Novel genomic loci influencing plasma homocysteine levels

Iftikhar Jan Kullo, Keyue Ding, Eric Boerwinkle, Stephen T Turner, Thomas H. Mosley, Sharon L R Kardia, Mariza De Andrade

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE - Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites. METHODS - Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63±10 years, 70% women) and 964 non-Hispanic whites (61±7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach. RESULTS - Mean (±SD) homocysteine levels were 10.4±5.27 μmol/L in blacks and 10.0±2.84 μmol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h=0.70) and in non-Hispanic whites (h=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds≥3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13). CONCLUSIONS - Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.

Original languageEnglish (US)
Pages (from-to)1703-1709
Number of pages7
JournalStroke
Volume37
Issue number7
DOIs
StatePublished - Jul 2006

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Homocysteine
Chromosomes
Vascular Diseases
Microsatellite Repeats
Fasting
Creatinine
Estrogens
Body Mass Index
Stroke
Genotype
High Pressure Liquid Chromatography

Keywords

  • Genetic linkage
  • Homocysteine
  • Stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Novel genomic loci influencing plasma homocysteine levels. / Kullo, Iftikhar Jan; Ding, Keyue; Boerwinkle, Eric; Turner, Stephen T; Mosley, Thomas H.; Kardia, Sharon L R; De Andrade, Mariza.

In: Stroke, Vol. 37, No. 7, 07.2006, p. 1703-1709.

Research output: Contribution to journalArticle

Kullo, Iftikhar Jan ; Ding, Keyue ; Boerwinkle, Eric ; Turner, Stephen T ; Mosley, Thomas H. ; Kardia, Sharon L R ; De Andrade, Mariza. / Novel genomic loci influencing plasma homocysteine levels. In: Stroke. 2006 ; Vol. 37, No. 7. pp. 1703-1709.
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AU - Kullo, Iftikhar Jan

AU - Ding, Keyue

AU - Boerwinkle, Eric

AU - Turner, Stephen T

AU - Mosley, Thomas H.

AU - Kardia, Sharon L R

AU - De Andrade, Mariza

PY - 2006/7

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N2 - BACKGROUND AND PURPOSE - Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites. METHODS - Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63±10 years, 70% women) and 964 non-Hispanic whites (61±7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach. RESULTS - Mean (±SD) homocysteine levels were 10.4±5.27 μmol/L in blacks and 10.0±2.84 μmol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h=0.70) and in non-Hispanic whites (h=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds≥3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13). CONCLUSIONS - Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.

AB - BACKGROUND AND PURPOSE - Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites. METHODS - Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63±10 years, 70% women) and 964 non-Hispanic whites (61±7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach. RESULTS - Mean (±SD) homocysteine levels were 10.4±5.27 μmol/L in blacks and 10.0±2.84 μmol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h=0.70) and in non-Hispanic whites (h=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds≥3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13). CONCLUSIONS - Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.

KW - Genetic linkage

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