanashi prefecwe (population 880 000)
must undergo medical examination, including an
electrocardiogram (ECG) when they enter elementary school
(aged 6-7 years), junior high school (12-13 yean), or high
school (1 5-1 6 years). Ventricular we-excitation was
diagnosed if PR interval was less than 0.12 s, 0" less than p
axis 90' or less, and there was a delta wave. We kept the
records of all schoolchildren with ventricular pre-excitation
since 1994. We have already reported that venuicular preexcitation ECC in younger schoolchildren is less hequent than
other reports,'-' and that the prevalence of venmcular preexcitation and left-sided accessory pathway increase with age.'
In a longitudinal study, we compared the prevalence of
venuicuular pre-excitation in the same students in the first year
of junior high school in 1994, and first year of high school in
1997. There were five students with pre-excitadon in 1994;
only two students had venmcular pre-excitation in 1994 and
in 1997. One of those was diagnosed as having intermittent
pre-excitation by ambulatory ECG. Two students with
1786
accessoly pathway had a normal ECG in 1997. We do not
know whttber pre-excitation disappeared or became
intermittent. One student diagnosed with pre-excitation in
I994 moved to anorher school district.
Eight students were newly diagnosed with pre-excitation in
1997; two of the eight students had a normal ECG in 1994.
Six sfudents were newly remgnised with accessory pathways
in 1997. 'There was no significant ditference in the prevalence
of pre-excitation in high-school students in 1997 and juniorhigh-school students in 1994. There was intermittent disappearance of accessory pathwayr in nine (75%) of 12 students.
In all, 13 students had pre-excited ECCs a t one of two
school medical examinations, end only five students were
detected at first school examination; sensitivity of first school
medical examination for diagnosis of pre-excitation was
385%. A single ECG at younger ages may not predict WolffParkinson-White syndrome in later life. Based on these
observations, we presume that more accessory pathways
become manifest in the ECG as children grow because
auiovenmcular conduction through the AV node slows with
age.
Klein GJ,Yee R, Sharma AD. bngitudinal electophyriologic
ssmsrncnt of asymptomrcic patienu wirh Wolff-Parkinson-White
elecuourdio@aphic pancm. N &ndJMed 1989;320: 1229-33.
2 Kmhn AD, Marhda J, R O ~ CE,
R Taw RB,Mahnvson FAL,
Cuddy TE The narunl history of clemocardiognphic prrntciudon in
men: The Maniioba follow-up study. Ann f n r m Mtd 1992;116:
I
45660.
3 Munger TM, Packer DL Hammill SC, et al. A popdadon study of h e
oanull Xistory of WOE-Puknson-Wrc syndrome in Olmsred County,
Minnesola, 1953-1989.Cirnclolwr 1993;87: 8 6 6 1 3 .
4 S u o S, Komori S, Amano T,et a!. The prevalence o l v t n m d a r
pre-excitarion in Japultrc schoolchildren. Hun 1998; 79: 374-78.
The Second Department of Internal Medlclne, YamMashl Medkal
Unlverslty, Tamaho, Nalukoma, YamaMshl40938, Japan ( S Sano) and
The Heart exam1udgntt-d commtttee of the medlul assoclatlon In
Yamanash1 pnfbctun
AB0 blood group and Inhaled nitric
oxide in acute respiratory distress
syndrome
Wrg Weimann, Hara\d Bauer, Luca Bigafello,
Kennefh 0 Bloch. Eike Martin, Warren M Z a p t
Xnhaladon of low concenuations of nimc oxide augments
arterial oxygenation in patients with the acute respiratory
distxess syndrome (ARDS).'However, 3 0 4 0 % of patients
with A R D S do not have an increase in arterial partial pressure
of oxygen (PaOl).'-l We investigated whether genetic factors
conmbute to che ability of inhaled nimc oxide to increase
oxygenation in patients with ARDS.
We reviewed the medical records of I38 patients (95 at
Massachusetts General Hospital and 43 a t University Hospital
Heidelberg) with ARDS (aged 20-85 years) who received
inhaled niuic odde in research protocoIs beween 1991 and
1997. The aetiology of A R D S in these padents included
infectious pneumonia (24), primary sepsis (19), lung resection
(18), trauma and bum injury (15), aspiration (13), acute
pancreatitis (four), and miscellaneous disorders (45). The
blood-group distniution was similar to chat in the normal
population. Mean (SE) baseline values, including the ratio of
PaO, to the fraction of inspired oxygen (PaOFiO,; 13.1
[0*4]kPa) as an index of rhe efficiency of arterial oxygenadon,
the mean pulmonary artery pressure (36 [I] mm Hg),the
Murray lung injury score (3.0 [0*1], n=51),' and the
APACHE II score (24 [l], n=103) did not differ among
patients of either sex or AB0 and Rhesus-factor blood groups.
Padents inhaled between five parts per million and 40 pans
per million nimc oxide. ?he oxygenation response to inhaled
THE M C E T 0 Vol351 June 1 3 , 1998